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 claims 1-3, 29, and 31 (Group I) in the reply filed on 08/25/2025 is acknowledged.
Claims 30, 32-38, 40, and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/25/2025.
Accordingly, claims 1-3, 29, and 31 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The effective filing date of the instant application is 04/30/2019.
Information Disclosure Statement
Receipt of information disclosure statements on 10/29/2021, 11/25/2021, and 09/08/2023 is acknowledged. The signed and initialed PTO-1449‘s have been mailed with this action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. The instant specification discloses that Figures 1A-1C depict the predicted secondary structure of a single guide RNA from Butyrivibrio sp. AC2005 (OMNI-39) (paragraph [0014]). While the image quality is poor (as set forth in objections to the Drawings), it appears that the structures depict nucleic acid residue sequences forming said structures. These sequences must be accompanied by sequence identifiers in either the drawings themselves or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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.
Drawings
The drawings are objected to because:
Figures 1A-1C are of insufficient quality to be clearly legible and interpretable. It would be remedial to increase the quality of the images such that they are clearly legible and interpretable.
Figure 5A depicts SEQ ID NOs: 134 and 135 with 6 residues underlined in each depicted sequence. Neither the drawings themselves nor the instant specification clarify the significance of the underlined residues. To facilitate clear interpretation of the instantly claimed invention by those of ordinary skill in the art, it would be remedial to clarify the significance of these underlined residues, either in the drawings themselves or in the Brief Description of the Drawings of the instant specification.
Figure 5B depicts SEQ ID NOs: 136-139 with 5 residues underlined in each depicted sequence. As set forth above, neither the drawings themselves nor the instant specification clarify the significance of the underlined residues. To facilitate clear interpretation of the instantly claimed invention by those of ordinary skill in the art, it would be remedial to clarify the significance of these underlined residues, either in the drawings themselves or in the Brief Description of the Drawings of the instant specification. Additionally, while Figure 5B depicts 4 sequences and lists 4 sequence identifiers, these sequence identifiers are not clearly associated with the sequences of Figure 5B. To facilitate clear interpretation of the instantly claimed invention by those of ordinary skill in the art, it would be remedial to clearly depict which sequences are associated with which sequence identifiers, as in Figure 5A.
Figure 5C depicts SEQ ID NOs: 145-148 with 4 residues underlined in each depicted sequence. As set forth above, neither the drawings themselves nor the instant specification clarify the significance of the underlined residues. To facilitate clear interpretation of the instantly claimed invention by those of ordinary skill in the art, it would be remedial to clarify the significance of these underlined residues, either in the drawings themselves or in the Brief Description of the Drawings of the instant specification. Additionally, while Figure 5C depicts 4 sequences and lists 4 sequence identifiers, these sequence identifiers are not clearly associated with the sequences of Figure 5C. To facilitate clear interpretation of the instantly claimed invention by those of ordinary skill in the art, it would be remedial to clearly depict which sequences are associated with which sequence identifiers, as in Figure 5A.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The specification includes several tables that are not numbered consistently and consecutively or are unnumbered. The specification discloses Tables A and B, followed by an unnumbered table at paragraph [00168], and finally followed by Tables 1-5. In addition, Tables 2 and 3 are split into several continuations, the formatting of which is inconsistent and cumbersome to interpret. It would be remedial to amend the instant specification to set forth the disclosed tables with consistent and consecutive numbering, as well as to consolidate or separate Tables 2 and 3 such that the formatting is consistent and clearly interpretable.
Appropriate correction is required.
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 1, 2, 29, and 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomena without significantly more. The claims recite a CRISPR nuclease comprising a sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 4, and 149-166, or a nucleic acid molecule comprising a sequence encoding said CRISPR nuclease. The claims further recite RNA molecules that can include a DNA-targeting RNA molecule and a transactivating RNA (tracrRNA). The broadest reasonable interpretation of the claimed product is that it reads on a CRISPR nuclease found in nature as well as a nucleic acid or fragment thereof found in nature, as at least SEQ ID NOs 1, 4, and 149 are identical to naturally-occurring CRISPR endonucleases. Accordingly, the claims recite natural phenomena.
The judicial exception is not integrated into a practical application.
With regard to claim 1, which recites “a non-naturally occurring composition comprising a CRISPR nuclease comprising a sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 4, and 149-166 or a nucleic acid molecule comprising a sequence encoding the CRISPR nuclease,” although the claim preamble recites that the instantly claimed composition does not occur naturally, at least SEQ ID NOs 1, 4, and 149 are identical to CRISPR endonucleases found in nature, as reflected in paragraph [00177] of the instant specification, which discloses that the nucleases disclosed therein “may be isolated or derived from a natural source,” such as any living organism. SEQ ID NO: 1 is 100% identical to WP_026658149.1 (type II CRISPR RNA-guided endonuclease Cas9 [Butyrivibrio sp. AC2005]; see alignment in Appendix I), disclosed in Haft et al., 2005 (as cited in the IDS filed 10/29/2021). SEQ ID NO: 4 is 100% identical to WP_243032270.1 (type II CRISPR RNA-guided endonuclease Cas9 [Clostridium sp. AF02-29]; see alignment in Appendix II), disclosed in Haft et al., 2005 (as cited in the IDS filed 10/29/2021). SEQ ID NO: 149 is 100% identical to WP_111888005.1 (type II CRISPR RNA-guided endonuclease Cas9 [Acetobacterium sp. KB-1]; see alignment in Appendix III), disclosed in Haft et al., 2005 (as cited in the IDS filed 10/29/2021). Given that at least these claimed sequences set forth above are identical to CRISPR endonucleases found in nature, the limitation that the CRISPR nuclease and nucleic acid components are not naturally occurring does not impart patentability to the claims. Accordingly, claim 1 only recites naturally-occurring CRISPR endonucleases and is thus directed to the judicial exception without significantly more.
With regard to claims 2, 29, and 31, which further disclose, respectively, that the claimed composition comprising a CRISPR nuclease further comprises a “DNA-targeting RNA molecule or a DNA polynucleotide encoding a DNA-targeting RNA molecule, wherein the DNA-targeting RNA molecule comprises a nucleotide sequence that is complementary to a sequence in a target region,” said DNA-targeting RNA molecule further “compris[ing] a nucleotide sequence that can form a complex with the CRISPR nuclease,” as well as that the claimed composition comprising a CRISPR nuclease further comprises “a tracrRNA molecule comprising a nucleotide sequence that can form a complex with a CRISPR nuclease or a DNA polynucleotide comprising a sequence encoding a tracrRNA molecule that can form a complex with the CRISPR nuclease,” it is well-known that bacteria produce both the instantly claimed CRISPR nuclease (as set forth above) and its associated machinery in nature (reviewed in Haft et al., 2005 (as cited in the IDS filed 10/29/2021) and Jiang and Doudna, 2017).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Viewed as a whole, the additional claim elements do not provide meaningful limitation(s) to transform the judicial exception such that the claims amount to significantly more than the judicial exception itself.
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.
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, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Haft et al., 2005 (as cited in the IDS filed 10/29/2021) in view of WO 2018/083128 A2 (hereinafter Van Der Oost) and WO 2018/154462 A2 (hereinafter Lundberg), as evidenced by WO 2018/035387 A1 (hereinafter Zhang), Jiang and Doudna, 2017, and Auburger et al., 2017.
With regard to claim 1, which recites “a non-naturally occurring composition comprising a CRISPR nuclease comprising a sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 4, and 149-166 or a nucleic acid molecule comprising a sequence encoding the CRISPR nuclease,” as set forth above in Claim Rejections - 35 USC § 101, Haft et al., 2005 discloses type II CRISPR RNA-guided endonuclease Cas9 species derived from Butyrivibrio sp. AC2005, as indicated in GenPept entriy WP_026658149.1, which corresponds to instantly claimed SEQ ID NO: 1 with 100% identity (see alignments in Appendix I). While Haft et al., 2005 does not disclose a composition comprising said CRISPR nuclease, this deficiency is cured by Van Der Oost.
Van Der Oost discloses methods for microbial genome editing, said methods utilizing nucleases such as Cas9 derived from Butyrivibrio sp. being introduced into the cells to be edited (page 4, lines 12-15; page 15, lines 17-24; page 19). As set forth above, instant SEQ ID NO: 1 is 100% identical to Cas9 derived from Butyrivibrio sp. AC2005 (Haft et al., 2005; WP_026658149.1). While Van Der Oost does not explicitly disclose that the Cas9 derived from Butyrivibrio sp. is introduced as a composition, Cas9 is routinely delivered to cells as a composition, as taught in Zhang, which discloses systems, methods, and compositions (including non-naturally occurring compositions) related to CRISPR and components thereof capable of delivering CRISPR nucleases and components thereof for genome editing (paragraphs [0003] and [0667]). Thus, Haft et al., 2005, Van Der Oost, and Zhang collectively disclose a non-naturally occurring composition comprising a CRISPR nuclease comprising a sequence having at least 95% identity to SEQ ID NO: 1, as instantly claimed and set forth in greater detail below.
With regard to claim 2, which recites “the composition of claim 1 further compris[es] a DNA-targeting RNA molecule or a DNA polynucleotide encoding a DNA-targeting RNA molecule, wherein the DNA-targeting RNA molecule comprises a nucleotide sequence that is complementary to a sequence in a target region, wherein the DNA-targeting RNA molecule and the CRISPR nuclease do not naturally occur together,” Van Der Oost further discloses that the microbial genome editing methods taught therein comprise introduction of both Cas9 (i.e. Cas9 derived from Butyrivibrio sp.) and at least one guide RNA (comprising a crRNA and a tracrRNA) (page 4, lines 12-15; page 8, lines 4-15; page 15, lines 17-24; page 19). As taught in Jiang and Doudna, 2017, Cas9 guide RNAs comprise both crRNA and tracrRNA sequences, which respectively confer target specificity and facilitate Cas9 recruitment (page 512, paragraph 3). These naturally-occurring Cas9 guide RNAs can be synthetically produced as single-guide RNAs (sgRNAs) that can be user-programmed to target virtually any DNA sequence of interest in a genome (abstract; page 509, paragraph 2). For example, Lundberg discloses sgRNAs (comprising crRNAs) that comprise spacer sequences complementary to the ATXN2 gene (paragraphs [00027] and [00068]), which is found exclusively in eukaryotes (reviewed in Auburger et al., 2017). Given that the prokaryotic CRISPR-Cas9 system evolved to recognize and respond to bacteriophage infection via acquired immunity (reviewed in Jiang and Doudna, 2017), one of ordinary skill in the art would not reasonably expect the instantly claimed Cas9 derived from Butyrivibrio sp. to naturally occur with a crRNA sequence complementary to an exclusively eukaryotic gene. Thus, Van Der Oost, Lundberg, and Jiang and Doudna, 2017 collectively disclose the instantly claimed DNA-targeting RNA molecule.
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With regard to claim 3, which recites “the composition of claim 2, wherein the CRISPR nuclease comprises…e) a sequence having at least 95% identity to SEQ ID NO: 1 and wherein the DNA-targeting RNA molecule comprises a crRNA repeat which comprises the sequence of SEQ ID NO: 226,” as set forth above regarding instant claim 1, Haft et al., 2005 discloses type II CRISPR RNA-guided endonuclease Cas9 species derived from Butyrivibrio sp. AC2005, as indicated in GenPept entry WP_026658149.1, which corresponds to instantly claimed SEQ ID NO: 1 with 100% identity (see alignment in Appendix I). Additionally, as set forth above, Lundberg discloses sgRNAs (comprising crRNAs) that comprise spacer sequences complementary to the ATXN2 gene (paragraphs [00027] and [00068]). Lundberg discloses at claim 60 that the spacer sequences disclosed therein correspond to any one of SEQ ID NOs: 5305-108,217. As shown in the alignment below, SEQ ID NO: 34,129 of Lundberg (bottom sequence) comprises instant SEQ ID NO: 226 (top sequence) with 100% identity, as instantly claimed.
Thus, Haft et al., 2005 and Lundberg disclose a composition comprising a CRISPR nuclease with at least 95% identity to SEQ ID NO: 1 and a DNA-targeting RNA molecule comprising a crRNA repeat comprising SEQ ID NO: 226, as instantly claimed.
With regard to claim 29, which recites “the DNA-targeting RNA molecule of claim 2 comprises a nucleotide sequence that can form a complex with the CRISPR nuclease,” as set forth above, Van Der Oost further discloses that the microbial genome editing methods taught therein comprise introduction of both Cas9 (i.e. Cas9 derived from Butyrivibrio sp.) and at least one guide RNA (comprising a crRNA and a tracrRNA) (page 4, lines 12-15; page 8, lines 4-15; page 15, lines 17-24; page 19). As taught in Jiang and Doudna, 2017, Cas9 guide RNAs comprise both crRNA and tracrRNA sequences, which respectively confer target specificity and facilitate Cas9 recruitment (page 512, paragraph 3). The tracrRNA facilitates Cas9 recruitment by complexing with the Cas9 (Figure 2), as instantly claimed. Thus, Van Der Oost and Jiang and Doudna, 2017 collectively disclose a DNA-targeting RNA molecule comprising a nucleotide sequence that can form a complex with the CRISPR nuclease, as instantly claimed.
With regard to claim 31, which recites “the composition of claim 1 further compris[es] a tracrRNA molecule comprising a nucleotide sequence that can form a complex with a CRISPR nuclease,” as set forth above, Van Der Oost further discloses that the microbial genome editing methods taught therein comprise introduction of both Cas9 (i.e. Cas9 derived from Butyrivibrio sp.) and at least one guide RNA (comprising a crRNA and a tracrRNA) (page 4, lines 12-15; page 8, lines 4-15; page 15, lines 17-24; page 19). As taught in Jiang and Doudna, 2017, Cas9 guide RNAs comprise both crRNA and tracrRNA sequences, which respectively confer target specificity and facilitate Cas9 recruitment (page 512, paragraph 3). The tracrRNA facilitates Cas9 recruitment by complexing with the Cas9 (Figure 2), as instantly claimed. Thus, Van Der Oost and Jiang and Doudna, 2017 collectively disclose a tracrRNA comprising a nucleotide sequence that can form a complex with the CRISPR nuclease, as instantly claimed.
Given that Haft et al., 2005 discloses naturally-occurring RNA-guided endonuclease Cas9 species derived from Butyrivibrio sp. AC2005 that are 100% identical to instant SEQ ID NO: 1, that Van Der Oost discloses methods for microbial genome editing using Cas9 derived from Butyrivibrio sp. (which encompasses Butyrivibrio sp. AC2005) and guide RNAs comprising a crRNA and a tracrRNA, and that Lundberg discloses sgRNAs that comprise spacer (or crRNA) sequences such as SEQ ID NO: 34,129 (which comprises instant SEQ ID NO: 226), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the Cas9 species disclosed in Haft et al., 2005 and the sgRNAs disclosed in Lundberg in the genome editing methods disclosed in Van Der Oost to predictably target the gene specified by the user-defined crRNA (i.e. ATXN2 as in Lundberg) with Cas9, as facilitated by tracrRNA. One would have been motivated to make such a modification in order to receive the expected benefit of targeting the gene specified by the user-defined crRNA (i.e. ATXN2 as in Lundberg) with Cas9 for editing of the targeted gene.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./ Primary Examiner, Art Unit 1637
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Appendix I-Instant SEQ ID NO: 1 vs WP026658149.1 (Haft et al., 2005)
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Appendix II-Instant SEQ ID NO: 4 vs WP243032270.1 (Haft et al., 2005)
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Appendix III-Instant SEQ ID NO: 149 vs WP111888005.1 (Haft et al., 2005)
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