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 .
Claims Status
Claims 10-12, 20-21, 23-25, 27 is/are cancelled. Claims 1-9, 13-19, 22, 26 is/are currently pending and is/are under examination.
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 - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
The disclosure contains “SEQ ID NOs” (see, for example, paragraph [0033]), but no sequence listing has been provided with the disclosure. With providing a sequence listing, an incorporation by reference paragraph will be required.
Information Disclosure Statement
The information disclosure statement filed 05/23/2024 contained a citation which was missing part of the title of the corresponding NPL document. The IDS has been annotated to correct the title of this reference.
Claim Objections
Claims 7 and 15 are objected to because of the following informalities:
“NLS” in claim 7 should be preceded by “the” (line 1).
Claim 15 ends with a semicolon instead of a period.
Appropriate correction is required.
The amendment to the claims filed on 02/20/2024 does not comply with the requirements of 37 CFR 1.121(c) because applicant does not provide a listing of claims 11-12 with appropriate status identifiers. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.”
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number.
Claim Rejections - 35 USC § 112
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 1-9, 13-19, 22, 26 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.
The following limitations indicate a polypeptide linked to a polynucleotide (emphasis added):
Claim 1: “a nucleotide encoding an amino-terminal linker connected to the amino-terminal end of the CasPhi” (lines 4-5); “a nucleotide encoding a carboxy-terminal linker connected to the carboxy-terminal end of the CasPhi” (lines 6-7); “a nucleotide encoding a nuclear localization signal (NLS) downstream from the CasPhi and carboxy-terminal linker” (lines 8-9);
Claim 4: “The nucleic acid of claim 1, and further comprising a repressor domain or an activator domain”;
Claim 5: “The nucleic acid of claim 1, and further comprising a repressor domain downstream from the CasPhi and carboxy-terminal linker”;
Claim 6: “wherein the repressor domain is between the carboxy-terminal linker and the NLS”;
Claim 7: “wherein NLS is between the carboxy-terminal linker and the repressor domain”;
Claim 13: “The nucleic acid of claim 5, and further comprising a second repressor domain”;
Claim 14: “wherein the second repressor domain is connected to the amino-terminal end of the amino-terminal linker”;
Claim 15: “The nucleic acid of claim 1, and further comprising a first promoter operably connected to the repressor domain or the dCasPhi”.
These claims and claim limitations recite the linkage of polypeptide segments and polynucleotides, and recite that the nucleic acid of claim 1 comprises polypeptide segments. The disclosure does not teach polypeptide-polynucleotide fusions. As such, it is unclear whether these claims and their dependent claims require polypeptide-polynucleotide fusions not disclosed in the disclosure. If what is instead intended is recitation of a nucleic acid encoding a fusion polypeptide, wherein said fusion polypeptide comprises a CasPhi domain, an NLS domain, amino acid linkers, a repressor domain, and/or an activator domain, the examiner suggests the following amendment of claim 1:
A nucleic acid encoding a fusion protein, the fusion protein comprising:
a CasPhi, wherein there are no amino acid substitutions, or wherein proline residues at amino acids 749 and 753 have been substituted;
an amino-terminal linker connected to the amino-terminal end of the CasPhi;
a carboxy-terminal linker connected to the carboxy-terminal end of the CasPhi; and
a nuclear localization signal (NLS) C-terminal from the CasPhi and carboxy-terminal linker.
If the above suggested amendment is used, the examiner suggests the following amendments of dependent claims:
Claims 4-5: amending “and further comprising” to “wherein the fusion protein further comprises”.
Claim 13: amending “and further comprising” to “wherein the fusion protein further comprises”.
Claim 15: amending “operably connected to the repressor domain or the dCasPhi” to “operably connected to the sequence encoding the repressor domain or the dCasPhi”.
Claims 2-3, 8-9, 16-19, 22, and 26 depend on claim 1 but do not clarify this indefiniteness, and so are rendered indefinite.
Claim 15 recites the limitation "the dCasPhi" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, on which claim 15 depends, recites a CasPhi, but does not recite a dCasPhi.
112(a):
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-4, 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claim 2 recites “a protein domain for facilitating a CRISPR application”. This creates an enormous genus of protein domains, as dependent claim 3 renders clear that such applications are not limited to RNA-guided DNA binding and cleaving (the applications recited in claim 3 include imaging, transcriptional activation, and transcriptional repression). Such a genus of proteins encompasses any protein without limit, as by the nature of the fusion of said protein domain to a CRISPR Cas protein, it will “facilitate a CRISPR application”. While the claims recite applications of gene editing, transcriptional activation, and imaging, the only protein domains which are disclosed fused to a CRISPR Cas protein are protein domains which enable transcriptional repression (paragraphs [0031]-[0032]; claim 8). An artisan would not be able to determine that the applicants were in possession of any other such protein domain than those recited in claim 8 or paragraph [0032], which enable transcriptional repression. Claims 3-4 read on these limitations which are not sufficiently described in the disclosure and do not provide sufficient written description, and as such, are likewise rejected for lacking sufficient written description.
Claim 22 recites “a component for delivery” (line 2). This creates an enormous genus of “components” which have any structure and which have any function linked to delivery of a composition, wherein the receiver of such delivery or the mechanism of such delivery is not limited. The disclosure does not provide a definition for the term “component”, and as such, an artisan would not be able to determine the structures or functions required of a component of claim 22. As claim 22 does not disclose the receiver of the delivery, an artisan would not be able to infer the structures and functions required of a component “for delivery”. Moreover, the claims and disclosure do not describe what is meant by the phrase “for delivery”, and as such, the component of claim 22 is not limited to structures which facilitate or enable delivery to a particular target (e.g., a nucleic acid in a cell-free environment, a cell, an organism in vivo). As such, the genus of “component for delivery” encompasses an enormous genus of species, including but not limited to water, air, a pipette, a pharmaceutical excipient, or a human researcher, as any of these may be used “for delivery” to any target. The disclosure describes methods of delivering a CasPhi to a cell nucleus (paragraph [0003]) using an AAV particle (paragraph [0005]), a nanoparticle, particle, PEG, bombardment, or agrobacterium (paragraph [0040]). The disclosure thus only provides sufficient written description of delivery to a cell, wherein a “component for delivery” has the requisite function of facilitating or enabling delivery to cells, and wherein such a component is an AAV particle and its component parts, a nanoparticle, a particle, PEG, apparatuses and reagents required for bombardment, or an agrobacterium.
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.
Claim(s) 1, 15, 17-18, 22, 26 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lai (US 20220002691 A1, filed 11/15/2019), as evidenced by Pausch (2020, of record).
MPEP §2131.01 provides guidance as to 35 U.S.C. 102 rejections over multiple references. Such rejection has been held to be proper when the extra references are cited to: (C) Show that a characteristic not disclosed in the reference is inherent.
The MPEP states: “To serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill.” Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991) (The court went on to explain that “this modest flexibility in the rule that 'anticipation' requires that every element of the claims appear in a single reference accommodates situations in which the common knowledge of technologists is not recorded in the reference; that is, where technological facts are known to those in the field of the invention, albeit not known to judges.” 948 F.2d at 1268, 20 USPQ at 1749-50.). Note that the critical date of extrinsic evidence showing a universal fact need not antedate the filing date. See MPEP §2124.
Regarding claim 1, Lai teaches a nucleic acid encoding a Cas12j (CasPhi) protein fused with a C- and N-terminal linker and at least one NLS (Abstract; paragraphs [0001], [0007], [0480]-[0483], [0126]-[0132], [0429]; claims 1-7, 30). Pausch teaches that Cas12j is another term for CasPhi (page 1).
Regarding claim 15, Lai teaches a first promoter operably linked to the CasPhi (paragraphs [0411], [0421]; claim 23).
Regarding claims 17-18, Lai teaches that the nucleic acid further comprises a guide RNA (paragraphs [0385]-[0391], [0141]-[0372]; claims 8-12) operably linked to a second promoter (paragraphs [0410]-[0412], [0422]; claim 23).
Regarding claim 22, Lai teaches a delivery composition comprising the nucleic acid and a delivery particle (paragraphs [0432]-[04356]; claims 23, 32).
Regarding claim 26, Lai teaches a vector comprising the nucleic acid (paragraphs [0393]-[0431]; claims 17, 23).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-9, 13-19, 22, 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lai (US 20220002691 A1, filed 11/15/2019), as evidenced by Pausch (2020, of record), in view of Rex (US 20210222139 A1).
Regarding claim 1, Lai teaches a nucleic acid encoding a Cas12j (CasPhi) protein fused with a C- and N-terminal linker and at least one NLS (Abstract; paragraphs [0001], [0007], [0480]-[0483], [0126]-[0132], [0429]; claims 1-7, 30). Pausch teaches that Cas12j is another term for CasPhi (page 1).
Regarding claim 15, Lai teaches a first promoter operably linked to the CasPhi (paragraphs [0411], [0421]; claim 23).
Regarding claims 17-18, Lai teaches that the nucleic acid further comprises a guide RNA (paragraphs [0385]-[0391], [0141]-[0372]; claims 8-12) operably linked to a second promoter (paragraphs [0410]-[0412], [0422]; claim 23).
Regarding claim 22, Lai teaches a delivery composition comprising the nucleic acid and a delivery particle (paragraphs [0432]-[04356]; claims 23, 32).
Regarding claim 26, Lai teaches a vector comprising the nucleic acid (paragraphs [0393]-[0431]; claims 17, 23).
However, while Lai teaches that the CasPhi fusion protein may comprise one of an NLS or a repressor domain, including a KRAB domain (see claim 7), and that the CasPhi fusion protein may comprise more than one NLS (paragraph [0429]) at the C- and/or N-terminal, Lai does not teach or suggest a CasPhi fusion protein comprising both a KRAB domain (or other transcriptional repressor domain) and one or more NLS.
Rex teaches a Cas9 fusion protein comprising both a KRAB domain and an NLS.
Regarding claims 1-4, Rex teaches a fusion protein comprising a Cas12 domain linked via a first linker to a transcriptional repressor domain and via a second linker to an NLS domain (claims 1, 6, 9-11).
Regarding claim 5, Rex teaches that the repressor domain may be C-terminal of the CasPhi and the C-terminal linker (paragraphs [0095], [0104]-[0105]).
Regarding claims 6-7, Rex teaches that the NLS may be C-terminal (paragraph [0093]). For both the repressor domain and NLS to be C-terminal of the Cas protein, one must necessarily be C-terminal of the other, rendering obvious instant claims 6-7.
Regarding claims 8-9, Rex teaches that the repressor domain is KRAB fused to the Cas protein (claim 9).
Regarding claims 13-14, Rex teaches that the Cas fusion protein comprises “a repressor domain” (claim 1), and further teaches that the article “a” encompasses “one or more” (paragraph [0073]). Rex thus teaches that the fusion protein may comprise one or more repressor domains. Rex teaches that a repressor domain may be N-terminal and attached to the Cas protein by a linker (paragraph [0058]). It would have been obvious to an artisan that the fusion protein comprising more than one repressor domain may comprise the repressor domains in any combination of positions relative to the Cas protein which are taught by Rex; in other words, it would have been obvious that each repressor domain may be positioned N-terminal, C-terminal, or internal to the Cas protein, as Rex teaches that each is a possibility for the positioning of a repressor domain (paragraphs [0058], [0095], [0104]-[0105]).
Regarding claims 15-19, Rex teaches that the promoters operably linked to the sequences encoding the gRNA and the Cas fusion protein are both RNA polymerase II promoters (claims 12, 16), and that one nucleic acid encodes both the Cas fusion protein and the gRNA (claim 1).
Rex teaches that the Cas protein of the Cas-KRAB-NLS fusion protein may be a Cas12 protein, but does not teach that it may be a Cas12j protein, specifically (i.e., a CasPhi protein). Lai teaches a Cas12j (CasPhi) protein linked to either an NLS or a KRAB domain. It would have been obvious to an artisan at the time of filing that the Cas12j fusion protein of Lai could be structured similarly to the Cas12 fusion proteins of Rex, such that it comprises both a KRAB domain and an NLS. Furthermore, it would have been obvious to said artisan to design the Cas12j fusion protein of Lai to comprise both a KRAB domain and an NLS to provide the fusion protein with the transcriptional repression function of the KRAB domain and enhance the ability of the fusion protein to target and act within a cell’s nucleus by providing the nuclear localization function of the NLS (see Rex paragraph [0103]).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
Prosecution Insights