DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 112-115, 118, 120, 123, 126, 130, 133, 142, and 186-187) in the reply filed on January 8, 2026 is acknowledged.
Claims 145, 148, 155, 171, 188-192 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 8, 2026.
Applicants also elected the species polypeptide (claim 115) and a D-element sequence that is at least 50% identical to SEQ ID NO: 219 without traverse. Therefore, claims 118, 126, and 133, directed to a polynucleotide, are also withdrawn from further consideration.
Claims 112-115, 120, 123, 130, 142, and 186-187 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original non-provisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AlA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, U.S. Provisional Patent Application Nos. 63/038,620 and 63/116,492, fail to provide adequate support in the manner provided by 35 U.S.C. 112(a) or pre-AlA 35 U.S.C. 112, first paragraph for the claims of this application. Specifically, claims 115 and 130 are drawn to a polymeric modification agent comprising a D element that is at least 50% identical to SEQ ID NOS: 196, 197, 219, 222, 225, or 226 (claim 115) or comprising an R element that is at least 50% identical to SEQ ID NOS: 208, 210, 212, 214, or 216 (claim 130). However, U.S. Provisional Patent Application Nos. 63/038,620 and 63/116,492 do not provide adequate support for SEQ ID NOS: 196, 197, 219, 222, 225, or 226 or SEQ ID NOS: 208, 210, 212, 214, or 216, as recited in claims 115 and 130, respectively. Instead, these sequences are first disclosed in PCT Patent Application No. PCT/US21/37113. Accordingly, while the claims 115 and 130 are entitled to the benefit of the prior PCT Patent Application No. PCT/US21/37113, filed June 11, 2021, they are not entitled to the benefit of the prior U.S. Provisional Patent Application Nos. 63/038,620 and 63/116,492.
Information Disclosure Statement
The Information Disclosure Statements filed April 10, 2023 and January 8, 2026 have been considered.
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Specifically, Figures 11, 13, 14A-14B, 15A-15B, 17, 20A-20B, 21-22, 24-26, 28-29, 31, 34-35, 39, 42, 47, 56-57, 59A-59B, 60A-60B, 62-63, 65, 67-69, 70-72, 75, 78-79, 81, 85-86, and 91A contain sequences that do not have accompanying sequence identifiers.
Required response – Applicant must provide:
Amended 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 (i.e., “SEQ ID NO:X” or the like) 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.
Specification
The use of the terms GIBSON ASSEMBLY® at page 78, line 25; PHUSION® at page 111, line 18; LIPOFECTAMINE® at page 127, line 17; RNAIMAX® at page 127, line 17; and DUOLINK® at page 126, lines 14 and 15; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claims 112-115, 120, and 143 are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed et al. (13 Plant Biotechnology Reports 459-472 (2019), and cited in the Information Disclosure Statement filed January 8, 2026) in view of Mandell et al. (34 Nucleic Acids Research W516-W523 (2006)), Friedrich et al. (1480 Biochimica et Biophysica Acta 145-159 (2000), and Isalan (U.S. Patent Application Publication No. 2019/0247519, published August 15, 2019).
Regarding claim 112, Ahmed discloses gene editing (modification) processes and enzymes that are able to perform such gene editing (modification) processes (abstract). Ahmed discloses a variety of sequence-specific nucleases (i.e., sequence specific binding element, which is interpreted as being the D element of the claimed structure), including zinc finger nucleases, TALE nucleases, and CRISPR nucleases (abstract). Ahmed discloses that zinc finger nucleases comprises four to six zinc finger domains, each of which recognizes (binds to) three base pairs of DNA (which is interpreted as being the D element of the claimed structure) paragraph bridging pages 462 and 463). Ahmed discloses that the zinc finger and TALE nucleases can be fused with FokI nucleases, with the FokI nuclease being the R element of the polymeric modification agent (Figures 1 and 2).
Regarding claim 113, Ahmed discloses that the CRISPR system Cas9 recognizes DNA at a target site upstream of a protospacer adjacent motif (PAM), which is interpreted as being a landing site for the binding of the CRISPR enzyme and the sequence specific binding element (i.e., a crRNA/tracr molecule) (page 463, column 2, first full paragraph). Ahmed discloses that the crRNA/tracr can be 20 nucleotides long (paragraph bridging pages 463 and 464). Ahmed discloses that zinc finger nucleases and TALE nucleases also bind to a target site (Figures 1 and 2).
Regarding claim 114, Ahmed discloses that zinc finger, TALE, and CRISPR nucleases activate non-homologous end joining or homology-directed repair at targeted sites, which is interpreted as no reduction in speed of DNA replication at the target site.
Regarding claim 120, Ahmed discloses compositions that comprise zinc finger nucleases, TALE nucleases, and CRISPR/Cas nucleases (page 461, paragraph bridging columns 1 and 2).
Ahmed fails to disclose the dissociation constant of the D or R elements. Ahmed fails to disclose or suggest that the polymeric modification agent comprises a linker. Ahmed fails to disclose or suggest the sequence of the D element of the polymeric modification agent.
Regarding claim 112, Mandell discloses zinc finger nucleases that have DNA binding domains and that can be designed to bind to any chosen target site (abstract). Mandell discloses that the zinc finger domains, when fused in modular fashion, are able to recognize DNA sequences of 9-18 base pairs with specificity and high affinity (page W516, paragraph bridging columns 1 and 2). Mandell discloses that the zinc fingers can include a Fok I catalytic domain (page W517, column 2, final full paragraph). Mandell discloses that the dissociation constants for zinc finger nucleases are in the low nanomolar range or better, which is interpreted as 10-3 or lower (page W516, paragraph bridging columns 1 and 2).
Regarding claim 143, Mandell discloses that the dissociation constants for the zinc finger nucleases (i.e., the D element) are in the low nanomolar range or better, which is interpreted as 10-3 or lower, which includes 10-6 (page W516, paragraph bridging columns 1 and 2).
Regarding claim 112, Friedrich discloses that the FokI methyltransferase recognizes an asymmetric DNA sequence (GGATG/CATCC) (abstract). Friedrich discloses that the C-terminal domain of FokI binds to DNA with a high affinity (abstract). Friedrich discloses that the FokI has a dissociation constant of 2x10-7, with the Kd in the 0.1-1 µM range (paragraph bridging pages 150 and 151).
Regarding claim 112, Isalan discloses a zinc finger molecule that can be used to treat polyglutamine diseases (abstract and paragraph [0020]). Isalan discloses that the agent can include a linker (paragraph [0022])
Regarding claim 115, Isalan discloses a zinc finger molecule that can be used to treat diseases (abstract and paragraph [0020]). Isalan discloses a zinc finger molecule that has a sequence that has 72.2% identity to instant SEQ ID NO: 219 (SEQ ID NO: 35) (Appendix I).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use any of Ahmed’s, Mandell’s, or Isalan’s zinc finger molecules fused with FokI, as disclosed by Ahmed, as the polymeric modification agent for genetic modification because each Ahmed, Mandell, and Isalan disclose zinc finger molecules that can be used for genetic modification. Further, as disclosed by Ahmed, the zinc finger nuclease can be fused with FokI, as disclosed by Mandell, in order to obtain a dissociation constant of the R element, such as FokI, as disclosed by Friedrich. As such, one of ordinary skill in the art would expect each of the zinc finger molecules of Ahmed, Mandell, and Isalan to function in the same fashion, and with the high specificity and low dissociation constants of Mandell, with the sequences dependent upon the desired target sequence.
Claim 123 is rejected under 35 U.S.C. 103 as being unpatentable over Ahmed, Mandell, Friedrich, and Isalan, as applied to claims 112-115, 120, and 143 above, and further in view of Pabo et al. (PCT Patent Application Publication No. WO 2005/014791, published February 17, 2005) or Holmes et al. (PCT Patent Application Publication No. WO 2019/084140, published May 2, 2019).
Ahmed, Mandell, Friedrich, and Isalan disclose and suggest a polymeric modification agent, as discussed above.
Ahmed, Mandell, Friedrich, and Isalan fail to disclose or suggest the sequence of the linker element.
Regarding claim 123, Pabo discloses compositions for targeted cleavage of a genomic sequence comprising a zinc finger domain (abstract). Pabo discloses fusion proteins that are used for targeted recombination (abstract). Pabo discloses that the zinc finger can be fused to a FokI nuclease (page 5, lines 1-5). Pabo discloses that the fusion proteins can be separated by a linker of 4 amino acids (page 6, lines 17-19). Pabo discloses a linker sequence that is identical to instant SEQ ID NO: 1 (SEQ ID NO: 107) (Appendix II).
Regarding claim 123, Holmes discloses compositions for modulations of genes involved in rare diseases (abstract). Holmes discloses that zinc finger proteins and TALE nucleases can be used for genetic modulation (paragraph [0010]). Holmes discloses fusion proteins that are used for targeted recombination (abstract). Holmes discloses that the nucleases can be FokI Holmes discloses that zinc finger nucleases can be separated by a linker (paragraph [0095]). Holmes discloses a linker sequence that is identical to instant SEQ ID NO: 13 (SEQ ID NO: 33) (Appendix III).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Pabo’s or Holmes’ linkers in the polymeric modification agent disclosed and suggested by Ahmed, Mandell, Friedrich, and Isalan, because as noted by Isalan, a linker can be present between two nucleases (i.e., a D element and an R element). One of ordinary skill in the art would have been motivated to include the presence of a linker because this provides for structures that have flexibility in the binding to DNA sequences of the target to be modified.
Claim 130 is rejected under 35 U.S.C. 103 as being unpatentable over Ahmed, Mandell, Friedrich, and Isalan, as applied to claims 112-115, 120, and 143 above, and further in view of Wang et al. (U.S. Patent No. 11,773,427, issued October 3, 2023, filed October 30, 2019, and claiming priority to PCT Patent Application No. PCT/US2019/022459, filed March 15, 2019 and U.S. Provisional Patent Application No. 62/644,697, filed March 19, 2018).
Ahmed, Mandell, Friedrich, and Isalan disclose and suggest a polymeric modification agent, as discussed above.
Ahmed, Mandell, Friedrich, and Isalan fail to disclose or suggest the sequence of the R element (FokI).
Regarding claim 130, Wang discloses compositions associated with a DNA-binding protein that can selectively cleave a target nucleic acid (abstract). Wang discloses that the nuclease domain can be a FokI nuclease (column 3, lines 62-65). Wang discloses a FokI nuclease having 68% identity with instant SEQ ID NO: 210 (SEQ ID NO. 11). (Appendix IV).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Wang’s FokI in the polymeric modification agent disclosed and suggested by Ahmed, Mandell, Friedrich, and Isalan, because each of Ahmed, Mandell, Friedrich, and Isalan disclose a polymeric modification agent comprising a zinc finger nuclease, a TALE nuclease, or a CRISPR nuclease (D element) that can be fused with a FokI nuclease (R element). One of ordinary skill in the art would have been motivated to include Wang’s FokI because the FokI is used for the same purpose in the same compositions as Ahmed, Mandell, Friedrich, and Isalan. As such, one of ordinary skill in the art would have been able to substitute one known FokI sequence for any other known FokI sequence with a predictable and reasonable expectation of success.
Claim 142 and 186-187 are rejected under 35 U.S.C. 103 as being unpatentable over Ahmed, Mandell, Friedrich, and Isalan, as applied to claims 112-115, 120, and 143 above, and further in view of Guilinger et al. (32(6) Nature Biotechnology 577-582 and Online Methods (2014), and cited in the Information Disclosure Statement filed April 10, 2023).
Ahmed, Mandell, Friedrich, and Isalan disclose and suggest a polymeric modification agent, as discussed above.
Ahmed, Mandell, Friedrich, and Isalan fail to disclose or suggest that the D element of the polymeric modification agent does not modify a target site or non-target site. Ahmed, Mandell, Friedrich, and Isalan fail to disclose or suggest disclose and suggest a polymeric modification agent having a dCas9 as the D element or having any of the D, L, or R elements not acting as a nuclease.
Guilinger discloses a Cas9-FokI nuclease fusion that improved the specificity of genome modification (abstract). Guilinger discloses that these fusion proteins can be joined by a linker (Figure I). Guilinger discloses that the Cas9-FokI fusion can include a dCas9 (dead/inactive Cas9) (paragraph bridging pages 577 and 578 and Figure I). Guilinger discloses that the dCas9 (D element) are able to bind to target sites do not possess nuclease activity, but that the FokI is catalytically active, which is interpreted as the dCas9 (D element) not able to modify a target or non-target site (abstract and Figure 1).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Guilinger’s dCas9-FokI fusion where the D element (dCas9) is inactive and does not modify a target or non-target site because the dCas9 provides high specificity to target sites and a catalytically active FokI provides for the genomic modification. One of ordinary skill in the art would have been motivated to fuse a dCas9 and FokI in order to provide high specificity binding by the dCas9 and gene modification by the FokI because this will have the effect of reducing off-target effects.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636