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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/30/2025 has been entered.
Election/Restrictions
Claims 1-23 are pending and claims 1-5, 17-20, and new claims 21-23 are examined here.
As noted in earlier action, the elected species previously designated as “45723” and now claimed as “b) F1 comprising SEQ ID NO: 7, F2 comprising SEQ ID NO: 8, F3 comprising SEQ ID NO: 9, and F4 comprising SEQ ID NO: 3” had been searched and found free of the art, and the Examiner selected further species for search and examination in accordance with MPEP 803.02(C)(2). Here, the ZFP, previously designated as “45294,” and now claimed as “a) F1 comprising SEQ ID NO: 4, F2 comprising SEQ ID NO: 1, F3 comprising SEQ ID NO: 4, F4 comprising SEQ ID NO: 1, and F5 comprising SEQ ID NO: 1” in claim 1 has been rejoined for search and examination. Also the limitation of claim 1a) and 1b) and its corresponding compound numbers “45294” and “45723”, respectively, are disclosed in the specification and are used interchangeably.
Claims 6-16 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim.
Priority
The benefit of U.S. provisional application 62/792701, filed on 01/15/2019, via its PCT/US2020/013661, filed on 01/15/2020, is acknowledged. Claims 1-5, 17-23 enjoy the benefit of ‘701, filed on 01/15/2019.
Claim Objections
Claims 21, 22, 23 are objected to because of the following informalities: the claims recite “comprising of” (line 1 of cl. 21-23) instead of “comprising.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
Rejection of claims 18-20 under 112(b) is withdrawn: the amendment of cl. 18 overcomes the lack of antecedent basis rejection.
Claim Rejections - 35 USC § 103
Rejection of claims 1-5, 17-20 is maintained, while new claims 21-22 are rejected as noted below.
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 1-5, 21, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Froelich (WO2017053753, pub. 03/30/2017, shares joint co-inventors, but is outside the grace period one-year exception, in IDS) and Isalan (WO2017077329, pub. 05/11/2017, in IDS), Beerli (2002, Nat. Biotech., 20, 135-141) and Zhang (WO2015070212, pub. 05/14/2015, in 02/15/2024 IDS).
ZFP and ZFP-TF are understood as two different genera of molecules. ZFP refers to zinc finger proteins which can be just DNA binding domains without any effector domains (par. 10), while ZFP-transcription factors (ZFP-TF) are artificial transcription factors comprising ZFPs operably linked to a transcriptional repression domain (e.g. KRAB, KOX, etc.) (par. 13).
Froelich discloses HTT-targeted 5 “fingered” zinc finger proteins (ZFP): ZFP designated 46025 comprising a SEQ ID NO: 4 with the amino acid (a.a.) domain comprising CPSHLTR for F1 and a SEQ ID NO: 1 with the amino acid domain comprising QSGDLTR for F2 and another ZFP designated 45643 comprising SEQ ID NO: 1 with a.a. domain QSGDLTR for F1, F2, F3, see below Table 1 (par. 82).
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Froelich discloses dose-dependent repression of mut-HTT (mHTT) having 45 CAG repeats in fibroblast cells derived from HD patients and treated with ZFP 46025 or ZFP 45643, while expression of the wild-type HTT (wtHTT) which has 18 CAG repeats was maintained fairly constant (see Fig. 8, pg. 1, par. 42; also see Fig. 13A-13C for repression in vivo in mouse model carrying knock-in allele of human Htt gene with 48 CAGs and treated with AAV9 vector encoding ZFP 46025 and ZFP 45643, par. 47). The repressor of the mutant Htt allele may be a ZFP-TF, for example, a fusion protein comprising a ZFP that binds specifically to a mutant Htt allele and has a transcriptional repression domain (e.g. KOX, KRAB, etc.) (par. 26, relevant to instant cl. 1). Froelich discloses a nucleotide sequence encoding a peptide of SEQ ID NO: 4 and SEQ ID NO: 1 (par. 16; relevant to instant cl. 2); discloses utilizing rAAV vectors for efficient and stable gene delivery due to integration into the genomes of the transduced cell (par. 138, par. 162 – discloses that ZFP-TFs are functional repressors when formulated as plasmids or an AAV vector; provides examples with the use of rAAV vector in rhesus monkey model (par. 163); relevant to instant cl. 3); discloses a pharmaceutical composition comprising one or more polynucleotides of zinc finger proteins in claim 7 (see also par. 16; relevant to instant cl. 5); discloses that ZFPs that bind to mutant poly-nucleotide repeat sites (CAG nt.) and frameshift mutation can alter the repeat sequence and the encoded protein/a.a. (par. 4).
Froelich does not disclose a ZFP comprising recognition helix regions comprising in the following order of SEQ ID NO: 4 (CPSHLTR), 1 (QSGDLTR), SEQ ID NO: 4, SEQ ID NO: 1, SEQ ID NO: 1 (cl. 1) and does not disclose an NLS (cl. 4).
Isalan discloses “designer transcription factors” noting characteristics to improve DNA binding and targeting specific sequences (pg. 28, line 29 to pg. 29-line 3); discloses various domain variations of SEQ ID NO: 1 (QSa/gDl/rt/kR:
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), including SEQ ID NO: 3, the QSGDLTR domain, that can be combined with other a.a. domains (pg. 32, line 32-pg. 33, line 3). Isalan discloses that the QSGDLTR domain (SEQ ID NO: 3) is a zinc-finger peptide domain designed to target double-stranded trinucleotide repeat nucleic acid sequences (pg. 33, line 1-10) comprising CAG-repeats encoding polyglutamine (polyQ) tracts, which are associated with various tri-nucleotide repeat diseases (pg. 3, line 15), thus suggesting the ability to switch DNA-binding domains within a ZFP. In fact, Isalan taught that “it will be understood that one or more recognition sequence of SEQ ID NO: 3 [QSGDLTR] may be replaced with SEQ ID NO: 4 [QSGDRKR]” pg. 33, line 19-20). (Isalan also discloses that SEQ ID NO: 2 (QSADLTR) may be replaced with the sequence of SEQ ID NO: 5 (QSADRKR), pg. 33.) Isalan taught that the CAG repeat (5’-CAGCAGCAGCAGCAG-3’) comprises AGC, CAG, and GCA repeats, thus regardless if a zinc finger domain binds to a CAG or GCA or AGC repeat, it is binding within the same sequence and would perform the same function of binding to the CAG trinucleotide repeat region (see pg. 22, lines 5-9). Isalan also disclosed incorporating a nuclear localization signal (NLS) to direct the protein into the nucleus (pg. 43, relevant to instant cl. 4).
Regarding the interchangeability of DNA binding domains (regarding instant cl. 1, 22), several references disclose the ability to switch DNA binding domains, i.e. the ZFPs. Beerli (2002, Nat. Biotech., 20, 135-141) in their review article of engineering polydactyl zinc-finger transcription factors, which contain at least two functional domains, a DNA-binding domain and an effector domain, including ZFP and repressor or activator domains, respectively (pg. 135); disclose that various strategies can be used to study the zinc-finger DNA-binding domains, and theirs is focused on the development and use of the parallel selection strategy of ZFPs, which requires a basic assumption that “zinc-finger domains are functionally independent and can therefore be recombined with one another in any desired sequence” and also note that the parallel selection approach is validated (pg. 136, 137). Further, assignee’s own publication of Zhang (WO2015070212, pub. 05/14/2015) discloses that “[w]hen designing zinc finger proteins to recognize the CAG region, a set of one- and two-finger modules can be employed in a ‘mix and match’ combinations. Those modules are shown below in Table 2C” (par. 187, Table 2C provides a list of various zinc finger modules/recognition helices used in ZFP-TF targeting CAG sequence, one module is QSGDLTR).
Further based on the results of Froelich noted above, where the QSGDLTR motif in ZFP 45643 is at the first three finger positions (i.e. F1, F2 and F3), and ZFP 46025 with both CPSHLTR (instant SEQ ID NO: 4) and QSGDLTR (instant SEQ ID NO: 1) at F1 and F2 positions, respectively, and regardless of the position of the ZFP domain, the ZFP-TF comprising QSGDLTR and CPSHLTR are still able to repress the expression mHTT with CAG repeats. Thus, confirming that the ZFP domains can be interchangeable, i.e. one can mix and match the ZFP domains, to bind to CAG repeats.
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Froelich discloses Huntington’s Disease, a trinucleotide repeat expansion disorder that encodes a miscoded huntingtin (Htt) protein, as a recognized problem. Froelich demonstrate a couple of ZFP-TFs, with the ZFP comprising five “finger” recognition helix region (i.e. domains) that bind to trinucleotide-repeats and suppress their expression. Based on identification of compounds “45643” and “46025,” each comprising five-domains that like fingers interact with gene regions with excess of trinucleotide repeats and the knowledge that the domains can be mixed and matched, a skilled artisan could have substituted the finite number of domains of “45643” and/or “46025” that demonstrated suppression of expression of expanded trinucleotide repeat genes, such as Htt.
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the placement of finger-domains of ZFP-TFs “45643” or “46025” of Froelich in view of Isalan, Beerli and Zhang and arrive at the claimed invention with a reasonable expectation of success. Based on identification of compounds “45643” and “46025,” each comprising five-domains that like fingers interact with and suppress the expression of gene regions with excess of trinucleotide repeats of Froelich and the knowledge that the domains can be mixed and matched of Isalan, Beerli and Zhang, a skilled artisan could have substituted the finite number of domains of “45643” and/or “46025” (SEQ ID NOs 1-5) to design a ZFP(s) with five-finger domains that binds to and suppresses the expression of expanded trinucleotide repeat genes, such as Htt. Thus, claims 1-5, 22 are obvious.
Regarding instant cl. 21, the limitation reads in part, “(ZFP) comprising of . . . a) F1 consisting of SEQ ID NO: 4, F2 consisting of SEQ ID NO: 1.” The use of “consisting of” language, although interpreted as closed language, requires specifically the nucleotide sequence of SEQ ID NO: 4 or 1. However, MPEP 2111.03(II) indicates that when the phrase “consisting of” is used in the body of the claims, the phrase did not limit the open-ended ‘comprising’ language in the claims:
See also In re Crish, 393 F.3d 1253, 73 USPQ2d 1364 (Fed. Cir. 2004) (The claims at issue "related to purified DNA molecules having promoter activity for the human involucrin gene (hINV)." Id., 73 USPQ2d at 1365. In determining the scope of applicant’s claims directed to "a purified oligonucleotide comprising at least a portion of the nucleotide sequence of SEQ ID NO:1 wherein said portion consists of the nucleotide sequence from … to 2473 of SEQ ID NO:1, and wherein said portion of the nucleotide sequence of SEQ ID NO:1 has promoter activity," the court stated that the use of "consists" in the body of the claims did not limit the open-ended "comprising" language in the claims (emphases added).
Thus, here, Froelich discloses specifically SEQ ID NO: 4 and SEQ ID NO: 1, thus the limitation is met, and thus the claim is obvious.
Claims 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Froelich (WO2017053753, pub. 03/30/2017, shares joint co-inventors, but is outside the grace period one-year exception, in IDS) and Isalan (WO2017077329, pub. 05/11/2017, in IDS), Beerli (2002, Nat. Biotech., 20, 135-141) and Zhang (WO2015070212, pub. 05/14/2015, in 02/15/2024 IDS) as applied to claims 1-5, 21-22 above, and further in view of Froelich et al. (US20190322711, pub. 10/24/2019, referred as ‘711).
The applied reference of ‘711 has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a 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 thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The disclosure applying to rejection of claims 1-5 is noted above.
Froelich, Isalan, Beerli and Zhang do not disclose SEQ ID NO: 20.
‘711 discloses an amino acid sequence of ZFP-TF, a SEQ ID NO: 64, claim 1 (see alignment below). Claim 1 discloses a few of the ZFP-TFs (SEQ ID NO: 64-67) and as indicated by the results, each will bind to Htt gene with poly-CAG trinucleotide repeats (see Fig. 1D, 1G). SEQ ID NO: 64 is designated as ZFP-A, for which the results demonstrate its ability to inhibit the expression of Htt gene with a high-number of CAG-repeats but not for the wild-type number of CAG-repeats (see Fig. 1D). ‘711 discloses that the ZF domains and/or multi-fingered ZFPs may be linked together using any suitable linker sequences and notes that “the proteins described herein may include any combination of suitable linkers between the individual zinc fingers of the protein” (par. 93). The results demonstrate that ZFP-TF linker sequence of SEQ ID NOs: 64-67 (cl. 1) does not disrupt the activity of its DNA binding ZF-domains.
Alignment between Instant SEQ ID NO: 20(Qy) and ‘711 SEQ ID NO: 64(Db)
Qy 1 MAPKKKRKVGIHGVPAAMAERPFQCRICMRNFSCPSHLTRHIRTHTGEKPFACDICGRKF 60
||||||||||||||||||||||||||||||||| | |:|||||||||||||||||||||
Db 1 MAPKKKRKVGIHGVPAAMAERPFQCRICMRNFSQSSDLSRHIRTHTGEKPFACDICGRKF 60
Qy 61 AQSGDLTRHTKIHTG-EKPFQCRICMRNFSCPSHLTRHIRTHTGEKPFACDICGRKFAQS 119
|| |||||||| :||||||||||||| | |:|||||||||||||||||||||||
Db 61 AQWSTRKRHTKIHTGSQKPFQCRICMRNFSQSSDLSRHIRTHTGEKPFACDICGRKFAQW 120
Qy 120 GDLTRHTKIHTGSQKPFQCRICMRKFAQSGDLTRHTKIHLRQKDAARGSGMDAKSLTAWS 179
|||||||| :||||||||||||||||||||||||||||||||||||||||||||||
Db 121 STRKRHTKIHTG-EKPFQCRICMRKFAQSGDLTRHTKIHLRQKDAARGSGMDAKSLTAWS 179
Qy 180 RTLVTFKDVFVDFTREEWKLLDTAQQIVYRNVMLENYKNLVSLGYQLTKPDVILRLEKGE 239
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Db 180 RTLVTFKDVFVDFTREEWKLLDTAQQIVYRNVMLENYKNLVSLGYQLTKPDVILRLEKGE 239
Qy 240 EPWLVEREIHQETHPDSETAFEIKSSV 266
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Db 240 EPWLVEREIHQETHPDSETAFEIKSSV 266
The differences are underlined. Thus, the majority of the differences are for the ZF domains, which are underlined and bolded, along with a couple of two amino acids (a.a.) alterations (see underline/italicized sequence only). Thus, the instant ZFP-TF, i.e. instant SEQ ID NO: 20, substituted different and interchangeable ZF domains at the location of ‘711’s ZF domains.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified placements of ZF domains of SEQ ID NO: 4 (CPSHLTR) and SEQ ID NO: 1(QSGDLTR) of Froelich in view of Isalan, Beerli and Zhang and ‘711 and arrive at the claimed invention with a reasonable expectation of success. Since Froelich discloses that ZFP-TF with the ZF domains CPSHLTR and QSGDLTR are functional in repressing expression of mutated levels of CAG repeats, and Isalan/Beerli/Zhang disclose that ZF domains can be mixed and matched, and ‘711 discloses the linker sequences where ZF domains can be incorporated for functional protein expression, the substitution of Froelich’s CPSHLTR and QSGDLTR ZF domains in the ZF domain locations in SEQ ID NOs: 64-67 amino acid sequence of ‘711 will successfully result in, at least, binding to poly-CAG repeats and the linker sequence will not disrupt the ZF DNA-binding domains. Thus, claim 17 is obvious.
Regarding instant cl. 18, instant SEQ ID NO: 15 is not disclosed in ‘711, neither are the nucleotide sequences encoding the amino acid sequences of SEQ ID NO: 64-67 are disclosed in ‘711. However, a skilled artisan based on a protein sequence of SEQ ID NOs 64-67 of ‘711 can reverse engineer either a DNA/RNA nucleotide sequence (the site: bioinformatics.org/sms2/rev_trans.html also helps in converting protein sequence to DNA nucleotide sequence). Thus, claim 18 is obvious.
Regarding instant cl. 19 and 20, Froelich discloses utilizing rAAV vectors for efficient and stable gene delivery due to integration into the genomes of the transduced cell (par. 138, par. 162 – discloses that ZFP-TFs are functional repressors when formulated as plasmids or an AAV vector; provides examples with the use of rAAV vector in rhesus monkey model (par. 163); relevant to instant cl. 19); and discloses a pharmaceutical composition comprising one or more polynucleotides of zinc finger proteins in claim 7 (see also par. 16; relevant to instant cl. 20).
Response to Arguments
Applicant's arguments filed 07/30/2025 (“the Remarks”), which repeat the arguments noted in the Remarks of 02/28/2025, have been fully considered but they are not persuasive. The arguments specifically focus on the ordered sequence of 45294: “skilled artisan is left with the insurmountable task of selecting specific sequences for DNA binding domains that are capable of mHTT binding and then evaluating each combination of sequences for mHTT binding and expression activity” and this would require “an unreasonable amount of undue experimentation” (pg. 7-8). Thus the Remarks suggest that the specific ZNF-TF cited were cherry-picked by an improper hindsight driven obviousness rejection (pg. 8).
This argument is not persuasive.
Amended claimed invention provides that the F1 to F5 are ordered in the following manner: SEQ ID NOs: 4, 1, 4, 1, 1 for compound “45294”. Here, as noted in the obvious to try rationale, it would be obvious to try to substitute one of the helix-regions (i.e. domains or motifs) with another to improve the functionality of the ZFPs based on the finite number of helix-region domains (SEQ ID NOs 1-5) demonstrated by Froelich in view of Beerli, Isalan, and Zhang, each teaching the ability to mix and match the helix-region domains of ZFP to bind to the trinucleotide repeats. Compound “45643” of Froelich has SEQ ID NO: 1 (QSGDLTR) at F1, F2 and F3, while 46025 has SEQ ID NO: 4 and 1 at positions F1 and F2, respectively. Froelich’s 46025 has a ZFP-TF with only one SEQ ID NO: 1 at position at F2 and demonstrates effective binding. Similarly, Froelich’s 45643 has SEQ ID NO: 1 at positions F1, F2, F3 and also demonstrates effective binding. It should be noted that other helix regions of ZFP-TF are also switched between 46025 and 45643 of Froelich, e.g. SEQ ID NO: 2 (KHGNLSE) is at position F4 in 45643, while at position F3 in 46025. This strongly suggests that a skilled artisan would reasonably expect success in mixing and matching the helix regions (i.e. domains or motifs) of 46025 and 45643.
Further the observation noted in the Remarks (“the claimed ZFP-TFs repress transcription of the mHTT allele . . in HD patient allele”, pg. 7) is also observed in Froelich and other references cited.
Regarding the narrower scope, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, Froelich discloses the relevant SEQ ID NOs that are functional as ZFPs before applicant’s disclosure and the Remarks fail to provide evidence that the claimed invention that was “cherry picked” and chosen is meaningfully different than the other ZFP-TFs comprising different finger domains that are used to bind to tri-nucleotide CAG sequence. A skilled artisan appreciates that the binding affinity maybe different, but based on Froelich’s examples of functionality at different positions, the finger domains would be functional even if they are re-arranged. Ultimately, the invention is neither novel nor non-obvious since the claimed elements are known in the art and used for the same purpose as the present invention.
Thus the rejection is maintained.
Double Patenting
The rejection of claims 1-5, 17-20 are maintained, while new claims 21-22 are rejected as noted below.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 10435441
Claims 1, 2, 3, 4, 5, 21, 22 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 5 of U.S. Patent No. 10435441 to Froelich (issued 10/08/2019, referred as Sangamo) in view of Isalan (WO2017077329, pub. 05/11/2017, in IDS).
Sangamo’s claims are copied below:
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Sangamo’s claim 1 teaches zinc finger proteins 45643 and 456025, the 45643 comprising 5 zinc finger domains ordered F1 to F5 comprising from N to C terminal, three domains of F1, F2 and F3, each comprising a QSGDLTR domain, while F1 and F2 domains of 46025 comprises a CPSHLTR domain and a QSGDLTR domain, respectively. Sangamo cl. 2 corresponds with instant cl. 2; Sangamo claim 3 corresponds with instant cl. 3. Sangamo cl. 5 corresponds with instant cl. 5.
Sangamo does not teach a ZFP comprising recognition helix regions comprising in the following order of SEQ ID NO: 4 (CPSHLTR), 1 (QSGDLTR), SEQ ID NO: 4, SEQ ID NO: 1, SEQ ID NO: 1 (cl. 1) and does not disclose an NLS (cl. 4).
Isalan discloses “designer transcription factors” noting characteristics to improve DNA binding and targeting specific sequences (pg. 28, line 29 to pg. 29-line 3); discloses various domain variations of SEQ ID NO: 1 (QSa/gDl/rt/kR:
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), including SEQ ID NO: 3, the QSGDLTR domain, that can be combined with other a.a. domains (pg. 33, line 3), discloses the QSGDLTR domain (SEQ ID NO: 3), a zinc-finger peptide domain to target double-stranded trinucleotide repeat nucleic acid sequences (pg. 33, line 1-10) comprising CAG-repeats of polyglutamine (polyQ) tracts associated diseases (pg. 3, line 15); thus suggesting ability to switch recognition domains within a ZFP, “it will be understood that one or more recognition sequence of SEQ ID NO: 3 may be replaced with SEQ ID NO: 4” (pg. 33, line 19-20).
Isalan discloses “designer transcription factors” noting characteristics to improve DNA binding and targeting specific sequences (pg. 28, line 29 to pg. 29-line 3); discloses various domain variations of SEQ ID NO: 1 (QSa/gDl/rt/kR:
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), including SEQ ID NO: 3, the QSGDLTR domain, that can be combined with other a.a. domains (pg. 33, line 3). Isalan discloses that the QSGDLTR domain (SEQ ID NO: 3) is a zinc-finger peptide domain designed to target double-stranded trinucleotide repeat nucleic acid sequences (pg. 33, line 1-10) comprising CAG-repeats of polyglutamine (polyQ) tracts associated diseases (pg. 3, line 15), thus suggesting ability to switch recognition domains within a ZFP. In fact, Isalan taught that “it will be understood that one or more recognition sequence of SEQ ID NO: 3 may be replaced with SEQ ID NO: 4” (pg. 33, line 19-20). Isalan taught that the CAG repeat (5’-CAGCAGCAGCAGCAG-3’) comprises AGC, CAG, and GCA repeats, thus regardless if a zinc finger domain binds to a CAG or GCA or AGC repeat, it is binding within the same sequence and would perform the same function of binding to the CAG trinucleotide repeat region (see pg. 22, lines 5-9). Isalan also disclose incorporating nuclear localization signal (NLS) to direct the protein into the nucleus (pg. 43, relevant to instant cl. 4).
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Sangamo teaches treating Huntington’s Disease, a trinucleotide repeat expansion disorder that encodes a miscoded huntingtin (Htt) protein. Sangamo teaches a couple of ZFP-TFs, with the ZFP comprising five “finger” recognition helix region (i.e. domains) that bind to trinucleotide-repeats and suppress their expression. Based on identification of compounds “SBS#45643” and ““SBS#46025,” each comprising five-domains that like fingers interact with gene regions with excess of trinucleotide repeats and the knowledge that the domains can be mixed and matched, a skilled artisan could have substituted the finite number of domains of “SBS#45643” and/or “SBS#46025.”
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the placement of finger-domains of ZFP-TFs “SBS#45643” or “SBS#46025” of Sangamo in view of Isalan and arrive at the claimed invention with a reasonable expectation of success. Based on the five-finger compounds “SBS#45643” and “SBS#46025” each comprising five-domains that like fingers interact with and suppress the expression of gene regions with excess of trinucleotide repeats of Sangamo and the knowledge that the domains can be mixed and matched of Isalan a skilled artisan could have substituted the finite number of domains of “SBS#45643” and/or “SBS#46025,” (SEQ ID NOs 1-5) to design a ZFP(s) with five-finger domains that binds to and suppresses the expression of expanded trinucleotide repeat genes, such as Htt. Thus, claims 1-5, 21-22 are obvious.
U.S. Patent No. 11,123,443 (referred as Sangamo ‘443)
Claims 1-5, 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3 of U.S. Patent No. 11,123,443 (issued 09/21/2021, referred as Sangamo ‘443) in view of Isalan (WO2017077329, pub. 05/11/2017, in IDS).
Sangamo ‘443 claim 1 is copied below.
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Sangamo ‘443 claim 1 teaches a ZFP designated as 46025 comprising 5 zinc finger domains with F1 is CPSHLTR domain and F2 is QSGDLTR domain and the 45643 comprising 5 zinc finger domains ordered F1 to F5 comprising from N to C terminal, three domains of F1, F2 and F3, each comprising a QSGDLTR domain. Sangamo ‘443 cl. 2 and cl. 3 corresponds with instant cl. 2 and cl. 3.
Sangamo ‘443 does not teach a ZFP comprising recognition helix regions comprising in the following order of SEQ ID NO: 4 (CPSHLTR), SEQ ID NO: 1 (QSGDLTR), SEQ ID NO: 4, SEQ ID NO: 1, SEQ ID NO: 1 (cl. 1) and does not disclose the NLS.
Isalan discloses “designer transcription factors” noting characteristics to improve DNA binding and targeting specific sequences (pg. 28, line 29 to pg. 29-line 3); discloses various domain variations of SEQ ID NO: 1 (QSa/gDl/rt/kR:
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), including SEQ ID NO: 3, the QSGDLTR domain, that can be combined with other a.a. domains (pg. 33, line 3), discloses the QSGDLTR domain (SEQ ID NO: 3), a zinc-finger peptide domain to target double-stranded trinucleotide repeat nucleic acid sequences (pg. 33, line 1-10) comprising CAG-repeats of polyglutamine (polyQ) tracts associated diseases (pg. 3, line 15); thus suggesting ability to switch recognition domains within a ZFP, “it will be understood that one or more recognition sequence of SEQ ID NO: 3 may be replaced with SEQ ID NO: 4” (pg. 33, line 19-20). Isalan also disclose incorporating nuclear localization signal (NLS) to direct the protein into the nucleus (pg. 43, relevant to instant cl. 4); discloses pharmaceutical composition comprising nucleic acid molecules (including vectors) as a therapeutic agent, pg. 10, line 28; relevant to instant cl. 5).
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Sangamo ‘443 teaches treating Huntington’s Disease, a trinucleotide repeat expansion disorder that encodes a miscoded huntingtin (Htt) protein. Sangamo ‘443 teaches a couple of ZFP-TFs, with the ZFP comprising five “finger” recognition helix region (i.e. domains) that bind to trinucleotide-repeats and suppress their expression. Based on identification of compounds “SBS#45643” and ““SBS#46025,” each comprising five-domains that like fingers interact with gene regions with excess of trinucleotide repeats and the knowledge that the domains can be mixed and matched, a skilled artisan could have substituted the finite number of domains of “SBS#45643” and/or “SBS#46025.”
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the placement of finger-domains of ZFP-TFs “SBS#45643” or “SBS#46025” of Sangamo ‘443 in view of Isalan and arrive at the claimed invention with a reasonable expectation of success. Based on the five-finger compounds “SBS#45643” and “SBS#46025” each comprising five-domains of Sangamo ‘443 and the knowledge that the domains can be mixed and matched of Isalan a skilled artisan could have substituted the finite number of domains of “SBS#45643” and/or “SBS#46025,” (SEQ ID NOs 1-5) to design a ZFP(s) with five-finger domains that binds to and suppresses the expression of expanded trinucleotide repeat genes, such as Htt. Thus, claims 1-5, 21-22 are obvious.
US Pat. 11421007
Claims 1-5, 17-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 5 of U.S. Patent No. 11,421,007 (issued 08/23/20233, referred as ‘007) in view of Froelich (WO2017053753, pub. 03/30/2017, shares joint co-inventors, but is outside the grace period one-year exception, in IDS) and Isalan (WO2017077329, pub. 05/11/2017, in IDS), Beerli (2002, Nat. Biotech., 20, 135-141) and Zhang (WO2015070212, pub. 05/14/2015, in 02/15/2024 IDS).
Claims 1-13 of ‘007 are copied below:
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‘007 claim 1 discloses the amino acid sequences of SEQ ID NO: 64-67. E.g. SEQ ID NO: 64 discloses ZF domains and linker sequences (see alignment on pg. 10 above). SEQ ID NO: 65 and 67 each disclose a ZF domain: QSGDLTR (see underlined sequence above, relevant to instant cl. 1 and 17, 22). A patent’s claimed product is presumed to be enabled. ‘007 claim 2 corresponds to instant claims 2 and 18; claim 4 corresponds to instant cl. 3 and 19; each SEQ ID NO: 64-67 comprises a nuclear localization signal: PKKKRKV, as evidenced by Isalan (pg. 37, line 27-30), corresponding to instant cl. 4; ‘007 claim 6 corresponds to instant cl. 5 and 20.
‘007 claims do not disclose CPSHLTR.
Froelich discloses HTT-targeted 5 “fingered” zinc finger proteins (ZFP): ZFP designated 46025 comprising a SEQ ID NO: 4 with the amino acid (a.a.) domain comprising CPSHLTR for F1 and a SEQ ID NO: 1 with the amino acid domain comprising QSGDLTR for F2 and another ZFP designated 45643 comprising SEQ ID NO: 1 with a.a. domain QSGDLTR for F1, F2, F3, see Table 1 above (par. 82, relevant to instant cl. 1). Froelich discloses dose-dependent repression of mut-HTT (mHTT) having 45 CAG repeats in fibroblast cells derived from HD patients and treated with ZFP 46025 or ZFP 45643, while expression of the wild-type HTT (wtHTT) which has 18 CAG repeats was maintained fairly constant (see Fig. 8, pg. 1, par. 42; also see Fig. 13A-13C for repression in vivo in mouse model carrying knock-in allele of human Htt gene with 48 CAGs and treated with AAV9 vector encoding ZFP 46025 and ZFP 45643, par. 47).
Isalan discloses “designer transcription factors” noting characteristics to improve DNA binding and targeting specific sequences (pg. 28, line 29 to pg. 29-line 3); discloses various domain variations of SEQ ID NO: 1 (QSa/gDl/rt/kR:
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), including SEQ ID NO: 3, the QSGDLTR domain, that can be combined with other a.a. domains (pg. 33, line 3). Isalan discloses that the QSGDLTR domain (SEQ ID NO: 3) is a zinc-finger peptide domain designed to target double-stranded trinucleotide repeat nucleic acid sequences (pg. 33, line 1-10) comprising CAG-repeats of polyglutamine (polyQ) tracts associated diseases (pg. 3, line 15), thus suggesting the ability to switch recognition domains within a ZFP. In fact, Isalan taught that “it will be understood that one or more recognition sequence of SEQ ID NO: 3 may be replaced with SEQ ID NO: 4” (pg. 33, line 19-20). Isalan taught that the CAG repeat (5’-CAGCAGCAGCAGCAG-3’) comprises AGC, CAG, and GCA repeats, thus regardless if a zinc finger domain binds to a CAG or GCA or AGC repeat, it is binding within the same sequence and would perform the same function of binding to the CAG trinucleotide repeat region (see pg. 22, lines 5-9).
Regarding the interchangeability of DNA binding domains, several references disclose the ability to switch DNA binding domains, i.e. the ZFPs. Beerli (2002, Nat. Biotech., 20, 135-141) in their review article of engineering polydactyl zinc-finger transcription factors, which contain at least two functional domains, a DNA-binding domain and an effector domain, including ZFP and repressor or activator domains, respectively (pg. 135); disclose that various strategies can be used to study the zinc-finger DNA-binding domains, and theirs is focused on the development and use of the parallel selection strategy of ZFPs, which requires a basic assumption that “zinc-finger domains are functionally independent and can therefore be recombined with one another in any desired sequence” and also note that the parallel selection approach is validated (pg. 136, 137). Further, assignee’s own publication of Zhang (WO2015070212, pub. 05/14/2015) discloses that “[w]hen designing zinc finger proteins to recognize the CAG region, a set of one- and two-finger modules can be employed in a ‘mix and match’ combinations. Those modules are shown below in Table 2C” (par. 187, Table 2C provides a list of various zinc finger modules/recognition helices used in ZFP-TF targeting CAG sequence, one module is QSGDLTR).
Further based on the results of Froelich noted above, where the QSGDLTR motif in ZFP 45643 is at the first three finger positions (i.e. F1, F2 and F3), and ZFP 46025 with both CPSHLTR (instant SEQ ID NO: 4) and QSGDLTR (instant SEQ ID NO: 1) at F1 and F2 positions, respectively, and regardless of the position of the ZFP domain, the ZFP comprising QSGDLTR and CPSHLTR are still able to repress the expression mHTT with CAG repeats. Thus, confirming that the ZFP domains can be interchangeable, i.e. one can mix and match the ZFP domains, to bind to CAG repeats.
The KSR’s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
One of the KSR rationale that may be used to support a conclusion of obviousness is obvious to try. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have combined the elements of 5 zinc-finger binding domains of ‘007 in view of Froelich and Isalan and arrive at the claimed invention with a reasonable expectation of success. Because ‘007 discloses an enabled ZFP-TF, e.g. SEQ ID NO: 65 and 67 with QSGDLTR zinc-finger domain and Froelich discloses ZFP-TF 45643, containing 3 sequential SEQ ID NO: 1 (comprising QSGDLTR) and ZFP-TF 46025, comprising a single SEQ ID NO: 1 and SEQ ID NO: 4 (comprising CPSHLTR) that represses expression of Htt gene with poly-CAG trinucleotide sequence, a skilled artisan would have been motivated to replace the ZF domains of ZFP-TF (SEQ ID NOs: 64-67) of ‘007 with the zinc-finger DNA-binding domains, QSGDLTR and CPSHLTR, of Froelich in the process of optimizing binding to mHTT triplet expansion (i.e. CAG repeats). Replacing combination of Froelich’s SEQ ID NO: 4 and SEQ ID NO: 1 at various “finger” domain locations in ZFP-TF sequence of ‘007 would successfully result in binding to DNA containing CAG repeats. Thus, claims 1-5, 17, 19-20, 22 are obvious.
Regarding instant cl. 18, instant SEQ ID NO: 15 is not disclosed in ‘007. However, a skilled artisan based on a protein sequence of SEQ ID NOs: 64-67 of ‘007 can reverse engineer either a DNA/RNA nucleotide sequence (the site: bioinformatics.org/sms2/rev_trans.html also helps in converting protein sequence to DNA nucleotide sequence). Thus, claim 18 is obvious.
Regarding instant cl. 21, the limitation reads in part, “(ZFP) comprising of . . . a) F1 consisting of SEQ ID NO: 4, F2 consisting of SEQ ID NO: 1.” The use of “consisting of” language, although interpreted as closed language, requires specifically the nucleotide sequence of SEQ ID NO: 4 or 1. However, MPEP 2111.03(II) indicates that when the phrase “consisting of” is used in the body of the claims, the phrase did not limit the open-ended ‘comprising’ language in the claims:
See also In re Crish, 393 F.3d 1253, 73 USPQ2d 1364 (Fed. Cir. 2004) (The claims at issue "related to purified DNA molecules having promoter activity for the human involucrin gene (hINV)." Id., 73 USPQ2d at 1365. In determining the scope of applicant’s claims directed to "a purified oligonucleotide comprising at least a portion of the nucleotide sequence of SEQ ID NO:1 wherein said portion consists of the nucleotide sequence from … to 2473 of SEQ ID NO:1, and wherein said portion of the nucleotide sequence of SEQ ID NO:1 has promoter activity," the court stated that the use of "consists" in the body of the claims did not limit the open-ended "comprising" language in the claims (emphases added).
Thus, here, prior art references disclose specifically SEQ ID NO: 4 and SEQ ID NO: 1, thus the limitation is met, and thus the claim is obvious.
Response to Arguments
Applicant's arguments filed 07/30/2025 have been fully considered but they are not persuasive. The argument indicates that “Applicant respectfully defers addressing the outstanding double patenting rejections until the resolution of allowable subject matter” (pg. 9) but does add that neither ‘441 nor the ‘443 teach or suggest the claimed of DNA binding domains of ZFP-TF (pg. 10).
The argument is unpersuasive.
Here, both Sangamo and Sangamo ‘443 disclose the relevant SEQ ID NOs that are functional as ZFPs before applicant’s disclosure and the Remarks fail to provide evidence that the claimed invention that was picked and chosen is meaningfully different than the other ZFP-TFs comprising different finger domains that are used to bind to tri-nucleotide CAG sequence. Ultimately, the invention is neither novel nor non-obvious since the claimed elements are known in the art and used for the same purpose as the present invention. Thus, the rejection of claims 1-5, 17-22 is maintained.
Allowable Subject Matter
Claim 23 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims, and deleting limitations of claims 1a) and 21a).
Conclusion
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/KEYUR A VYAS/ Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600