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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/03/2025 has been entered.
Applicant's Amendment to the Claims filed on 11/03/2025 has been entered.
Claims 1-10, 14-15, and 24-49 are canceled.
Claims 11-13, and 16-23 are pending.
Claims 19-20 are withdrawn to non-elected Species.
Claims 11-13, 16-18, and 21-23 are under examination.
Election/Restrictions
Applicant’s election of the species is as follows:
The type of Acr protein is AcrIIC1Boe (claim 12); and
Response to Amendment
Any/all objections and rejections made in the previous office action and not repeated in this office action are withdrawn in view of the Applicants’ Amendment to the Claims filed on 11/03/2025.
Priority
This US Application 17/959019 filed on 10/03/2022 which is a CON of 16/084,397 filed on 09/12/2018 (now US Patent 11,530,394) which is a 371 of PCT/US17/22040 filed on 03/13/2017 which claims US priority benefit of US Provisionals 62/497,097 filed on 11/07/2016 and 62/308,417 filed on 03/15/2016.
As noted in the previous office action, disclosure of the prior-filed application, Application No. 62/308,417 filed on 03/15/2016, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for claims 12, 18, and 21. The following claim elements: wherein the Acr protein is AcrIIC1Boe…, (see claim 12), “G1 phase” (see claim 18), and “wherein the reduced editing is selected from the group consisting of at least 70%, 75%, 90% or greater and 100%” (claim 21) are not found in the ‘417 Provisional. Accordingly, claims 12, 18, and 21 have an effective filing date to US Provisional 62/497,097 filed on 11/07/2016.
Note that Acr1Bo is shown throughout the ‘417 Provisional but the ‘417 is silent to the term AcrIIC1Boe of instant claim 12. The ‘417 specifically shows the Acr1Bo protein having the 91 amino acid sequence of instant SEQ ID NO:2. (See ‘471 page 22, lines 5-8: Protein (91 amino acids): MKEVFKLKPE LVTYKGCGWA LACIKDGEID LTYVRDLGIE EYDENFDGLE PEHYYDVVAS QACKEVAYRY EEMGEFTFGL CSCWEFNVM (SEQ ID NO: 2). Further, truncated Acr proteins including a truncated protein derived from instant SEQ ID NO: 2 is disclosed in the ‘417 starting on page 28. Further, mutations to Acr proteins are contemplated in the ‘417 on page 31, Section D.
The term AcrIIC1Boe of present claim 12 is found in the 62/497097 Provisional. (See ‘097 claims and throughout the specification, especially Table 1 showing AcrllC1 Boe with a protein sequence: MAKEVFKLKP ELVTYKGCGW ALACIKDGEI IDLTYVRDLG IEEYDENFDG LEPEIIYYDV VASQACKEVA YRYEEMGEFT FGLCSCWEFN VM. This the sequence shown in the ‘097 for AcrIIC1Boe is different than the SEQ ID NO: 2 disclosed in the ‘417 for Acr1-Bo and is different than the sequence shown in the ‘097 for Acr1-Bo. The ‘097 refers to the term Acr1-Bo in Figs 11, 15, 16, page 27 (lines 14 & 19). On page 19, the ‘097 shows the Acr1Bo sequence is the same as the SEQ ID NO:2 of the ‘417 which is different than the ‘097 sequence for AcrllC1 Boe shown just above.
The instant specification describes a Brackiella oediposis Acr (Acr1Bo) having the amino acid sequence of SEQ ID NO:2 whereas AcrIIC1Boe is shown as instant SEQ ID NO: 27. Instant SEQ ID NO:27 is the same sequence shown in Table 1 (above).
The Applicants’ response to the Priority explanation in the previous office action has been fully considered but is unpersuasive regarding claims 12, 18, and 21. Applicants response does not point to where such support is found in the ‘417 Provisional for these limitations.
Claim Rejections - 35 USC § 112 – new grounds
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.
Currently amended claim 12 is 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 12 is presently amended to include SEQ ID NOs in parentheses following the protein name. The SEQ ID NO terms surrounded by a parenthesis render the claim indefinite because it is unclear whether the limitation(s) in parenthesis are part of the claimed invention. See MPEP § 2173.05(d). The instant specification states that the term “Acr2-Nm is interchangeable with AcrIIC2Nme’” (see page 9, lines 7-9) and that the term “Acr1-Bo is interchangeable with AcrIIC1Boe” and that these are a types of Type II-C anti-CRISPR (Acr) proteins. However, this statement is contrary to the instant specification which describes a Brackiella oediposis Acr (Acr1Bo) having the amino acid sequence of SEQ ID NO:2 whereas AcrIIC1Boe is shown as instant SEQ ID NO: 27. Thus it is unclear whether claim 12 intends to recite Acr1-Bo or AcrIIC1Boe. It is unclear whether the SEQ ID NO: 2 is required of the claims or is exemplary. For purpose of examination both terms were searched.
Written Description – updated for amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Currently amended claims 11-13, 16-18, and 21-23 stand 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 full scope of the claimed invention.
Currently amended claims are drawn to a method that requires a Type II-C anti-CRISPR (Acr) protein comprising a native phage-encoded sequence that is capable of binding with specific affinity to a binding site on a Type II-C Cas9 protein and is capable of reducing the editing function of a Type II-C Cas9/sgRNA complex, where the reduced editing prevents an off-target event of Cas9 binding (claim 16), where the reduced editing occurs during the G1 phase of the cell cycle (claim 18), where the reduction is at least 70% to 100% (claims 21), where the reduced editing is “precisely controlled” (claim 22).
During examination, claims must be given their broadest reasonable interpretation consistent with the specification. Claims encompass embodiments where the Acr protein comprises AcrIIC1Boe (elected species of claim 12). Claims encompass embodiments where the Cas9 is a Neisseria meningitidis Cas9 protein (claim 13).
Thus claim require the critically essential element of a genus of functional Acr proteins having specific functional properties. However, the instant specification does not provide sufficient number of species of a required structure of such Acr protein correlated with the required functional properties so that one of ordinary skill in the art would have been able to envision whether a given species of an Acr protein would be encompassed or excluded by the claimed genus of Acr protein. Neither the instant specification nor the state of the art before the effective filing date of the presently claimed invention disclose a sufficient number of species of this subgenus to represent the variants encompassed by the claim language of an Acr protein or wherein said Acr protein is the elected species of AcrIIC1Boe to represent this subgenus requiring the claimed functional properties because the Specification discloses that the terms “an Acr protein” or “an AcrIIC1Boe protein” encompasses variants of such proteins. For example, in the Specification on page 2, lines 26-27, it state that in one embodiment, “the Acr protein is a truncated protein”. In page 3, line 5 it states that the Acr protein is a mutated protein or portion of an amino acid sequence selected from the list shown in instant claim 12. Although the instant claim 12 is presently amended to add SEQ ID NOs in parentheses, as noted above, the AcrIIC1Boe protein of claim 12 is shown in the Specification as being SEQ ID NO:27 rather than SEQ ID NO:2. Thus, the generic term Acr protein is construed to encompass such Acr sequence variants because such interpretation is consistent with the Specification including claims as originally filed.
In one embodiment, the present invention contemplates a Type II-C anti-CRISPR (Acr) protein. In one embodiment, the Acr protein is a truncated protein. In one embodiment, the truncated protein is derived from an amino acid sequence including, but not limited to, SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, and/or SEQ ID NO: 16. (See ‘471 page 2, lines 16-20.)
The instant specification describes a Brackiella oediposis Acr (Acr1Bo) having the amino acid sequence of SEQ ID NO:2 and encoded by the nucleotide sequence of SEQ ID NO: 1. Also, in pages 37-38, the specification describes truncation Acr proteins comprising SEQ ID NOs 2, 4, 6, 8, 10, 12, 14, and 16. In Table 1, representative species of nucleotide and amino acid sequences of Type II NmeCas9 Inhibitor proteins are disclosed. AcrIIC1Boe is shown as instant SEQ ID NO: 27.
A working example of a AcrIIC1Boe protein is discussed in the instant specification on page 48. Although it is stated on page 48 that type II-C CRISPR-Cas system of N. meningitidus was inhibited by AcrIIC1Boe and AcrIIC1Nme proteins, the results referred to in Figs 19A-C only appear to show transformation results but do not directly show such inhibition results. Also, the specification does not appear to disclose what amino acid sequence was used as the AcrIIC1Boe protein.
However, neither the state of the art nor the instant specification shows a correlation to a specific Type II-C anti-CRISPR (Acr) protein having the required functional properties of the present claims so that one of ordinary skill in the art would be able to envision whether a given variant Acr protein would possess such functional properties. As presently written, the claims do not specify a full-length AcrIIC1Boe protein with a specific SEQ ID NO. The term “a native phage-encoded Acr open reading sequence” must have the functional property of being capable of binding with specific affinity to said binding site but the specification does not make clear which sequences correspond to this property. The Specification does not provide a limiting definition for what amino acid sequences are encompassed or excluded by the term “comprising a native phage-encoded sequence”. Further, the instant Specification discloses an unpredictability regarding different types of anti-CRISPR families, with AcrIIC3Nme being the most potent (e.g., 100% inhibition; see page 53, para 2).
Further, regarding the state of the art, he Bondy-Denomy Dissertation (2014; IDS reference) discloses methods and compositions comprising Type I anti-CRISPR (Acr) proteins but does not disclose Type II Acrs of the present invention. Also, the US-20140357523-A1 document to Zeiner et al (IDS reference) is related art but does not explicitly disclose a Type II-C anti-CRISPR (Acr) protein.
The limited disclosure of the specification in view of the vast genus of Type II Acr proteins including variants and portions of amino acid sequences encompassed by the claims does not adequately describe the entire genus of molecules encompassed by the claims.
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that the inventor(s) invented what is claimed.” (See Vas-Cath at page 1116).
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eh Lily & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) (‘In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. ..."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eh Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid or protein itself.
Thus, one of skill at the time of the invention could not have concluded that the inventor(s) were in possession of the genus of functional Type II-C anti-CRISPR (Acr) proteins that is required by the claimed method.
Response to Arguments
The Applicants’ Response filed on 11/03/2025 has been fully considered but is unpersuasive. The applicants argue that base claim 11 is presently amended to recite that the Acr protein is expressed from a plasmid comprising a native-encoded Acr open reading frame gene sequence. However, this argument is unpersuasive because during examination, claims must be given their broadest reasonable interpretation consistent with the specification. As presently written, the claims do not specify a full-length AcrIIC1Boe protein with a specific SEQ ID NO. The term “a native phage-encoded Acr open reading sequence” must have the functional property of being capable of binding with specific affinity to said binding site but the specification does not make clear which sequences correspond to this property. Dependent claim 13 lists types of Type II-C Cas9. Presently amended claim 12 recites that the Acr protein is AcrIIC1Boe (elected species) but follows with SEQ ID NO:2. SEQ ID NO:2 is the sequence for AcrBo whereas SEQ ID NO: 27 is the sequence for AcrIIC1Boe. Dependent claim 16 recites that the type of reduced editing “prevents at least one off-target event of Cas9 binding”. Dependent claim 21 requires parameters for reduced editing ranging from 70% to 100% whereas the instant Specification discloses an unpredictability regarding different types of anti-CRISPR families, with AcrIIC3Nme being the most potent (e.g., 100% inhibition; see page 53, para 2).
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eh Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid or protein itself.
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)(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.
Presently amended claim 12 STANDs rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pawluk et al (“Naturally Occurring Off-Switches for CRISPR-Cas9” Cell Vol 167, No 7, pages 1829-1838, published December 15, 2016; of record).
For reasons provided above, present claim 12 has an effective filing date of 11/07/2016 to US Provisional 62/497,097. Thus presently, this Pawluk et al reference qualifies as prior art. It is noted that this reference has an inventor or joint inventor in common with the instant application. Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a proper showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1).
Regarding claim 12, Pawluk et al discloses a method, comprising :
a) providing; i) a biological cell comprising at least one suspect gene; ii) a Type II-C Cas9/sgRNA complex wherein said sgRNA is capable of hybridizing to a target site of at least one suspect gene and said Type II-C Cas9 protein comprises a binding site; and
iii) a Type II-C anti-CRISPR (Acr) protein, specifically including the elected species of an AcrIIC1Boe and the unelected species of AcrIICINme, that are capable of binding with specific affinity to said binding site;
b) contacting said Type II-C Cas9/sgRNA complex with said biological cell such that said Type II-C Cas9/sgRNA complex hybridizes to said target site;
c) editing said suspect gene with said Type II-C Cas9/sgRNA complex; and
d) contacting said binding site with said Acr protein such that said editing is reduced.
Thus the Pawluk et al reference anticipates the present claim 12.
Response to Arguments
The Applicants’ Response filed on November 3, 2025 has been fully considered but is unpersuasive regarding present claim 12. The applicants argue that the Pawluk et al reference does not qualify as prior art for claims 12-13 based on the present deletion from claim 12 of claim elements AcrIIC4Hpa and AcrIIC5Smu and present deletion from claim 13 of the claim element Haemophilus influenza.
The examiner agrees that amendment to claim 13 changes the effective filing date of claim 13 to 03/15/2016 which removes this Pawluck et al reference as prior art to claim 13.
However, present claim 12 has an effective filing date of 11/07/2016 to US Provisional 62/497,097. Application No. 62/308,417 filed on 03/15/2016, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for claim 12. The applicants have not indicated where support may be found for the claim element: “wherein said Acr protein is selected from the group consisting of AcrIIC1Boe… in the ‘417 priority document. Thus the rejection is maintained.
Conclusion
No claim is allowed.
The Pawlick Dissertation (2016; IDS reference) is not considered prior art because it is either post-filing or within a year of the effective filing date of the presently claimed invention and is by a joint inventor of the presently claimed invention.
The US-20140357523-A1 document to Zeiner et al (IDS reference) is cited in the IPER however this document does not explicitly disclose a Type II-C anti-CRISPR (Acr) protein.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658