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 03/27/2026. Claims 1-6, 155-158, 161-164 are currently pending. Claims 155-157 and 163-164 are withdrawn from prosecution as being drawn to non-elected subject matter, there being no allowable generic or linking claim. Accordingly, claims 1-6, 158 and 161-162 are examined herein. The restriction requirement mailed 01/28/2026 is still deemed proper. Applicants elected a CRISPR nuclease amino acid sequence of SEQ ID NO: 18 and a CRISPR guide sequence for use with the nuclease comprising SEQ ID NO: 376, without traverse in the reply filed 03/27/2026.
Drawings
The drawings are objected to because Fig. 2A is mislabeled. The figure on sheet 4/52, which follows Fig. 1D, reads ‘Fig. 3A’ but, based on its placement before Fig. 2B, appears to actually be Fig. 2A, and the current label is a typographical error. 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.
For the purposes of examination and clarity, the figure on sheet 4/52 of the drawings will hereinafter be referred to as ‘Fig. 2A’.
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. Please see FIGs. 1A-D, 2A-C, and 46A-B, which show sgRNA scaffolds with their nucleobase sequences written in the circles.
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.
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 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
A note on claim interpretation:
Claim 1 recites, in its preamble, “a non-naturally occurring composition”, which is subject matter that falls within the product of nature exception. As MPEP 2106 states, " ...neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible."). Thus, a synthetic, artificial, or non-naturally occurring product such as a cloned organism or a human-made hybrid plant is not automatically eligible because it was created by human ingenuity or intervention. See, e.g., In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337, 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014) (cloned sheep); cf. J.E.M. Ag Supply, Inc. V. Pioneer Hi-Bred Int'l, Inc., 534 U.S. 130-132, 60 USPQ2d 1868-69 (2001) (hybrid plant). Instead, the key to the eligibility of all non-naturally occurring products is whether they possess markedly different characteristics from any naturally occurring counterpart." (emphasis added). Accordingly, the broadest reasonable interpretation of "non-naturally occurring" encompass synthetically made products. Without more, merely reciting "non-naturally occurring" in the preamble of claim to a product that is otherwise structurally and functionally identical to what occurs in nature will not be interpreted as a markedly different characteristic.
Subject Matter Eligibility Analysis
Claim 1:
Regarding step 1, the claim recites a composition of matter.
Regarding step 2A prong one, the claim recite a CRISPR nuclease comprising a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 2. The specification notes that the nucleases were predicted from metagenomic databases of environmental samples, i.e., naturally-occurring genome sequences:
[00397] CRISPR repeat (crRNA), trans-activating RNA (tracrRNA), nuclease polypeptide (OMNI), and protospacer adjacent motif (PAM) sequences were predicted from different metagenomic databases of sequences of environmental samples.
GenBank Accession No. MBQ6525639.1, a type II CRISPR RNA-guided endonuclease from a Metagenome Assembled Genome (MAG), has 94.6% to the full length of instantly claimed SEQ ID NO: 2 (please see the alignment in the attached OA appendix).
Claim 2 and its dependents are not rejected because claim 2 requires that the RNA molecules and CRISPR nuclease do not naturally occur together, and a search of the art did not reveal the specific RNA sequences recited in claims 3-6 associated with the nuclease.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 158, 161 and 162 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.
Claims 158 and 162 are indefinite because they reference Table 1. MPEP 2173.05(s) states "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).". In the instant case, the CRISPR nucleases and their associated PAMs may be recited in the claims similarly to how the nucleases and guide RNAs are recited in claims 3-6.
Claim 161 is indefinite because it recites, “a method of modifying a nucleotide sequence at a DNA target site” “comprising introducing into…the genome of the cell the composition of claim 2”. When reading the claim in the light of the specification, it is clear that the method comprises introducing plasmids expressing the nuclease (see e.g. para [00398]) and the sgRNA (para [00400]), or introducing the composition as RNPs (para [00403]). The specification does not disclose integration of the nuclease and sgRNA sequences into the genome. As a result, it is unclear what is meant by “introducing” the composition “into the genome of the cell”. In the interests of customer service and compact prosecution, the claim will be interpreted as encompassing introducing the composition into a cell-free system or into a cell, not the genome of the cell.
Claim Rejections - 35 USC § 112(b) – Improper Markush grouping
Claims 1-6, 158 and 161-162 are rejected on the basis that they contain improper Markush groupings of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of CRISPR nucleases with their corresponding sgRNAs and PAM sites is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each Cas nuclease has a different primary amino acid sequence and functions to recognize a different sgRNA scaffold and PAM sequence from the elected species, as evidenced by Tables 1, 2 and 3 (respectively) of the specification. Thus, the members of the grouping do not share a substantial structural feature that supports a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 158 and 161-162 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by U.S. Patent Publication 20230212562 A1 to Emmanuel et al. (effective filing date 05/28/2020, hereinafter ‘Emmanuel’).
Claim interpretation: Claim 1 is drawn to a “non-naturally occurring composition” comprising the recited nuclease. The specification defines “non-naturally occurring” as follows:
[00330] The terms "non-naturally occurring" or "engineered" are used interchangeably and indicate human manipulation.
The broadest reasonable interpretation of the claim encompasses any composition which comprises the recited nuclease (or a nucleic acid molecule encoding said nuclease), wherein that composition has been in some way manipulated by humans. It is important to note that the claims are drawn to a composition comprising a nuclease, not a nuclease itself. This leads to an interpretation in which the nuclease itself may be naturally occurring as long as it is in a human-manipulated composition, such as a buffer solution or the cytoplasm of a cell which has been engineered to express it. Additionally, a nuclease which has been synthesized in vitro, as opposed to naturally produced by a wild-type cell in the environment with no human intervention, would still be interpreted as non-naturally occurring, since it has been manipulated by humans (e.g., cloned into a vector and expressed in a cell or a cell-free expression system). It is also relevant to note that the specification provides the following example of how to apply the term when referring to nucleic acid molecules or polypeptides:
[00330] The terms, when referring to nucleic acid molecules or polypeptides may mean that the nucleic acid molecule or the polypeptide is at least substantially free from at least one other component with which they are naturally associated in nature and as found in nature.
Based on that example, the phrase, “substantially free from at least one other component with which they are naturally associated in nature and as found in nature” is interpreted as encompassing, for example, wild-type proteins which have been isolated from the cellular environment.
Regarding claim 1, Emmanuel teaches an OMNI-110 CRISPR nuclease, SEQ ID NO: 20277, which has 100% identity to instant SEQ ID NO: 18 (also disclosed as OMNI-110 in Table 1):
RESULT 1
BKI50085
(NOTE: this sequence has 2 duplicates in the database searched)
ID BKI50085 standard; protein; 1503 AA.
XX
AC BKI50085;
XX
DT 13-JAN-2022 (first entry)
XX
DE OMNI-110 CRISPR Nuclease, SEQ ID 20277.
XX
KW ATXPC syndrome; CRISPR nuclease; CRISPR nuclease system; Genome editing;
KW ataxia-pancytopenia syndrome; gene silencing; genetic disorder;
KW genetic-disease-gen.; therapeutic.
XX
OS Synthetic.
XX
CC PN WO2021243174-A2.
XX
CC PD 02-DEC-2021.
XX
CC PF 28-MAY-2021; 2021WO-US034794.
XX
PR 28-MAY-2020; 2020US-0031157P.
XX
CC PA (EMEN-) EMENDOBIO INC.
CC PA (EMMA/) EMMANUEL R.
CC PA (DICK/) DICKEN J.
CC PA (MASH/) GOLAN MASHIACH M.
XX
CC PI Emmanuel R, Dicken J, Golan Mashiach M;
XX
DR WPI; 2021-D92678/101.
XX
CC PT Modifying mutant allele of sterile alpha-motif domain containing 9 like
CC PT gene having mutation associated with ataxia-pancytopenia syndrome in
CC PT cell, by introducing composition containing clustered regularly
CC PT interspaced short palindromic repeats nuclease and first RNA molecule
CC PT comprising guide sequence.
XX
CC PS Example 2; SEQ ID NO 20277; 78pp; English.
XX
CC The present invention relates to a method for modifying in a cell a
CC mutant allele of the sterile alpha motif domain containing 9 like
CC (SAMD9L) gene having a mutation associated with ataxia-pancytopenia
CC (ATXPC) syndrome. The method involves introducing a composition
CC comprising at least one clustered regularly interspaced short palindromic
CC repeats (CRISPR) nuclease or a sequence encoding a CRISPR nuclease, and a
CC first RNA molecule comprising a guide sequence portion having 17-50
CC nucleotides or a nucleotide sequence encoding the same to the cell, where
CC a complex of the CRISPR nuclease and the first RNA molecule affects a
CC double strand break in the mutant allele of the SAMD9L gene. Also
CC described: (1) a first RNA molecule comprising a guide sequence portion
CC having 17-50 contiguous nucleotides in any one base pair sequence of SEQ
CC ID NO:1-20246 (BKI29809-BKI50054); (2) a composition comprising the first
CC RNA molecule and at least one CRISPR nuclease; and (3) method for
CC inactivating a mutant SAMD9L allele in a cell involving delivering the
CC above-mentioned composition to the cell. The composition is used for
CC treating ATXPC syndrome and inactivating a mutant SAMD9L allele in a cell
CC in subject having or at risk of having ATXPC syndrome, and treating
CC dominant genetic disorders in a patient.
XX
SQ Sequence 1503 AA;
Query Match 100.0%; Score 7855; Length 1503;
Best Local Similarity 100.0%;
Matches 1503; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSKTILGLDLGSNSIGWAVVKAEVSESGEERLTGIEAAGSRILPMDAKLLSKFEKGNSVS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSKTILGLDLGSNSIGWAVVKAEVSESGEERLTGIEAAGSRILPMDAKLLSKFEKGNSVS 60
Qy 61 QTETRRKARSARRRSERKKLRRARLLRTLRIIGWLPAHMASAIDDYGNIKRGSEPKMEWD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QTETRRKARSARRRSERKKLRRARLLRTLRIIGWLPAHMASAIDDYGNIKRGSEPKMEWD 120
Qy 121 GGNFMFTRAFEEMCAEFSARHPELKSVSHDWTVYYLRKKALREALTGQELAWVLLHFNQK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGNFMFTRAFEEMCAEFSARHPELKSVSHDWTVYYLRKKALREALTGQELAWVLLHFNQK 180
Qy 181 RGYMPSRTDANIPAAKEGEKKEIVDVRVVGCKAAEAAKGRKATKAVTLIFDDGGEMNMPY 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 RGYMPSRTDANIPAAKEGEKKEIVDVRVVGCKAAEAAKGRKATKAVTLIFDDGGEMNMPY 240
Qy 241 YGTTPEEMVGRQMELLKTTKEGKTPTYTNPGENDWTFKKEKSKERITSAHKTVGEYLYDS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 YGTTPEEMVGRQMELLKTTKEGKTPTYTNPGENDWTFKKEKSKERITSAHKTVGEYLYDS 300
Qy 301 LLEEPDVKLAGGKVTVLDRELYKSELEAILTKQAEFHDELKSPTLLAKCAEALYPNNPGH 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LLEEPDVKLAGGKVTVLDRELYKSELEAILTKQAEFHDELKSPTLLAKCAEALYPNNPGH 360
Qy 361 RAELMRHTMANLIMNDIILYQRPLKSKKSTIADCPFEYRTYMDKTGVEQVQKLKCAPRSH 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 RAELMRHTMANLIMNDIILYQRPLKSKKSTIADCPFEYRTYMDKTGVEQVQKLKCAPRSH 420
Qy 421 PLFQEFRLWQFVTNLRVTDEQTGNSEDILTDADRMKLFDALTPKSKVKAADVLKIVQKII 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 PLFQEFRLWQFVTNLRVTDEQTGNSEDILTDADRMKLFDALTPKSKVKAADVLKIVQKII 480
Qy 481 KPEESKKEKGAAPECHYRVNMVEGKDYPCYDMRAEIAACLTNKKSGPGLKAGDAYELITQ 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 KPEESKKEKGAAPECHYRVNMVEGKDYPCYDMRAEIAACLTNKKSGPGLKAGDAYELITQ 540
Qy 541 TREEGDMTNEEYLWHISYSVTDPKEFEKAIKKWAETNGLPAEETARAFCALKPNKNYASY 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 TREEGDMTNEEYLWHISYSVTDPKEFEKAIKKWAETNGLPAEETARAFCALKPNKNYASY 600
Qy 601 SLKAIKRLLPLMRMGRHWSFEAIDAKTRAKIEHFINGEEAEDMTPETMHKWAADKEDGGY 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 SLKAIKRLLPLMRMGRHWSFEAIDAKTRAKIEHFINGEEAEDMTPETMHKWAADKEDGGY 660
Qy 661 DLKQAEESFQGLQPWKACMVVYGKLSGDEGLKWQTADDVREWLDKFPHGSLRNPIVEQVV 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 DLKQAEESFQGLQPWKACMVVYGKLSGDEGLKWQTADDVREWLDKFPHGSLRNPIVEQVV 720
Qy 721 LETMRVVADVWDKHGRPDEIHIEMARELKKTNAERAEMTRQNAQREEDNERIRKILRELA 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 LETMRVVADVWDKHGRPDEIHIEMARELKKTNAERAEMTRQNAQREEDNERIRKILRELA 780
Qy 781 STCEDVKPFSPIQQARLKICVEGARLVAPAEEPKIEEIEKYKLWIKQNYKSPYTGESIEL 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 STCEDVKPFSPIQQARLKICVEGARLVAPAEEPKIEEIEKYKLWIKQNYKSPYTGESIEL 840
Qy 841 ARLFTSDYEIEHIIPRSRYYDDSFNNKVICEAKVNQDKDNKMAMEYINAAQGKEVDLGGG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 ARLFTSDYEIEHIIPRSRYYDDSFNNKVICEAKVNQDKDNKMAMEYINAAQGKEVDLGGG 900
Qy 901 RKVNILTPDEYVKRINDIYKNNSRKRENLLRTELPQDFNNRQMNDSRYIAVKVKELLNNA 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 RKVNILTPDEYVKRINDIYKNNSRKRENLLRTELPQDFNNRQMNDSRYIAVKVKELLNNA 960
Qy 961 VRAEVGDDGAGSKNVVVCTGTVTDRLKQDWGVNDKWNEIILPRFMAMNEKVADKSDRNNR 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 VRAEVGDDGAGSKNVVVCTGTVTDRLKQDWGVNDKWNEIILPRFMAMNEKVADKSDRNNR 1020
Qy 1021 FIAKSNGHLIPTVPTDMLKGFNKKRIDHRHHAMDAIVIACASRAMVQFFSNQSSNKGGNM 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 FIAKSNGHLIPTVPTDMLKGFNKKRIDHRHHAMDAIVIACASRAMVQFFSNQSSNKGGNM 1080
Qy 1081 FENLRKSLCHKDANNVWVVNMPWETFPTDVKNALESITVSIKHRQRIVTRTTNHYTVTKG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 FENLRKSLCHKDANNVWVVNMPWETFPTDVKNALESITVSIKHRQRIVTRTTNHYTVTKG 1140
Qy 1141 GRREVRKQATYAIRNSLHQETVWGLVNLQQKEQMSLKDAIKELRTFLSARIDDPQMRPKS 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GRREVRKQATYAIRNSLHQETVWGLVNLQQKEQMSLKDAIKELRTFLSARIDDPQMRPKS 1200
Qy 1201 QIVCKPLRRRISQLITAGKTDKEILALLDAESDVWSEEIKSGKVSVYTWSKDGGTRICAT 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 QIVCKPLRRRISQLITAGKTDKEILALLDAESDVWSEEIKSGKVSVYTWSKDGGTRICAT 1260
Qy 1261 RFLSSLSDLFSKLTDEEKIKNKIASITDTGIQKILFNHLAQWQGGAATAFSPDGIKWMNE 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 RFLSSLSDLFSKLTDEEKIKNKIASITDTGIQKILFNHLAQWQGGAATAFSPDGIKWMNE 1320
Qy 1321 NIQTLNGGKPHKPIYKVRRTETSDAKQQIGTNGNRSSKYVEAAKGTNLFFAVYVDDKGKR 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 NIQTLNGGKPHKPIYKVRRTETSDAKQQIGTNGNRSSKYVEAAKGTNLFFAVYVDDKGKR 1380
Qy 1381 TFSTTPLRTVISRQLQGQSPVPETIGDNERLCFYLSPNDLVYVPTHGERYIEDRNRIYKF 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 TFSTTPLRTVISRQLQGQSPVPETIGDNERLCFYLSPNDLVYVPTHGERYIEDRNRIYKF 1440
Qy 1441 VSCFENRAWFIPAYVAKVIVDKSEFGSQNKIEVIDGVSIKNVCLPVEVDRLGNVTLKKIG 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 VSCFENRAWFIPAYVAKVIVDKSEFGSQNKIEVIDGVSIKNVCLPVEVDRLGNVTLKKIG 1500
Qy 1501 EDD 1503
|||
Db 1501 EDD 1503
Emmanuel indicates that all of the nucleases tested, including OMNI-110, were cloned into expression vectors, i.e., non-naturally occurring under the interpretation described above:
[0216] Next, novel OMNI CRISPR nucleases with unique PAM requirements were tested for editing of SNPs. These nucleases were tested in HeLa cells as described above. To this end, per each OMNI CRISPR nuclease, the corresponding OMNI-P2A-mCherry expression vector (pmOMNI, Table 4) was transfected into HeLa cells together with a sgRNA designed to target a specific location in the human genome
Since the sgRNA is designed to target a specific location in the human genome, as opposed to, e.g., a bacteriophage which might naturally infect a bacterium and be targeted by a CRISPR/Cas system, it is interpreted as an sgRNA which does not naturally occur together with the nuclease.
Regarding claims 3-6, Emmanuel teaches the composition further comprising a sgRNA (i.e., a scaffold including tracrRNA and crRNA) molecule comprising SEQ ID NO: 367 (5’-guugugauucgcuucc-3’)
PNG
media_image1.png
315
387
media_image1.png
Greyscale
Regarding claim 158, Emmanual teaches that the OMNI-110 nuclease recognizes a PAM site with a sequence of GUAGGC:
PNG
media_image2.png
498
391
media_image2.png
Greyscale
While it is noted that the OMNI-110 Pam site as disclosed in the instant specification (Table 3, p. 113) comprises the sequence “NNVNNCNN”, with V = A, C or G (see the reference table on p. 57), and the prior art OMNI-110 PAM corresponds to the first six nucleotides thereof, the last two “NN” nucleotides (meaning any nucleotide) are an inherent structural characteristic of the target region in a genome as taught by Emmanuel, which has nucleotides downstream of the PAM site.
Regarding claim 161, Emmanuel teaches introducing the composition into a cell to modify a nucleotide sequence at a target site (see above).
Regarding claim 162, the instant specification evidences that the nucleases of the instant disclosure, including SEQ ID NO: 18, effect double strand breaks by noting that they all comprise Domains A+G+I, which cleaves a DNA strand that is displaced by a guide RNA molecule (para [00300]), and Domain H, which cleaves a DNA strand which a guide RNA molecule binds (para [00303]) (see also Supplemental Table 1). Insofar as SEQ ID NO: 18 and SEQ ID NO: 20277 share identical structures, they must inherently share the same function of effecting double strand breaks.
Conclusion
No claim is allowed at this time.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
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