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 .
Claim Status
Applicant’s amendment filed 7/9/2026 has been entered. Claims 134-153 are pending. Claims 150-153 are withdrawn. Claims 134-149 are examined herein.
Election/Restrictions
Claims 150-153 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 7/9/2026.
Applicant's election with traverse of Group I, claims 134-149 in the reply filed on 7/9/2026 is acknowledged. Newly amended claims 134 and 150 recite the limitation “wherein the DBP is not fused to a functional domain having cleavage activity”. The traversal is on the ground(s) that the DBP Orkin (US9822355B2; published 11/21/2027; cited in the PTO-892 of the restriction requirement mailed 5/15/2026) teaches is fused to nuclease that induces cleavage in +58 DHS of BLC11A. This is not found persuasive because Orkin also teaches genome editing using recombinant AAV based engineering, where the single-stranded DNA viral vectors stimulate endogenous homologous recombination in the absence of causing double strand DNA breaks in the genome (col. 48, line 67 through col. 49, line 18).
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 112 – Written Description
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 134-149 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.
The instant claims are directed to a nucleic acid encoding a recombinant DNA binding protein (DBP) comprising a plurality of repeat units (RUs), and only specify positions X12 and X13. Even at positions X12 and X13, claim 134 (a)-(e) recites a large array of possible combinations. The specification does not adequately describe this genus. The specification does not adequately describe the structure required for the function. The minimal species of the specification that fall within the broad formula of claim 134 are not representative of the entire claimed genus.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See 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 species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University V. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification's disclosure of species that were not representative of the entire genus. Furthermore, 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. Eli Lilly & 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 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (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 claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being a repeat unit within the broadly recited limitations of claim 143 that would function as claimed.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, "Written Description" Requirement", published at Federal Register, Vol.
66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether
adequate written description is present. The first step is to determine what the claim as a whole cover, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
For example, Hubbard et al. (Nature Methods, 12, 10, 2015, 939-944; cited in the IDS filed 10/10/2025) teach that a limitation of TALEs is that the 5' nucleotide of the target is specified to be T. Although promiscuous TALEs with no specificity at the 5' position have been described, no TALE variants that preferentially recognize 5' A or 5' C have been described. Moreover, TALEs bind appreciably to off-target sites within the genome, thereby limiting their potential as human therapeutics. No method has been reported that enhances the specificity of a particular TALE array by decreasing its ability to bind to specific off-target DNA sequences found in a genome (page 939).
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for RUs within the instant enormous genus that results in expression of fetal HBG as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 148-149 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 148 recites “A human cell comprising the nucleic acid of claim 134.” Claim 149 recites “The human cell of claims 148, wherein the cell is a hematopoietic progenitor cell, an erythroid progenitor, a pluripotent stem cell, or an induced pluripotent stem cell.” The specification states “The terms "patient" or "subject" are used interchangeably to refer to a human or a non-human animal (e.g., a mammal). ” (para 0051). Accordingly, the broadest reasonable interpretation of the term “a human cell” embraces a human cell residing in a human organism and therefore is otherwise inseparable from the human. In view of BRI, a human comprising the host cell would be encompassed by the claimed product.
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.
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 134 and 136-149 are rejected under 35 U.S.C. 103 as being unpatentable over Orkin et al. (US20150132269A1; published 5/14/2015), in view of Gregory et al. (US20190169640A1; published 6/6/2019).
Orkin’s disclosure is directed to genome engineering of the genome of a hematopoietic cell and targeting expression of the zinc finger protein BCL11A implicated in developmental stage-specific regulation of gamma globin expression (entire document; paras 0012-0014; 0034). Orkin teaches compositions and methods to modulate gene expression including gene activation, repression, and inactivation (para 0145). Orkin further teaches versatility of gene modulation systems with compositions comprising nucleases (CRISPR/Cas systems, TALENs, and ZFNs) with cleavage activity and nuclease variants with nickase activity or no cleavage activity (paras 19-30).
Regarding claim 134, Orkin teaches donor nucleic acids encoding a regulatory protein of interest (e.g. TALE TFs) that binds to and/or modulates expression of a gene of interest, by binding to a DNA sequence and prevent binding of other regulatory factors and/or by binding a regulatory protein may modulate (i.e. induce or repress) expression of a target DNA (para 0034). Orkin teaches that the specificity of TAL effectors depends of the sequences found in the tandem repeats and that DNA binding repeats have been assembled into proteins with new combinations and numbers of repeats, to make artificial transcription factors that are able to interact with new sequences and modulate expression (para 0160). Orkin teaches a polynucleotide encoding a TALE protein (DNA-binding protein) comprising a plurality of TALE repeat units, each repeat unit containing approximately 34 amino acids (X1-11X12X13X14-33, 34, or 35; Applicant’s SEQ ID NO: 4) comprising a hypervariable diresidue region (RVD) (claims 20, 22, and 24; paras 0118-0119; 0159-0160). Orkin teaches that X12X13 is selected from: (a) NN bind guanine (G); (b) NI bind adenine (A); (c) NG to bind thymine (T); and (d) HD to bind cytosine (C) (paras 0016; 0159-0160). Orkin further teaches SEQ ID NO: 35 with 100% sequence identity to Applicant’s SEQ ID NO: 180 present in the BCL11A gene promoter (see below; Example 2).
(Qy: Applicant’s SEQ ID NO: 180)
Qy 1 TGCTTTTATCACAGGCT 17
|||||||||||||||||
Db 21 TGCTTTTATCACAGGCT 5
(Db: Orkin’s SEQ ID NO: 35)
However, Orkin does not specifically teach that the number of repeat units of X1-11X12X13X14-33, 34, or 35 (Applicant’s SEQ ID NO: 4) is 16 and that the last RU at the C-terminus is a half-repeat comprising the amino acid sequence X1-11X12X13X14-19, 20, or 21; Applicant’s SEQ ID NO: 5.
Gregory’s disclosure is directed to novel TALE DNA-binding domains and methods of using these novel DNA-binding domains for modulation of gene expression and/or genomic editing of endogenous cellular sequences (entire document; paras 0247). Gregory teaches delivering polynucleotides encoding the TALE proteins to animal cells, plant cells, bacterial cells and other cells (paras 019).
Regarding claim 134, Gregory teaches that multi TALE repeat modules and TALE proteins comprising 16 full repeats and that there is a half repeat at the C-terminus (paras 0092; 0131-0134; 0142-0144; Example 1). Gregory teaches that TALE-repeat domains can be “engineered” to bind to a predetermined nucleotide sequence, for example via engineering (altering one or more amino acids) of the hypervariable diresidue region with atypical RVDs to improve specification (para 0127-0128).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have optimized Orkin’s nucleic acids encoding TALE proteins to bind to the BCL11A gene promoter by with different designs, such as 16.5 repeat units, as described by Gregory. Orkin teaches that the specificity of TAL effectors depends of the sequences found in the tandem repeats and that DNA binding repeats have been assembled into proteins with new combinations and numbers of repeats, to make artificial transcription factors that are able to interact with new sequences and modulate expression (para 0160). Gregory teaches that TALE-repeat domains can be “engineered” to bind to a predetermined nucleotide sequence, for example via engineering (altering one or more amino acids) of the hypervariable diresidue region with atypical RVDs to improve specification (para 0127). One would have been motivated to optimize the specificity of binding to the BCL11A gene promoter to optimize the gene expression modulation. One would have had a reasonable expectation of success because Orkin and Gregory are directed to using TALE DNA-binding proteins to modulate gene expression in cells.
Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 136, Gregory teaches SEQ ID NOs: 2 and 3-6 (Table 1), SEQ ID NO: 44 (Table 3), and SEQ ID NOs: 365 and 366 (Table 8) having 100% sequence identity to X1-11 of Applicant’s SEQ ID NO: 6 (LTPEQVVAIA S). Gregory further teaches SEQ ID NOs: 3, 9-15, 17-19 and 24 (Table 1), SEQ ID NOs: 44 and 45 (Table 3), and SEQ ID NOs: 333-337 and 339-340 (Table 8) having 100% sequence identity to X1-11 of Applicant’s SEQ ID NO: 11 (LTPDQVVAIA S).
Regarding claim 137, Gregory teaches SEQ ID NOs: 12-16, 17-21, and 23 (Table 1), SEQ ID NO: 45 (Table 3), and SEQ ID NOs: 333 and 338 (Table 8) having 100% sequence identity to the chain of 20, 21, or 22 continuous amino acids of Applicant’s SEQ ID NO: 15 (GGKQALETVQRLLPVLCQDHG).
Regarding claim 138, Gregory teaches SEQ ID NOs: 365 and 366 (Table 8), SEQ ID NOs: 69-70 (Table 12), SEQ ID NO: 218 (Example 14), and SEQ ID NO: 220 (Table 23) ) having 100% sequence identity to the chain of 7, 8, or 9 continuous amino acids of Applicant’s SEQ ID NO: 7 (GGRPALE).
Regarding claim 139, Gregory teaches an N-terminus region before the first RU binding to T (para 0021).
Regarding claim 140, Gregory teaches SEQ ID NO: 363 with 100% sequence identity to Applicant’s SEQ ID NO: 150 (see below).
(Qy: Applicant’s SEQ ID NO: 150)
Qy 1 MVDLRTLGYSQQQQEKIKPKVRSTVAQHHEALVGHGFTHAHIVALSQHPAALGTVAVKYQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MVDLRTLGYSQQQQEKIKPKVRSTVAQHHEALVGHGFTHAHIVALSQHPAALGTVAVKYQ 60
Qy 61 DMIAALPEATHEAIVGVGKQWSGARALEALLTVAGELRGPPLQLDTGQLLKIAKRGGVTA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DMIAALPEATHEAIVGVGKQWSGARALEALLTVAGELRGPPLQLDTGQLLKIAKRGGVTA 120
Qy 121 VEAVHAWRNALTGA 134
||||||||||||||
Db 121 VEAVHAWRNALTGA 134
(DB: Gregory’s SEQ ID NO: 363)
Regarding claim 141, Orkin teaches the nucleic acid operably linked to a promoter sequence for expression of the DBP (paras 0031, 0036, 0198; claim 33).
Regarding claim 142, Orkin teaches the sequence of the nucleic acid is codon optimized for expression of the DBP in a human cell (para 0018, 0127, and 0318).
Regarding claims 143-144, Orkin teaches that the nucleic acid can be RNA or DNA (paras 0023, 0142, 0213).
Regarding claim 145-147, Orkin teaches vectors comprising the nucleic acid encoding the DBPs and the vectors can be lentiviral vectors (paras 0031-0032; 0196).
Regarding claims 148 and 149, Orkin teaches ex vivo delivery of donor nucleic acids to human stem cell or precursor cell (HSC/PC) cells isolated from human bone marrow or human umbilical cords, thus teaching human cells comprising the nucleic acids encoding DBPs (paras 0029-0030; 0183). Orkin teaches that the cells can be erythroid progenitor cells, induced pluripotent stem cells, hematopoietic stem cells (paras 0106, 0214).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 135 is rejected under 35 U.S.C. 103 as being unpatentable over Orkin et al. (US20150132269A1; published 5/14/2015), in view of Gregory et al. (US20190169640A1; published 6/6/2019) as applied to claims 134 and 136-149 above, and further in view of Cong (Comprehensive interrogation of natural TALE DNA-binding modules and transcriptional repressor domains. Nat Commun 3, 968; published 7/24/2012).
The teachings of Orkin and Gregory are applied to claim 135 as they have been applied to claims 134 and 136-149 in the 103 rejection above. Orkin teaches that the specificity of TAL effectors depends of the sequences found in the tandem repeats and that DNA binding repeats have been assembled into proteins with new combinations and numbers of repeats, to make artificial transcription factors that are able to interact with new sequences and modulate expression (para 0160). Gregory teaches that TALE-repeat domains can be “engineered” to bind to a predetermined nucleotide sequence, for example via engineering (altering one or more amino acids) of the hypervariable diresidue region with atypical RVDs to improve specification (para 0127-0128).
However, Orkin and Gregory do not specifically teach that that NH is for binding to G in the X12X13 in the RUs from N-terminus to C-terminus are NG, NH, HD, NG, NG, NG, NG, NI, NG, HD, NI, HD, NI, NH, NH, HD, and NG.
Cong’s disclosure is directed to compositions and methods of using TALE DNA-binding modules and transcriptional repressor domains to improve the precision and effectiveness of genome engineering and modulate expression (entire document).
Regarding claim 135, Cong teaches that the naturally occurring repeat-variable diresidue Asn-His (NH) has high biological activity and specificity for guanine, a highly prevalent base in mammalian genomes (abstract; entire document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Orkin and Gregory’s TAL effector DNA binding proteins with the RVD of NH to achieve guanine-specific recognition as described by Cong because it would have amounted to a simple substitution of known RVDs to obtain predictable results. Orkin and Gregory teach improving specification of the DNA binding proteins (see above). One would have been motivated to further improve the specificity of by substituting NK or NN with NH to bind to G. One would have had a reasonable expectation of success because Orkin, Gregory, and Cong are directed to improving TAL effector DNA binding proteins to modulate gene expression.
Thus, the claimed invention as a whole is prima facie obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 9:30am-6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KHALEDA B HASAN/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
