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 .
Election/Restrictions
Applicant’s election without traverse of Claim 56, along with linking claims 1, 2, 7, 15, 17, 20, 27, 32 and 48, in the reply filed on 2/2/2026 is acknowledged.
Claims status
Claims 58-60, 86-89, 110-111, 132, 142, 144-145 and 148 is/are cancelled and claims 149-158 is/are newly added. Claims 1, 2, 7, 15, 17, 20, 27, 32, 48, 56, 149-158 is/are currently pending and is/are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See at least Sequences listed on Pages 3-6 and 44-48.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. See for examples NPLs recited on pages 31, 39, 212, 213.
Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See for examples pages 128 and 186.
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 154 is objected to because of the following informalities: Option (c) and (d) are essentially duplicates with option (c) reciting two tRNAs: tRNA and a second tRNA, and option (d) also reciting two tRNAs: a first tRNA and a second tRNA. Deletion of the duplicate option is recommended. Appropriate correction is required.
Claim 155 is objected to because of the following informalities: The periods after the clause “a nucleic acid encoding a first transfer RNA […] first gRNA” should be replaced with another appropriate punctuation. MPEP 608.01(m) requires that “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except
for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. In other words, a claim should only contain one period. Deletion of the period after the second clause is recommended. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 7, 15, 17, 30, 27 and 157 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 7 recites “two or three nucleic acids encoding the first tRNA”. Claim 7 depends from claim 1 that embraces a recombinant negative-strand RNA virus genome with one or more tRNA (see limitation pertaining to tRNA positioned at one or both of the ends of the gRNA). For claim 7, it is unclear if the “two or three nucleic acids” encode fragments of the same tRNA or if they are directed to an embodiment wherein the recombinant negative-strand RNA virus genome is required to comprise more than one tRNA. For the purpose of compact prosecution, the claim(s) 7 is/are interpreted as (i) “two or three nucleic acids” encode fragments of the same tRNA or (ii) “two or three nucleic acids” encode distinct yet complete copies of the same tRNA such that their expression results in more than one copy of the first tRNA. Example 5 supports both interpretations.
Claims 15, 17, 20, 27 is/are rejected due their dependence on claim 7 because they do not clarify the 112b issue noted with claim 7.
Claim 157 recites the limitation "gene editing system" in line 2. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 157 is/are interpreted as to be dependent from claim 156 that recites a gene editing system.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 158 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 158, depends from claim 153 that depends from claim 152. Both claims 158 and 152 recite the same limitation “wherein the therapeutic transgene encodes a therapeutic polypeptide or therapeutic nucleic acid”. Since a dependent claim embraces each of the limitation of the claim it depends from, claim 158 already embraces the limitation of claims 152 and 153. Thus, claim 158 does not further limit claims 153.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 1, 2, 7, 15, 32, 149-153, 156-158 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ma et al (Nature Plants, June 29, 2020, 6(7): 773-779; IDS 7/7/2023).
Regarding claim 1, Ma discloses a negative-strand RNA virus vector that comprises negative-strand RNA virus vector genome that comprises native viral genes and heterologous nucleic acid sequences (=claimed recombinant negative-strand RNA virus genome; Abstract, Figure 1a). The heterologous nucleic acid sequences encoded by the vector genome are gRNAs (one or more) that comprise 5’ and 3’ ends which are flanked by tRNAs (one or more) (Figure 1a, Extended Fig. 2c, Supplementary Figure 1a, 2a; Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9)).
Regarding claim 2, Ma discloses that the vector comprises sequences that encode at least two tRNA (=claimed first and second tRNA) wherein the sequence that encodes the first tRNA is positioned at the 3’end and the sequence that encodes the second tRNA is positioned at the 5’ end of the gRNA-encoding sequence, the sequences that encode the first and second tRNA are identical and specify the same amino acid (Supplementary Figure 1a; Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9).
Regarding claim 7, based on interpretation (ii) presented in the U.S.C. 112b rejection above, Ma discloses at least two nucleic acid sequences that encode two separate tRNAs one at each end of the gRNA-encoding sequence (Supplementary Figure 1a). Ma also discloses that the vector genome further comprises a second gRNA wherein the two gRNAs target different sequences in the same gene or different genes (Figure 2; Supplementary Table 1).
Regarding claim 15, Ma discloses first and second tRNA as tRNA-Glycine (Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9).
Regarding claim 32, Ma discloses that the vector genome comprises a cassette that expresses the gRNAs, wherein the cassette comprises from 3’ to 5’ a negative-strand RNA virus transcription initiation signal, a nucleic acid encoding the first tRNA, a nucleic acid encoding the first gRNA, a nucleic acid encoding the second tRNA, a nucleic acid encoding the second gRNA, a nucleic acid encoding the third tRNA and a transcription termination polyadenylation signal (=claimed options a-d). See description on page 1, col. 2, para 1 that discuses insertion of Cas9 and gRNA at the N/P gene junction that contains necessary cis-elements to direct viral L polymerase-mediated messenger RNA transcription (=claimed negative-strand RNA virus transcription initiation signal) and produces polyadenylated viral mRNAs transcription (=claimed transcription termination signal). See also description in Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9) regarding two gRNAs flanked by tRNAs on each end resulting in first and second gRNAs, and first, second and third tRNAs as claimed.
Regarding claim 149-151, Ma discloses that their vector genome comprises nucleic acid sequence that encodes a Cas9 enzyme, which is a gene editing protein (as recited in claim 150) of CRISPR gene editing system (as recited in claim 151) and a therapeutic polypeptide encoded by the therapeutic transgene (as recited in claim 149).
Regarding claim 149, 152, 153, 156, 157, 158, Ma discloses that their vector genome comprises nucleic acid sequence that encodes a Cas9 enzyme, which is a secreted gene editing protein (as recited in claim 153, 156) of CRISPR gene editing system (as recited in claim 157) and a therapeutic polypeptide (as recited in claim 152, 158) encoded by the therapeutic transgene (as recited in claim 149).
Therefore, Ma anticipates the claimed invention.
Claim Rejections - 35 USC § 103
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) 7, 17, 20, 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma as applied to claims 1 and 15 above, and further in view of Yang et al (US 2016/0264981 A1, Sep. 15, 2016).
The teachings from Ma as detailed in the U.S.C. 102 rejection of claims 1, 7 and 15 above are pertinent to and relied upon for the instant rejection.
For claim 7, interpretation (i) presented in the U.S.C. 112b rejection above is used.
Regarding claims 7, 17, 20, Ma teaches the negative-strand RNA virus genome of claim 1.
Regarding claim 27, Ma teaches the negative-strand RNA virus genome comprises nucleic acids that encode negative-strand RNA virus genes (Figure 1a, Extended Fig. 2c, Supplementary Figure 1a, 2a; Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9)).
Ma does not teach nucleic acids that encode fragments of the same tRNA, as required by claim 7-interpretation (i), or t-RNA like structures such as tRNA variants, as required by claims 20 and 27.
Yang also teaches expression cassette encoding CRISPR gene editing system comprising gRNAs flanked by tRNAs wherein splicing at tRNA cleavage sites results in release of gRNA from the transcript (Figure 1C). Regarding tRNAs that can be used to flank gRNAs, Yang teaches tRNA variants and tRNA cleavage sequences (i.e. fragments of tRNA; claims 8, 9; [0079, 0094, 0095]) (as required by claims 7, 17, 20, 27).
The combination of prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007): Exemplary rationales that may support a conclusion of obviousness are from MPEP 2143.
In the present situation, rationale B) Simple substitution of one known element for another to obtain predictable results is applicable. MPEP 2143 guides that for rationale B “Office personnel must articulate the following: (1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components; (2) a finding that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness”.
(1) The prior art of Ma teaches the base product which differs from the claimed product by the substitution of the following components: substituting Ma’s tRNAs with claimed tRNA fragments and variants.
(2) The substituted components were known in the art as taught by Yang, teaching fragments and variants of tRNAs to be used to flank gRNAs in CRISPR cassettes.
(3) Since both Ma and Yang are directed to a similar CRISPR based system wherein gRNAs are flanked by tRNAs, an ordinary artisan could substitute Ma’s tRNAs with Yang’s tRNA fragments and variants to achieve a predictable result wherein the gRNA is flanked by tRNA variants/fragments that are cleaved by tRNA splicing endonucleases to release the gRNA.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute tRNAs taught by Ma with fragments and variants of tRNA taught by Yang.
Claim(s) 48, 56, 154 and 155 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma as applied to claims 1 and 32 above, and further in view of Li et al (WO 2021129895 A2; 2021-07-01; IDS 7/7/2023; Machine translation provided in PTO-892; Citations below are in reference to Machine translation) and Chatterjee et al (Nat Neurosci, April 2018, 21(4): 638-646).
The teachings from Ma as detailed in the U.S.C. 102 rejection of claims 1 and 32 above are pertinent to and relied upon for the instant rejection.
Regarding claim 48, Ma teaches the negative-strand RNA virus genome of claim 1.
Regarding claim 56, Ma teaches that negative-strand RNA virus genome transcribe into a positive strand antigenome such that the transcribed sequence comprises a gRNA flanked by two tRNAs at the 5’ and 3’ ends (Supplementary Figure 2).
Regarding claim 154, Ma teaches a negative-strand RNA virus genome that comprises a cassette that expresses the gRNAs, wherein the cassette comprises from 3’ to 5’ a negative-strand RNA virus transcription initiation signal, a nucleic acid encoding the first tRNA, a nucleic acid encoding the first gRNA, a nucleic acid encoding the second tRNA, a nucleic acid encoding the second gRNA, a nucleic acid encoding the third tRNA and a transcription termination polyadenylation signal (=claimed options a-d). See description on page 1, col. 2, para 1 that discuses insertion of Cas9 and gRNA at the N/P gene junction that contains necessary cis-elements to direct viral L polymerase-mediated messenger RNA transcription (=claimed negative-strand RNA virus transcription initiation signal) and produces polyadenylated viral mRNAs transcription (=claimed transcription termination signal). See also description in Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9) regarding two gRNAs flanked by tRNAs on each end resulting in first and second gRNAs, and first, second and third tRNAs as claimed.
Regarding claim 155, Ma teaches a negative-strand RNA virus genome comprising nucleic acid sequences that encode gRNAs (one or more) that comprise 5’ and 3’ ends which are flanked by tRNAs (one or more) and a Cas9-encoding sequence, a therapeutic transgene (Figure 1a, Extended Fig. 2c, Supplementary Figure 1a, 2a; Supplementary Methods: Construction of SYNV vectors for expression of tgtRNA and Cas9 (pSYNV-tgtRNA-Cas9)).
Ma derives the negative-strand RNA virus genome from a type of rhabdovirus called Sonchus yellow net rhabdovirus (SYNV) (page 1, col.1-2 bridging para).
Regarding claims 48, 56, 154 and 155, Ma does not teach a negative-strand RNA virus genome derived from a lyssavirus such as a rabies virus.
Li provides teachings regarding various rhabdoviruses that include rhabdoviruses that infect animals, such as rabies virus which is a lyssavirus (as required by claims 48, 56, 154, 155), and rhabdoviruses that infect plants, such as SYNV, as taught by Ma (page 7, para 1). Li also teaches that the genomic structure of rhabdoviruses is conserved with same core genes that encode the same structural proteins (N, P, M, G and L) and mechanism of transcription also the same such that heterologous sequences could be included in the vector genome (page 7, para 2; page 7-8, bridging para). Li also teach rhabdovirus vectors that comprise Cas9, tRNA flanked, gRNAs (page 12, para 3 and 4).
Chatterjee teaches rabies viral vectors comprising rabies virus genomes that encode heterologous genes and methods to produce such vectors (as required by claims 48, 56, 154, 155; Figure 1; Methods: Rabies viral vector production and titration). Chatterjee also teaches that rabies viral vectors are particularly useful in neuroscience, specifically for monosynaptic tracing (Introduction, para 1).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the SYNV vector genome of Ma with the rabies viral vector genome of Chatterjee to generate a recombinant rabies virus genome comprising the CRISPR system (tRNA flanked gRNAs) of Ma. An ordinary artisan would be motivated to make such a substitution because of Li’s teachings regarding rabies virus’s ability to infect animal cells vs SYNV’s ability to infect plant cells. Teachings from Chatterjee regarding rabies viral vectors utility is neuroscience is also motivating. An ordinary artisan motivated to use Ma’s CRISPR system to target animals cells or neuronal manipulation would perform the said substitution. Based on the teachings in Li regarding the conserved sequences and transcriptional mechanisms across rhabdoviruses, such as rabies and SYNV, an ordinary artisan reasonably expects to substitute the SYNV vector genome of Ma with the rabies viral vector genome of Chatterjee such that the CRISPR system is included before or after viral genes with the cis-elements for transcription initiation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
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