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 .
DETAILED ACTION
Application status
Claims 1-20 are pending in this application.
Priority
The instant application is the 371 national stage entry of PCT/US2022/025346, filed on 02/04/2022, which claims benefit of 63145929 filed on 02/04/2021.
Election
Applicant's election without traverse of Group I, Claims 1-8 and 13 in the response filed on 05/15/2026, is acknowledged.
Claims 9-12 and 14-20 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention.
For the reasons provided above, this restriction requirement is deemed proper, and therefore, it is made final.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/03/2023, 12/27/2024 and 03/04/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections to the Specification
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825; Applicants’ attention is directed to the final rulemaking notice published at 55 FR 18230 (May 1, 1990), and 1114 OG 29 (May 15, 1990). To be in compliance, Applicants should identify nucleotide sequences of at least 10 nucleotides and amino acid sequences of at least 4 amino acids in the specification by a proper sequence identifier, i.e., “SEQ ID NO:” (see MPEP 2422.01). If these sequences have not been listed in the computer readable form and paper copy of the sequence listing, applicant must provide an initial computer readable form (CRF) copy of the “Sequence Listing”, an initial paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, and a statement that the content of the paper and CRF copies are the same and, where applicable, include no new matter as required by 37 C.F.R. 1.821(e) or 1.821(f) or 1.821(g) or 1.821(b) or 1.825(d).
See particularly Figures 1D, 3-5, 9, 13, 15-17, 19, 21 and 25-26 of the specification containing nucleic acid/amino acid sequences, and therefore, those sequences should be represented by proper sequence identifier numbers.
If the noted sequences are not in a sequence listing as filed, Applicants must provide (1) an updated copy of the sequence listing containing the requisite sequences in computer readable form (CRF), (2) an amendment directing its entry into the specification, (3) a statement that no new matter has been added and (4) an amendment to the specification to identify each of the identified sequences by SEQ ID NO:, and (5) an incorporation by reference statement with the date of creation, sequence file name and size in bytes. – See also MPEP 2422.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
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 1-8 and 13 are rejected under 35 U.S.C. § 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 (2-8 and 13 dependent therefrom) is confusing in the recitation of the phrase, “the modified protein having a changed DNA binding location relative to a DNA binding location of the protein in its unmodified form”. Does the phrase mean the location of the DNA binding domain within the modified protein is changed (italicized for added emphasis)? Or does it mean the DNA binding location (i.e., the target DNA location) is changed? Claim 2 adds to this confusion by stating that “the changed DNA binding location is on a chromosome, organelle DNA, or a plasmid” which seems to suggest that the phrase should be interpreted as a change in the target DNA location. In the interest of advancing prosecution, the Examiner has interpreted claim 1 as encompassing: “A modified protein comprising an introduced zinc finger DNA binding domain, the modified protein having a changed DNA binding location relative to a DNA binding location of the protein in its unmodified form,
[i] wherein the changed DNA binding location means change in the location of DNA binding domain within the modified protein relative to the protein in its unmodified form, or
[ii] wherein the change DNA binding location means change in the target DNA sequence to which the modified protein binds relative to the protein in its unmodified form,
wherein the modified protein comprises, in addition to the introduced zinc finger DNA binding domain, a gene expression activator domain or a gene expression repressor domain.”
Claim 3 recites the limitation "the changed DNA binding domain location" in claim 1 (italicized for added emphasis). There is insufficient antecedent basis for this limitation in the claim.
Claim 6 recites the phrase “the gene expression domain” in line 2 which is unclear. It is unclear whether the noted phrase is referring to the gene expression activator domain or the gene expression repressor domain (italicized for added emphasis). In the interest of advancing prosecution, the noted phrase is interpreted as “the gene expression repressor domain”.
Claims 8 and 13 recite the phrase “the introduced zinc finger domain is one of a plurality of zinc finger domains that are introduced into the modified protein to thereby provide a modified protein comprising a plurality of introduced zinc finger domains, and wherein the plurality of introduced zinc finger domains optionally comprise the same changed DNA binding domain” which contradicts the limitation of claim 1 which these claims depend from. The reason is that claim 1 clearly limits the number of introduced zinc finger DNA binding domain to one in the recitation of “an introduced zinc finger DNA binding domain” (italicized for added emphasis). As such, the introduction of a plurality of introduced zinc finger domains in these dependent claims 8 and 13 directly contradict with the limitation of claim 1. In the interest of advancing prosecution, claims 8 and 13 are interpreted as the following:
Claim 8. The modified protein of claim 7, wherein the modified protein further comprises one or more zinc finger DNA binding domains that are introduced into the modified protein, optionally wherein the introduced zinc finger DNA binding domains are the same.
Claim 13. A pharmaceutical composition comprising:
i) one or more modified proteins of claim 1;
ii) one or more mRNAs encoding one or more of said modified proteins; or
iii) one or more expression vectors encoding one or more of said modified proteins, optionally wherein the modified protein further comprises one or more zinc finger DNA binding domains that are introduced into the modified protein, and optionally wherein the introduced zinc finger DNA binding domains are the same.
The following is a quotation 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.
Claims 1-8 and 13 are rejected under 35 U.S.C. § 112(a), written description, 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(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to a genus of modified proteins comprising an introduced zinc finger DNA binding domain, the modified protein having a changed DNA binding location relative to a DNA binding location of the protein in its unmodified form, wherein the modified protein comprises, in addition to the introduced zinc finger DNA binding domain, a gene expression activator domain or a gene expression repressor domain. (see above 112(b) rejection for the claim interpretation)
To satisfy the written description aspect of 35 U.S.C. § 112(a) for a claimed genus of [compositions or methods], it must be clear that: (1) the identifying characteristics of the claimed [compositions or methods] have been disclosed, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these; and (2) a representative number of species within the genus must be disclosed.
The Court of Appeals for the Federal Circuit has recently held that a “written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as be structure, formula [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical Inc. v. Gen-Probe Inc. (CAFC (2002) 63 USPQ2d 1609).
The specification discloses two representative species of [1] a modified human KLF6 protein (gene expression activator domain) with its native zinc finger DNA binding domain (ZF DBD, hereafter) replaced with Tet3-targeting ZF arrays as set forth in SEQ ID NO: 57; and [2] a modified human Zim3 protein containing KRAB domain (gene expression repressor domain) with its native ZF DBD replaced with Tet3-targeting ZF arrays as set forth in SEQ ID NO: 56 (see Figure 16).
However, these two disclosed species fail to provide adequate written description for a genus of modified proteins comprising an introduced zinc finger DNA binding domain, the modified protein having a changed DNA binding location relative to a DNA binding location of the protein in its unmodified form, wherein the modified protein comprises, in addition to the introduced zinc finger DNA binding domain, a gene expression activator domain or a gene expression repressor domain, which encompasses a genus of any modified proteins having any structure of any origin, wherein a ZF DBD is inserted anywhere in said modified protein, with the presence of any activator or any repressor domain, as the claim does not require the ZF DBD and the activator/repressor domain be part of the same polypeptide chain or that they be covalently linked (italicized for added emphasis). The reason for this interpretation is that “comprising” and “in addition to” as recited in claim 1 is ‘open-ended’ language which reads on [1] any single-chain covalent fusion polypeptide, as well as [2] any multi-component or non-covalent complexes. In this case, the specification fails to describe any identification of structural characteristics or properties of a genus of any modified proteins having any structure of any origin, wherein a ZF DBD is inserted anywhere in said modified protein, with the presence of any activator or any repressor domain. While M.P.E.P. section 2163 acknowledges that a single species can describe a genus, it also acknowledges that for a genus that encompasses widely variant species, disclosure of a single species within the genus fails to adequately describe all members of the genus. Please refer to the M.P.E.P. section 2163.05 [R-7.2022] under I, B for more details with respect to sufficient number of representative species that should be disclosed to describe a widely variant genus.
Given the lack of additional representative species of any modified proteins having any structure of any origin, wherein a ZF DBD is inserted anywhere in said modified protein, with the presence of any activator or any repressor domain, as encompassed by the claim, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112(a) published in the Official Gazette and also available at www.uspto.gov.
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 1-3, 5-8 and 13 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Cox et al. (US Patent No. 6824978).
The instant claims are drawn to a modified protein comprising an introduced zinc finger DNA binding domain, the modified protein having a changed DNA binding location relative to a DNA binding location of the protein in its unmodified form, wherein the modified protein comprises, in addition to the introduced zinc finger DNA binding domain, a gene expression activator domain or a gene expression repressor domain. (see above 112(b) rejection for the claim interpretation).
Cox et al. teach examples of ZF DBD fused to KRAB, ERD or SID transcriptional repressor domain, or VP16 or VP64 transcriptional activator domain (see column 3 lines 57-65) in addition to other examples disclosed in columns 3 and 4. Cox et al. specifically teach a modified protein comprising VEGF-targeted ZF DBD fused to KRAB, which represses gene expression in mammalian cells (i.e., by binding to target sites in the genome, see Figures 1-10). Cox et al. further teach that ZFPs can be designed to bind desired DNA target sequences and fused to regulatory domains for gene expression activation or repression (see column 3, lines 5-20; column 5; and claims 1-66). Cox et al. further teach the use of multiple ZF DBD, i.e., chimeric six ZFs (see column 3 lines 57-65). Therefore, teachings of Cox et al. anticipate Applicants’ claims 1-3, 5-8 and 13.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (US Patent No. 6824978) in view of Dang et al. (The biology of the mammalian Krüppel-like family of transcription factors, The International Journal of Biochemistry & Cell Biology, 32 (2000) 1103–1121), Alerasool et al. (An efficient KRAB domain for CRISPRi applications in human cells, Nature Methods, VOL 17, November 2020, 1093–1096), and Isalan et al. (A rapid, generally applicable method to engineer zinc fingers illustrated by targeting the HIV-1 promoter, Nature Biotechnology, VOLUME 19, JULY 2001, pg 656-660).
The instant claims are drawn to a modified protein comprising an introduced zinc finger DNA binding domain, the modified protein having a changed DNA binding location relative to a DNA binding location of the protein in its unmodified form, wherein the modified protein comprises, in addition to the introduced zinc finger DNA binding domain, a gene expression activator domain or a gene expression repressor domain. (see above 112(b) rejection for the claim interpretation).
The teachings of Cox et al. are as described above.
Cox et al. do not teach the use of KLF6.
Dang et al. teach that KLF6 protein is a well-characterized transcriptional activator (see pg 1112, right column continued to pg 1113).
Alerasool et al. teach that Zim3 comprising KRAB domain is a well-characterized, potent transcriptional repressor (see pg 1093).
Islan et al. teach methods for rapid design and engineer of zinc finger arrays with desired DNA-binding specificity (see abstract and pg 657-659).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to make and use the modified protein taught by Cox et al. and replace the effector domain with KLF6 transcriptional activator as taught by Dang et al. or alternatively replace the effector domain with Zim3 transcriptional repressor as taught by Alerasool et al. while designing ZF DBD as taught by Islan et al. for desired DNA-binding specificity. A POSITA would have been motivated to make and use such composition because both of the references, Cox et al. and Islan et al., are directed to the same field of targeted gene regulation using fusion proteins comprising ZF DBD and effector domains, and Islan et al. provides a rapid method of generating ZF DBD used in the modified protein taught by Cox et al. A POSITA would have had a reasonable expectation of success to make and use such composition because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Cox et al., Dang et al., Alerasool et al. and Islan et al prior to the filing of the instant application. For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1-8 and 13 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
Prosecution Insights