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 .
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/US2021/061963 (filed 12/06/2021). Acknowledgement is made of Applicants’ claim for benefit of U.S. Provisional Application No. 63/123,413 (filed 12/09/2020).
Election/Restrictions
Applicant’s election without traverse of Group I (claims 82-88 and 94-97) in the reply filed on 01/05/2026 in response to a restriction requirement is acknowledged.
Upon reconsideration, the restriction requirement between the inventions of Group I and Group II, i.e., the product claims, is withdrawn. The restriction requirement between the inventions of Groups (I-II) and Groups (III-IV) is maintained.
In view of the updated restriction requirement, claims 82-101 are pending, with claims 98-101 withdrawn. Claims 82-97 read on the elected invention and are examined on the merits herein.
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claim 86: This claim recites the limitation further comprising a nuclear localization signal having SEQ ID NO: 12 or SEQ ID NO: 13; a TAT domain having SEQ ID NO: 14 or SEQ ID NO: 15; a Myc tag having SEQ ID NO:16, or a combination of two or more thereof; the nuclear localization signal, TAT domain, Myc tag, and combination of two or more thereof is interpreted as a list of alternatively useable members known as a Markush group; i.e., a fusion protein that meets the requirements of claim 85 which comprises a nuclear localization signal (NLS) sharing 100% sequence identity to the sequence set forth in SEQ ID NO: 12 satisfies the limitations of the instant claim.
Regarding claim 87: This claim is drawn to a complex comprising the fusion protein of claim 83 bonded to a promoter sequence of a cystic fibrosis transmembrane conductance regulator gene. Under broadest reasonable interpretation, the term bonded is interpreted as including both covalent bonds (e.g., operably linked gene elements in a recombinant vector) and non-covalent bonds (e.g., transcription factor bonded to a gene via hydrogen bonds and/or ionic interactions).
Claim Objections
Claim 87 is objected to because of the following informalities: “A complex comprising the fusion protein claim 83…” should read “A complex comprising the fusion protein of claim 83…”.
Appropriate correction is required.
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.
Claim 82 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Smith, et al. (US 2022/0348908).
Smith, et al. teaches agents and compositions for modulating expression of a hepatocyte nuclear factor 4 alpha gene (Abstract).
Regarding claim 82: Smith, et al. teaches a site-specific disrupting agent comprising a site-specific hepatocyte nuclear factor 4 alpha (HNF4α) targeting moiety, wherein the moiety comprises a polynucleotide encoding a DNA-binding domain of a zinc finger (ZNF) polypeptide (pars. 0008-0010, 0016), and wherein the DNA-binding domain of the ZNF polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 1770 (par. 0017; Table 10, pg. 174). SEQ ID NO: 1770 shares 90.2% sequence identity with SEQ ID NO: 8; please see end of Office action for all sequence alignments. Thus, the targeting moiety comprising a nucleic acid encoding a ZNF polypeptide having an amino acid sequence of SEQ ID NO: 1770 anticipates the zinc finger domain having at least 90% sequence identity to SEQ ID NO: 8 limitation recited in claim 82.
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.
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 82-85, 89, 92, and 96-97 are rejected under 35 U.S.C. 103 as being unpatentable over Smith, et al. (US 2022/0348908) in view of Willenbring, et al. (US 2018/0057839), Wang, et al. (Sci Rep. 2017), Viart, et al. (Eur Respir J. 2015), as evidenced by Yoshimura, et al. (J Biol Chem. 1991).
The teachings of Smith, et al. are set forth above; claim 82 is anticipated by Smith, et al.
Willenbring, et al. teaches in vivo methods of delivering recombinant virions or viral vectors to a subject suspected of having liver fibrosis (Abstract).
Wang, et al. teaches FOXA2-mediated hepatocyte protection in hepatic fibrosis (Abstract).
Viart, et al. teaches lung development-specific transcription factors and microRNAs regulate cystic fibrosis transmembrane conductance regulator gene expression (Abstract).
Regarding claims 83, 89: It is set forth above the HNF4α targeting moiety of Smith, et al. anticipates the zinc finger domain of claim 82. Smith, et al. teaches an embodiment wherein the disrupting agent comprises a nucleic acid molecule encoding a fusion protein comprising the HNF4α targeting moiety and an effector molecule (par. 0048), wherein the effector molecule is a peptide or protein moiety, such as a transcription factor (pars. 0301-0302); the disclosure does not teach the limitation recited in the instant claim.
However, Willenbring, et al. teaches a nucleic acid encoding transcription factor FOXA2 (par. 0005). As Viart, et al. teaches, FOXA transcription factors, including FOXA2, bind to the promoter region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (pg. 120; Fig. 1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the fusion protein of Smith, et al. by using the FOXA2 transcription factor as the effector molecule, as taught by Willenbring, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. Smith, et al. teaches the disrupting agent comprising the fusion protein is useful for modulating expression of an HNF4α gene in a subject for the treatment of HNF4α-associated disease, e.g., fibrotic liver disease. As taught by Wang, et al., upregulation of FOXA2 in the liver ameliorates fibrogenesis (Fig. 4), hepatocyte-specific overexpression of FOXA2 alleviates liver fibrosis (Fig. 5), and FOXA2 modulates ER stress as well as prevents hepatocyte apoptosis in liver fibrosis (pg. 10; pars. 3-5). Thus, a skilled artisan would have been motivated to make such a modification for the attenuation of liver fibrosis and hepatocyte protection from ER stress and apoptosis, as disclosed by Wang, et al. Further, as Smith, et al. teaches the effector molecule portion of the fusion protein may be a transcription factor (pars. 0301-0302), and as Willenbring, et al. teaches a nucleic acid encoding FOXA2 in a vector which also encodes HNF4α (par. 0005), one skilled in the art would have more than a reasonable expectation of success.
Therefore, the modified fusion protein of Smith, et al. as set forth above reads on the wherein the fusion protein is capable of binding to the promoter sequence of a cystic fibrosis transmembrane conductance regulator gene limitation recited in claim 83, as well as the nucleic acid encoding the fusion protein limitation recited in claim 89.
Regarding claim 84: Following the above discussion, as evidenced by Yoshimura, et al. with GenBank Accession No. M58478 (pg. 9140; footnotes), the promoter region of the CFTR gene shares 100% sequence identity with SEQ ID NO: 1; please see end of Office action for all sequence alignments. Thus, the modified fusion protein of Smith, et al. reads on the wherein the promoter sequence of the cystic fibrosis transmembrane conductance regulator gene has at least 95% sequence identity to SEQ ID NO: 1 limitation recited in claim 84.
Regarding claim 85: Following the above discussion, Smith, et al. teaches an embodiment wherein the effector molecule comprises a combination of epigenetic recruiters (par. 0035), and wherein the epigenetic recruiter comprises a transcriptional enhancer (pars. 0035, 0039), which is a VPR (VP64-p65-Rta) having the amino acid sequence set forth in SEQ ID NO: 66 (par. 0040-0041); thus, Smith, et al. teaches an embodiment wherein the effector molecule of the fusion protein comprises the VPR molecule in addition to the transcription factor (par. 0302) as set forth above. As SEQ ID NO: 66 shares 100% sequence identity to SEQ ID NO: 9, 100% sequence identity to SEQ ID NO: 10, and 99.8% sequence identity to SEQ ID NO: 11, this reads on the VP64 having at least 90% sequence identity to SEQ ID NO: 9, p65 having at least 90% sequence identity to SEQ ID NO: 10, and Rta having at least 90% sequence identity to SEQ ID NO: 11 limitation recited in claim 85.
However, it would have been prima facie obvious to a person having ordinary skill in the art to encode the fusion protein as comprising, from N-terminus to C-terminus, the zinc finger domain then the VPR. This conclusion of obviousness is based on the “obvious to try rationale”. As Smith, et al., teaches the VPR molecule with the specified directionality of the instant claim (par. 0352), there is only two possible arrangements for the structure of the fusion protein, i.e., either the zinc finger domain or the VPR at the N-terminus. Therefore, it would be obvious for a skilled artisan to try both an N-terminus – zinc finger domain – VPR – C-terminus construct, as well as an N-terminus – VPR – zinc finger domain – C-terminus construct; both of these are well within the purview of those in the art. Additionally, as Smith, et al. teaches the second polypeptide of the fusion protein may be fused to either the amino-terminus or the carboxyl-terminus of the first polypeptide, one skilled in the art would have more than a reasonable expectation of success. This rationale aligns with choosing from a finite number of identified, predictable solutions with a reasonable expectation of success; see MPEP 2143(I)(E).
This renders obvious the limitations recited in claim 85.
Regarding claims 92, 96: Following the above discussion, Smith, et al. teaches the disrupting agent may be expressed from a vector, e.g., viral vector or cell (par. 0025); this reads on the vector comprising a nucleic acid encoding the fusion protein limitation recited in claim 92, as well as the cell comprising the fusion protein limitation recited in claim 96.
Regarding claim 97: Following the above discussion, Smith, et al. teaches the disrupting agent may be formulated in a pharmaceutical composition using one or more excipients (par. 0380); this reads on the pharmaceutical composition comprising the fusion protein and a pharmaceutically acceptable excipient limitation recited in claim 97.
Claims 82 and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Smith, et al. (US 2022/0348908) in view of Willenbring, et al. (US 2018/0057839), Wang, et al. (Sci Rep. 2017), and Viart, et al. (Eur Respir J. 2015), further in view of Zhao and Lian (US 2019/0144852).
The teachings of Smith, et al., Willenbring, et al. Wang, et al., and Viart, et al., are set forth above; claim 82 is anticipated by Smith, et al.
Zhao and Lian (hereinafter Zhao) teaches a multi-functional genome-wide CRISPR system (Abstract).
Regarding claim 86: Following the above discussion, Smith, et al. teaches an embodiment wherein the fusion protein further comprises a nuclear localization signal (NLS) (par. 0524), but does not disclose an NLS sequence.
Zhao teaches an NLS is an amino acid sequence that tags a protein for import into the cell nucleus by nuclear transport; also disclosed is an NLS having the amino acid sequence as set forth in SEQ ID NOs: 577 or 578 (par. 0146). As SEQ ID NO: 577 shares 100% sequence identity with SEQ ID NO: 13, and SEQ ID NO: 578 shares 100% sequence identity with SEQ ID NO: 12, this reads on the nuclear localization signal having SEQ ID NO: 12 or SEQ ID NO: 13 limitation recited in claim 86.
It would have been prima facie obvious to a person having ordinary skill in the art to have further modified the fusion protein of Smith, et al. by incorporating an NLS sequence comprising SEQ ID NOs: 577 or 578, as taught by Zhao. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would have been motivated to do so to tag the fusion protein for import into the cell nucleus, as taught by Zhao, and it would have been obvious to a skilled artisan to use an NLS sequence known in the art. Further, as Smith, et al. discloses an embodiment wherein the fusion protein comprises an NLS sequence, one would have more than a reasonable expectation of success.
This renders obvious the limitations recited in claim 86.
Claims 82 and 87-88 are rejected under 35 U.S.C. 103 as being unpatentable over Smith, et al. (US 2022/0348908) in view of Willenbring, et al. (US 2018/0057839), Wang, et al. (Sci Rep. 2017), and Viart, et al. (Eur Respir J. 2015), further in view of Pals, et al. (J Cys Fibros. 2019).
The teachings of Smith, et al., Willenbring, et al. Wang, et al., and Viart, et al., are set forth above; claim 82 is anticipated by Smith, et al.
Pals, et al. teaches cirrhosis associated with cystic fibrosis (Abstract).
Regarding claims 87-88: It is set forth above the modified fusion protein of Smith, et al. renders obvious the fusion protein of claim 83. Smith, et al. teaches the disrupting agent comprising the fusion protein may be formulated within a cationic complex (par. 0369); this reads on the complex comprising the fusion protein limitation recited in the instant claims. Smith, et al. further discloses the complex may be administered to a subject in vivo (par. 0364), but does not explicitly teach administration of the complex to a subject in the context of cystic fibrosis (CF) nor the most common CFTR mutation associated with CF, the ΔF508 mutation, as evidenced by Okay, et al. (Abstract. Clinics. 2005).
However, Smith, et al. discloses the fusion protein is useful for treating cirrhosis (par. 0132), and Pals, et al. teaches the 6-year survival rate and median age at death is significantly lower in CF patients with cirrhosis (CFC) (pg. 387; pars. 3.4, 3.5), from a retrospective analysis of CFC patients in the Netherlands over six years (pg. 386; “Methods”, par. 2). Pals, et al. further discloses a significantly higher incidence of patients homozygous for the ΔF508 mutation in the CFC group (pg. 387; par. 3.1).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the administration method of Smith, et al. by administering the complex comprising the fusion protein to CFC patients with the ΔF508 mutation. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so in an effort to mitigate the decreased survival rate and lower median age of death associated with CFC patients, as taught by Pals, et al. Additionally, as Smith, et al. teaches administration of the complex for cirrhosis (pars. 0132, 0364), one would have a reasonable expectation of success.
Thus, the administered complex to CFC patients with the ΔF508 mutation reads on the complex comprising the fusion protein bonded to a promoter sequence of a cystic fibrosis transmembrane conductance regulator gene limitation recited in claim 87, as well as the wherein the cystic fibrosis transmembrane conductance regulator gene has a deletion of a phenylalanine residue at position 508 limitation recited in claim 88.
Claims 82, 90-91, and 93 are rejected under 35 U.S.C. 103 as being unpatentable over Smith, et al. (US 2022/0348908) in view of Willenbring, et al. (US 2018/0057839), Wang, et al. (Sci Rep. 2017), and Viart, et al. (Eur Respir J. 2015), further in view of Labat, et al. (US 2005/0255114), Doronin, et al. (WO 2020/264186), and Gourdie, et al. (WO 2020/028439).
The teachings of Smith, et al., Wang, et al., Viart, et al., and Willenbring, et al. are set forth above; claim 82 is anticipated by Smith, et al.
Doronin, et al. teaches methods of delivering an oligonucleotide into a cell (Abstract).
Labat, et al. teaches methods for treating and diagnosing preeclampsia (Abstract).
Regarding claims 90-91, 93: It is set forth above the modified teachings of Smith, et al. renders obvious the limitations recited in claims 89 and 92. Smith, et al. does not teach the limitations recited in the instant claims.
Doronin, et al. teaches oligonucleotides can be passed through gap junctions formed by connexin proteins via gap junction mediated communication (par. 0004). Labat, et al. teaches SEQ ID NO: 1273, an amino acid sequence encoding connexin 43 (pg. 111; Table 1), which shares 100% sequence identity with SEQ ID NO: 18; please see end of Office action for all sequence alignments.
It would have been prima facie obvious to a person having ordinary skill in the art to have further modified the vector comprising the nucleic acid encoding the fusion protein of Smith, et al. by including SEQ ID NO: 1273 to encode connexin 43, as taught by Labat, et al. This conclusion of obvious is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so for the delivery of the nucleic acid via gap junction mediated communication, as taught by Doronin, et al. Further, one would have a reasonable expectation of success because, as evidenced by Gourdie, et al., the use of polynucleotides encoding connexin polypeptides is a known technique in the art (pg. 42; par. 1).
Thus, the modified vector as set forth above renders obvious the nucleic acid further encoding a connexin 43 peptide limitation recited in claim 90, the wherein the connexin 43 peptide comprises SEQ ID NO: 18 limitation recited in claim 91, and the vector further comprising a nucleic acid encoding a connexin 43peptide limitation recited in claim 93.
Claims 82 and 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over Smith, et al. (US 2022/0348908) in view of Willenbring, et al. (US 2018/0057839), Wang, et al. (Sci Rep. 2017), and Viart, et al. (Eur Respir J. 2015), further in view of Gourdie, et al. (WO 2020/028439).
The teachings of Smith, et al., Wang, et al., Viart, et al., and Willenbring, et al. are set forth above; claim 82 is anticipated by Smith, et al.
Gourdie, et al. teaches engineered vesicles that contain engineered hemichannels (Abstract).
Regarding claims 94-95: It is set forth above the modified fusion protein of Smith, et al. renders obvious the limitations recited in claim 83. Smith, et al. does not teach the limitations recited in the instant claims.
However, Gourdie, et al. teaches vesicles comprising engineered hemichannels for improved delivery of therapeutics and compounds into target cells (pg. 34; pars. 2-3), wherein the hemichannel comprises an engineered connexin 43 polypeptide (pg. 35; par. 1). In a specific embodiment, the vesicle in which the engineered hemichannel is embedded is an exosome (pg. 60; par. 2). The engineered vesicles containing one or more hemichannel are useful to control and optimize uptake, transport, and/or delivery of the cargo molecules (pg. 59; par. 3).
It would have been prima facie obvious to a person having ordinary skill in the art to have used the exosome comprising the engineered connexin 43 polypeptide taught by Gourdie, et al. for delivery of the modified fusion protein of Smith, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. Smith, et al. teaches the fusion protein may be delivered using a drug delivery system (par. 0369); thus, one would be motivated to use the exosome comprising connexin 43 for the control of the uptake, transport, and delivery of the fusion protein as taught by Gourdie, et al. (pg. 59; par. 3). Further, as Smith, et al. teaches lipids, dendrimers, or polymers can be induced to form a vesicle for drug delivery of the fusion protein (par. 0369), one would have a reasonable expectation of success.
This renders obvious the exosome comprising the fusion protein limitation recited in claim 94, as well as the further comprising a connexin 43 peptide limitation recited in claim 95.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
After a review of the specification, and in the interest of advancing compact prosecution, a sequence search was performed on additional, unclaimed sequences. The Examiner performed this search after identifying potentially allowable subject matter; specifically, the untagged and flag-tagged zinc finger protein(CFZF)-VPR constructs (pars. 0251, 0273).
A fusion protein comprising a CFZF-VPR fusion protein having the amino acid sequence set forth in SEQ ID NO: 3, as well as a fusion protein comprising a flag-tagged CFZF-VPR fusion protein having the amino acid sequence set forth in SEQ ID NO: 2 are free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
SEQUENCE ALIGNMENTS
Query, ‘Qy’ (SEQ ID NO: 8) vs. Database, ‘Db’ (Smith, et al.; SEQ ID NO: 1770)
PNG
media_image1.png
367
686
media_image1.png
Greyscale
Query, ‘Qy’ (SEQ ID NO: 1) vs. Database, ‘Db’ (Yoshimura, et al.; GenBank Accession No. M58478)
PNG
media_image2.png
175
682
media_image2.png
Greyscale
Query (SEQ ID NO: 9) vs. Subject (Smith, et al; SEQ ID NO: 66)
PNG
media_image3.png
133
643
media_image3.png
Greyscale
SEQUENCE ALIGNMENTS (continued)
Query (SEQ ID NO: 10) vs. Subject (Smith, et al; SEQ ID NO: 66)
PNG
media_image4.png
363
679
media_image4.png
Greyscale
Query (SEQ ID NO: 11) vs. Subject (Smith, et al; SEQ ID NO: 66)
PNG
media_image5.png
332
645
media_image5.png
Greyscale
Query, ‘Qy’ (SEQ ID NO: 12) vs. Database, ‘Db’ (Zhao and Lian; SEQ ID NO: 578)
PNG
media_image6.png
169
677
media_image6.png
Greyscale
SEQUENCE ALIGNMENTS (continued)
Query, ‘Qy’ (SEQ ID NO: 13) vs. Database, ‘Db’ (Zhao and Lian; SEQ ID NO: 577)
PNG
media_image7.png
131
644
media_image7.png
Greyscale
Query, ‘Qy’ (SEQ ID NO: 18) vs. Database, ‘Db’ (Labat, et al.; SEQ ID NO: 1273)
PNG
media_image8.png
361
682
media_image8.png
Greyscale