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 .
Applicant’s amendments to the claims dated 7/14/23 are acknowledged. Claims 1-44 are cancelled. Claims 45-64 are new. Prosecution on the merits commences for claims 45-64.
PRIORITY
The instant application, filed 10/11/2022, is a CONTINUATION of US Patent No. 12,152,240, filed 4/23/17, which is a 371 National Stage Application of PCT/IB2015/058202, filed 10/23/15; which claims priority to GB14189658, filed 10/24/14. Therefore, the earliest possible priority for the instant application is 10/24/14.
INFORMATION DISCLOSURE STATEMENT
The information disclosure statements(IDS) submitted on July 14, 2023 has been considered by the examiner and an initialed copy of the IDS is included with the mailing of this office action.
Specification
The disclosure is objected to because of the following informalities: The specification references colors within the text when referencing the figures. The figures are in black and white, and thus any references to colors should be deleted. See, at least paragraphs [0197], [0212], and [0215] of the published specification. Applicant is requested to review the specification for any additional references to colors within figures and delete as necessary.
Appropriate correction is required.
CLAIMS
PNG
media_image1.png
200
400
media_image1.png
Greyscale
Independent claims 45, 55 and 62 are directed to methods of administering to a subject a composition comprising one or more artificial transcription factors comprising a DNA binding domain and an effector domain. The effector domains (a) — (c) are selected from (a) a KRAB domain, (b) a DNMT3a, DNMT3B domain, or a DNMT1 domain; and (c) a DNMT3Ldomain. The combination of effector domains comprises (a) and (b) and/or (a) and (c).
PNG
media_image2.png
127
538
media_image2.png
Greyscale
Claim 45, requires a specific pair of ATRs comprising (a) and (b) OR (a) and (c):
PNG
media_image3.png
146
457
media_image3.png
Greyscale
Claim 55 requires one ATR, wherein the ATR comprises 2 different effector domains comprising (a) and (b) OR (a) and (c):
Claim 62 requires two ATRs, wherein each ATR comprises 2 different effector domains:
PNG
media_image4.png
130
454
media_image4.png
Greyscale
The visual representations above are merely one structural relationship of the DNA binding domains and the effector domains within the ATRs and not limiting in any way.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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 45-51 and 53-61 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2007/0192880 to Muyan of record, cited on Applicant’s IDS dated 7/14/23, further in view of Siddique et al. Targeted Methylation and Gene Silencing of VEGF-A in Human Cells by Using a Designed Dnmt3a-Dnmt3L Single-Chain Fusion Protein with Increased DNA Methylation Activity. Journal of Molecular Biology, 2013. 425:479-91, of record, cited on Applicant’s IDS dated 7/14/23.
Claims 45 and 55 are drawn to methods of administering to a subject a combination of transcription factor repressors (ATRs), wherein the ATRs encompass embodiments accordingly:
PNG
media_image5.png
160
604
media_image5.png
Greyscale
Claim 45 requires a specific pair of ATRs comprising (a) and (b) OR (a) and (c):
OR
PNG
media_image6.png
155
387
media_image6.png
Greyscale
Claim 55 requires one ATR, wherein the ATR comprises 2 different effector domains comprising (a) and (b) OR (a) and (c):
OR
With regard to claims 45 and 55, Muyan methods of administering one or more artificial transcription factors, or nucleic acids encoding them, to a subject in need thereof (paragraphs [0159]-[0178], [0187]-[0189], [0220]-[0235]). Muyan discloses the recombinant transcription factors comprise a DNA-binding domain operably linked to at least one activation or repressor domain (paragraphs [0084]-[0089]). Muyan discloses the one or more activation or repressor domains can be linked to either of the N-terminus or the C-terminus of the recombinant transcription factor, and wherein the one or more repressor domains can be the same, or different (paragraphs [0089]-[0090]). Muyan discloses that more than one recombinant transcription factor can be used (paragraph [0092]), and suggests that the use of multiple recombinant transcription factors can be synergistic (paragraph [0092]).
PNG
media_image7.png
156
750
media_image7.png
Greyscale
Thus, Muyan generates recombinant transcription factors accordingly:
Muyan discloses the repressor domains comprises repressor domains “that when brought within proximity of a particular transcription start site, will cause transcription from that site to be decreased relative to transcription in the absence of the repressor domain” (paragraph [0105]).
PNG
media_image8.png
348
965
media_image8.png
Greyscale
Muyan generates, and reduces to practice, recombinant transcription repressors comprising KRAB and SID domains, wherein the transcription factor comprises a N- or C-terminal KRAB domain, an N- or C-terminal SID domain, and transcriptional repressors comprising both KRAB and SID, on both the N-terminal and C-terminal of the transcription factor (See, FIGs 7-9):
Muyan discloses the KRAB and SID proteins recruit histone deacetylase protein (HDAC) complexes to the target regions to affect their repression (paragraph [0107]-[0110]). Muyan shows the KRAB repressors are stronger repressors than the SID repressors (paragraph [0360]). Muyan discloses methylation of genes using DNMTs is a known pathway for gene suppression, and that while methylation is required to suppress some genes, methylation alone of some genes is not sufficient for gene suppression (paragraphs [0057]-[0058]). Muyan suggests both DNMT and HDAC pathways are important for regulating gene expression (paragraph [0058]).
However, Muyan does not disclose
- a first transcription repressor (ATR) comprising a KREB domain and a second transcription factor (ATR) comprising a second repressor domain, wherein the second repressor domain is one selected from the group consisting of DNMT3a, DNMT3b, or DNMT1, or
-a first transcription repressor (ATR) comprising a KREB domain and a second transcription repressor (ATR) comprising a DNMT3L domain, according to instant claim 45; or
- one or more single transcription repressors (ATR) comprising two or more repressor domains, wherein the first repressor domain comprises a KREB domain and the second repressor domain is one selected from the group consisting of DNMT3a, DNMT3b, or DNMT1, or
- one or more single transcription repressors (ATR) comprising two or more repressor domains, wherein the first repressor domain comprises a KREB domain and the second repressor domain is DNMT3L according to instant claim 55.
Siddique discloses an artificial transcription repressor comprising a zinc-finger DNA binding domain operably linked to a DNMT3a domain and a DNMT3L domain (Abstract, page 482-483; 487, FIG 5a, 5b, 5c). Siddique discloses the methylation/silencing using both the DNMT3a and DNMT3L was greater than the methylation of the DNMT3a alone (FIGs 3, 4, 5).
Siddique discloses the ZF-targeted DNMT3a and DNMT3L fusion construct mimics the stable heterodimer catalytic domains which form in vivo and in vitro, thus increasing the catalytic activity of a single DNMT3a domain (page 480). Further Siddique discloses the catalytic functionality of the zinc-finger -DNMT3a -DNMT3L fusion is due to intermolecular interactions between distinct fusion proteins forming additional complexes, instead of intramolecular interaction (page 486).
It would have been obvious to combine the disclosure of Muyan further with the disclosure of Siddique. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the DNMT3a and DNMT3L fusion repressor of Siddique for the SID repression domain of Muyan because all are explicitly taught as being useful for ligating onto a DNA-binding domain to form functional transcriptional repressors. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
A skilled artisan would have been motivated to substitute the DNMT3a and DNMT3L fusion repressor domain of Siddique for the SID repression domain of Muyan (thus leaving the KRAB repressor domain) because Muyan discloses suppression of some genes is a balance of HDACs - effected by KRAB/SID- and methylation - effected by DNMTs- and that KRAB is a more potent inhibitor than SID. See MPEP 2144.06 II (Substituting Equivalents known for the Same Purpose). In the instant case both the SID repressor domain was known to repress transcription when operably linked to a DBD, and the DNMT3a and DNMT3L fusion on an artificial repressor was shown to repress transcription.
A skilled artisan would thus have recognized that including the DNMT3a and DNMT3L fusion on an artificial repressor comprising KRAB or SID would provide both HDAC activity and methylation activity to effect suppression of a target gene. See MPEP 2144.06 I (Combining Equivalents Known for the same function) “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Further with regard to the requirement for claim 45, wherein the transcriptional repressors are individual proteins, each comprising a DNA-binding domain and a functional repressor domain, the structure of having two transcriptional repressors, one encoding KRAB, and one encoding a DNMT protein flows naturally from Muyan. Muyan generates individual transcriptional repressors and tests them individually (FIGs 7-9). Muyan further discloses that more than one recombinant transcription factor can be used (paragraph [0092]), and suggests that the use of multiple recombinant transcription factors can be synergistic (paragraph [0092]).
A skilled artisan would have had a reasonable expectation of success that the combination of ATRs or ATRs comprising different repressor domains would successfully function to silence a target gene, gene element or splicing element in a cell because all of the claimed repressor domains have been shown to suppress target genes by reduction to practice, as individual or combined ATRs, or because the art suggests that ATRs can comprise multiple protein repressor domains of a protein complex can be used to effect targeted suppression (Siddique).
With regard to claim 46, Muyan discloses the KRAB protein therein is encoded by SED ID NO: 44, which is 90 base pairs in length. Instant SEQ ID NO:1, which encodes a KRAB protein, is encoded by a sequence of 117 base pairs. The 90 bases of Muyan’s KREB is 100% identical to nucleotides 21-110 of instant SEQ ID NO:1. This results in a 76.9% identify of Muyan’s KREB to instant SEQ ID NO:1.
With regard to claim 47, Muyan discloses the transcriptional repressors are encoded on vectors (paragraphs [[0159]-[0178]); and one or more transcriptional repressors are part of the invention (paragraphs [0092]). Thus, encoding the transcriptional repressors on one or more vectors is obvious from the disclosure of Muyan.
With regard to claim 48, the claim encompasses an embodiment wherein a separate effector protein, not operably linked to a DNA-binding domain is provided, wherein the separate effector protein that is not operably linked to a DBD is selected from KRAB, DNMT3A, DNMT3b or DNMT1. As iterated above, Muyan in view of Siddique renders obvious individual ATRs comprising KREB and a DNMT3a-3L fusion. Muyan does not disclose wherein a separate effector protein of KRAB, DNMT3A, DNMT3b or DNMT1 is provided. However, Siddique discloses that isolated DNMT3b catalytic domains are capable of de novo methylation, and that DNMT3a, DNMT3b and DNMT3L form protein complexes in vitro and in vivo, and that DNMT3L has been shown to stimulate the activity of DNMT3a and DNMT3b (page 480). Further, Siddique discloses the function of the recombinant ATR therein (DBD-DNMT3a-3L) appears to be from intramolecular interactions (between two or more different DBD-DNMT3a-3L fusion proteins forming large intracellular complexes), instead of intermolecular interactions of the two repressor domains within a single ATR (page 486). Thus, it would have been obvious to add in an additional effector protein, such as DNMT3b, which is not operably linked to a DBD, to a complex comprising DNMT3a and DNMT3L. A skilled artisan would have recognized the additional effector protein of the DNMT complex would interact with the DNMT effector domains operably linked to the DBDs of Muyan in view of Siddique.
With regard to claim 49, Muyan discloses the compositions can be formulated as pharmaceutical compositions (paragraph [0188]).
With regard to claims 50 and 57, Muyan discloses the compositions can be expressed in cells ex vivo and administered to the patient (paragraphs [0188]-[0189], [0258]).
With regard to claims 51 and 58, Muyan discloses the compositions can be integrated into the chromosome of a cell, including the germline, what can be used to generate cells expressing the compositions (paragraphs [0258]-[0261]), thus Muyan discloses a cell comprising a descendent of a cell expressing the transcriptional repressor as claimed.
With regard to claims 53 and 60, comprising an ATR comprising a DBD-KRAB and an ATR comprising a DBD-DNMT3L (claim 53) or an ATR comprising a DBD-KRAB and a DBD-DNMT3L (claim 60), the claims are obvious for the same reasons as stated above for claims 45 and 55. Muyan generates individual transcriptional repressors and tests them individually (FIGs 7-9). Muyan further discloses that more than one recombinant transcription factor can be used (paragraph [0092]), and suggests that the use of multiple recombinant transcription factors can be synergistic (paragraph [0092]).
With regard to claims 54 and 61, comprising an ATR comprising a DBD-KRAB and a DBD-DNMT3a (claim 54) or an ATR comprising a DBD-KRAB and a DBD-DNMT3a (claim 61), the claims are obvious for the same reasons as stated above for claims 45 and 55. Muyan generates individual transcriptional repressors and tests them individually (FIGs 7-9). Muyan further discloses that more than one recombinant transcription factor can be used (paragraph [0092]), and suggests that the use of multiple recombinant transcription factors can be synergistic (paragraph [0092]).
With regard to claim 56, Muyan discloses the transcriptional repressors are encoded as nucleic acids (paragraphs [0159]-[0178]).
With regard to claim 59, the claim requires an embodiment wherein the transcriptional repressor comprises a DBD operably linked to KRAB, DNMT3a and DNMT3L. This claim is obvious for the same reasons as stated above for claim 45. Muyan discloses an ATR comprising KRAB and SID; that KRAB is a stronger repressor domain; methylation of genes using DNMTs is a known pathway for gene suppression, and that while methylation is required to suppress some genes, methylation alone of some genes is not sufficient for gene suppression; and both DNMT and HDAC pathways are important for regulating gene expression (paragraph [0107]-[0110], [0360], [0057]-[0058]). Siddique discloses an artificial transcription repressor comprising a zinc-finger DNA binding domain operably linked to a DNMT3a domain and a DNMT3L domain (Abstract, page 482-483; 487, FIG 5a, 5b, 5c).
A skilled artisan would have been motivated to substitute the DNMT3a and DNMT3L fusion repressor domain of Siddique for the SID repression domain of Muyan (thus leaving the KRAB repressor domain) because Muyan discloses suppression of some genes is a balance of HDACs - effected by KRAB/SID- and methylation - effected by DNMTs- and that KRAB is a more potent inhibitor than SID. See MPEP 2144.06 II (Substituting Equivalents known for the Same Purpose).
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2007/0192880 to Muyan, of record, cited on Applicant’s IDS dated 7/14/23, in view of Siddique et al. Targeted Methylation and Gene Silencing of VEGF-A in Human Cells by Using a Designed Dnmt3a-Dnmt3L Single-Chain Fusion Protein with Increased DNA Methylation Activity. Journal of Molecular Biology, 2013. 425:479-91, of record, cited on Applicant’s IDS dated 7/14/23, as applied to claims 45-51 and 53-61, and further in view of US Patent Application Publication No. 2009/0023153 to Wolffe of record, cited on Applicant’s IDS dated 7/14/23. Claim 52 encompasses an embodiment wherein the claim comprises 3 separate ATRs, one comprising a DBD-KRAB, one comprising DBD-DNMT3L and one comprising DBD-DNMT3a.
The disclosures of Muyan and Siddique are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Muyan and Siddique combine to render obvious a plurality of ATRs (DBD-effectors), each with different effector domains, wherein the plurality of ATRs encodes DBD-KRAB and/or DBD-DNMT3a-DNMT3L, and/or DBD-KRAB-DNMT3a-DNMT3L.
Siddique also discloses DNMT3a and 3b are capable of de novo methylation, and both have been shown to interact with DNMT3L; and that DNMT3L interaction with DNMT3a and 3b has been shown to simulate their activity in vivo and in vitro (page 480, first column). Siddique discloses the ZF-targeted DNMT3a-DNMT3L fusion construct mimics the stable heterodimer catalytic domains which form in vivo and in vitro, thus increasing the catalytic activity of a single DNMT3a domain (page 480). Siddique discloses the ZF-targeted DNMT3a-DNMT3L fusion construct mimics the stable heterodimer catalytic domains which form in vivo and in vitro, thus increasing the catalytic activity of a single DNMT3a domain (page 480). Further Siddique discloses the catalytic functionality of the zinc-finger -DNMT3a -DNMT3L fusion is due to intermolecular interactions between distinct fusion proteins forming additional complexes, instead of intramolecular interactions (page 486). Thus, suggesting the DNMT3L domain of one fusion protein interacts with the DNMT3a domain of another fusion protein.
However, Muyan nor Siddique disclose individual ATRs as claimed, one an ATR comprising DBD-KRAB, a second ATR comprising DBD-DNMT3L, and a third ATR comprising DBD-DNMT3a, as required by instant claim 52.
Wolffe discloses recombinant transcription factors comprising a DNA-binding domain operably linked to a repressor domain (paragraphs [0014]-[0033]). Wolffe discloses exemplary repressor domains include KRAB, SID and members of the DNMT family, including DNMT1, DNMT3a and DNMT3b (paragraph 207). Wolffe generates functional artificial transcription repressors comprising DNMT3a (pVF3a/1-DNMT3a), DNMT3b (pVF3a/1-DNMT3a), or DNMT1, OR KREB (pVF3a/1-KRAB) (See FIGs 6 and 7). Wolffe shows that these recombinant transcriptional repressors all share the same DNA-binding domain (“PVF3a/1 refers to the VEGF3/a DNA binding domain described in examples 3 and 13”), and that DNMT3a (pVF3a/1-DNMT3a), DNMT3b (pVF3a/1-DNMT3a), and KREB (pVF3a/1-KRAB) are capable of acting as a repressor for the same gene, using the same DNA binding domain (see arrows added for clarity) a FIG 8:
PNG
media_image9.png
409
617
media_image9.png
Greyscale
Thus, Wolffe establishes an ATR comprising DBD-KRAB and a second ATR comprising DBD-DNMT3a function independently as targeted repressors.
It would have been obvious to combine the disclosure of Muyan and Siddique on a plurality of ATRs (DBD-effectors), each with different effector domains, wherein the plurality of ATRs encodes DBD-KRAB and DBD-DNMT3a-DNMT3L, and/or DBD-KRAB-DNMT3a-DNMT3L, further with the disclosure of Wolffe to arrive at 3 separate ATRs, one comprising a DBD-KRAB, one comprising DBD-DNMT3L and one comprising DBD-DNMT3a, as required by instant claim 52. Muyan discloses multiple ATRs, each comprising a different repressor domain can be used. Wolffe establishes DBD-KRAB, DBD-DNMT3a function independently as targeted repressors. Siddique establishes that the art recognized that DNMT3 and DNMT3L directly interact, wherein DNMT3L stimulates DNMT3a activity, and Siddique discloses the DBD-DNMT3a-3L efficacy therein is due to intermolecular interactions, not intramolecular interactions. Thus, it would have been obvious to generate individual DBD-ATRs from the teachings of the prior art. See, MPEP 2143(i)A: (A) Combining prior art elements according to known methods to yield predictable results. In the instant case, the prior art included each element claimed, and in combination each element performs the same function as it does separately. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as generating multiple ATRs comprising different repressor domains was known in the art at the time of the invention.
Claims 62-64 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2007/0192880 to Muyan, of record, cited on Applicant’s IDS dated 7/14/23, in view of US Patent Application Publication No. 2009/0023153 to Wolffe of record, cited on Applicant’s IDS dated 7/14/23, and Siddique et al. Targeted Methylation and Gene Silencing of VEGF-A in Human Cells by Using a Designed Dnmt3a-Dnmt3L Single-Chain Fusion Protein with Increased DNA Methylation Activity. Journal of Molecular Biology, 2013. 425:479-91, of record, cited on Applicant’s IDS dated 7/14/23.
Claim 62 requires two ATRs, wherein each ATR comprises 2 different effector domains
PNG
media_image6.png
155
387
media_image6.png
Greyscale
and
With regard to claim 62, Muyan methods of administering one or more artificial transcription factors, or nucleic acids encoding them, to a subject in need thereof (paragraphs [0159]-[0178], [0187]-[0189], [0220]-[0235]). Muyan discloses the recombinant transcription factors comprise a DNA-binding domain operably linked to at least one activation or repressor domain (paragraphs [0084]-[0089]). Muyan discloses the one or more activation or repressor domains can be linked to either of the N-terminus or the C-terminus of the recombinant transcription factor, and wherein the one or more repressor domains can be the same, or different (paragraphs [0089]-[0090]). Muyan discloses that more than one recombinant transcription factor can be used (paragraph [0092]), and suggests that the use of multiple recombinant transcription factors can be synergistic (paragraph [0092]).
PNG
media_image7.png
156
750
media_image7.png
Greyscale
Thus, Muyan generates recombinant transcription factors accordingly:
Muyan discloses the repressor domains comprises repressor domains “that when brought within proximity of a particular transcription start site, will cause transcription from that site to be decreased relative to transcription in the absence of the repressor domain” (paragraph [0105]).
PNG
media_image8.png
348
965
media_image8.png
Greyscale
Muyan generates, and reduces to practice, recombinant transcription repressors comprising KRAB and SID domains, wherein the transcription factor comprises a N- or C-terminal KRAB domain, an N- or C-terminal SID domain, and transcriptional repressors comprising both KRAB and SID, on both the N-terminal and C-terminal of the transcription factor (See, FIGs 7-9):
Muyan discloses the KRAB and SID proteins recruit histone deacetylase protein (HDAC) complexes to the target regions to affect their repression (paragraph [0107]-[0110]). Muyan shows the KRAB repressors are stronger repressors than the SID repressors (paragraph [0360]). Muyan discloses methylation of genes using DNMTs is a known pathway for gene suppression, and that while methylation is required to suppress some genes, methylation alone of some genes is not sufficient for gene suppression (paragraphs [0057]-[0058]). Muyan suggests both DNMT and HDAC pathways are important for regulating gene expression (paragraph [0058]).
Thus, Muyan suggests at least one ATR comprising two different functional repressor domains, wherein at least one is a KREB domain, and the other is a different repressor domain. Muyan suggests a plurality of ATRs can be produced.
However, Muyan does not disclose embodiments comprising two transcription repressors, such that a first transcription repressor (ATR) comprises a KREB domain and a DNMT3a, DNMT3b, or DNMT1 domain, and a second transcription repressor (ATR) comprises a KREB domain and a DNMT3L domain, according to instant claim 62.
PNG
media_image9.png
409
617
media_image9.png
Greyscale
Wolffe discloses recombinant transcription factors comprising a DNA-binding domain operably linked to a repressor domain (paragraph [0014]-[0033]). Wolffe discloses exemplary repressor domains include KRAB, SID and members of the DNMT family, including DNMT1, DNMT3a and DNMT3b (paragraph 207). Wolffe generates functional artificial transcription repressors comprising DNMT3a (pVF3a/1-DNMT3a), DNMT3b (pVF3a/1-DNMT3a), or DNMT1, OR KREB (pVF3a/1-KRAB) (See FIGs 6 and 7). Wolffe shows that these recombinant transcriptional repressors all share the same DNA-binding domain (“PVF3a/1 refers to the VEGF3/a DNA binding domain described in examples 3 and 13”), and that DNMT3a (pVF3a/1-DNMT3a), DNMT3b (pVF3a/1-DNMT3a), and KREB (pVF3a/1-KRAB) are capable of acting as a repressor for the same gene, using the same DNA binding domain (see arrows added for clarity) a FIG 8:
Siddique discloses an artificial transcription repressor comprising a zinc-finger DNA binding domain operably linked to a DNMT3a domain and a DNMT3L domain (Abstract, page 482-483; 487, FIG 5a, 5b, 5c). Siddique discloses the methylation/silencing using both the DNMT3a and DNMT3L was greater than the methylation of the DNMT3a alone (FIGs 3, 4, 5).
Siddique also discloses DNMT3a and 3b are capable of de novo methylation, and both have been shown to interact with DNMT3L; and that DNMT3L interaction with DNMT3a and 3b has been shown to simulate their activity in vivo and in vitro (page 480, first column). Siddique discloses the ZF-targeted DNMT3a and DNMT3L fusion construct mimics the stable heterodimer catalytic domains which form in vivo and in vitro, thus increasing the catalytic activity of a single DNMT3a domain (page 480). Further Siddique discloses the catalytic functionality of the zinc-finger -DNMT3a -DNMT3L fusion is due to intermolecular interactions between distinct fusion proteins forming additional complexes, instead of intramolecular interactions (page 486).
It would have been obvious to combine the disclosures of Muyan further with the disclosures of Wolffe and Siddique. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the DNMT3a and/or DNMT3b repressors of Wolffe for the SID repression domain of Muyan because all are explicitly taught as being useful for ligating onto a DNA-binding domain to form functional transcriptional repressors. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Muyan generates an ATR comprising at least two distinct repressor domains (KREB and SID), and discloses multiple ATRs can be generated. A skilled artisan would have been motivated to substitute the DNMT3b or DNMT3a fusion repressor of Wolffe for the SID repression domain of Muyan (thus leaving the KRAB repressor domain) because Muyan discloses suppression of some genes is a balance of HDACs -effected by KRAB/SID- and methylation -effected by DNMTs- and that KRAB is a more potent inhibitor than SID. A skilled artisan would thus have recognized that including the DNMT3a or 3b on an artificial repressor comprising KRAB or SID would provide both HDAC activity and methylation activity to effect suppression of a target gene. See MPEP 2144.06 (Combining Equivalents Known for the same function) “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
It would have likewise been obvious to combine the entire ATR (DBD-DNMT3a-3L fusion repressor) of Siddique with the ATRs of Muyan. A skilled artisan would have recognized that including Siddique’s ATR (DBD-DNMT3a and DNMT3L fusion) with the artificial transcription factors of Muyan provide methylation activity to effect suppression of a target gene. See MPEP 2144.06 I (Combining Equivalents Known for the same function) “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Muyan generates an ATR comprising at least two distinct repressor domains (KREB and SID), and discloses multiple ATRs can be generated. Muyan discloses suppression of some genes is a balance of HDACs -effected by KRAB/SID- and methylation -effected by DNMTs- and that KRAB is a more potent inhibitor than SID. A skilled artisan would thus have recognized that including the ATR of Siddique, comprising a DBD-DNMT3a-3L with the artificial transcription repressors of Muyan comprising KRAB would provide both HDAC activity and methylation activity to effect suppression of a target gene. See MPEP 2144.06 (Combining Equivalents Known for the same function) “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
A skilled artisan would have had a reasonable expectation of success that the combination of repressor domains would successfully function to silence a target gene, gene element or splicing element in a cell because all of the claimed repressor domains have been shown to suppress target genes by reduction to practice, as individual or combined ATRs, or because the art suggests that ATRs can comprise multiple protein repressor domains of a protein complex can be used to effect targeted suppression (Siddique).
With regard to claim 63, Muyan discloses the compositions can be expressed cells ex vivo and administered to the patient (paragraphs [0188]-[0189], [0258]).
With regard to claim 64, Muyan discloses the compositions can be integrated into the chromosome of a cell, including the germline, what can be used to generate cells expressing the compositions (paragraphs [0258]-[0261]), thus Muyan discloses a cell comprising a descendent of a cell expressing the transcriptional repressor as claimed.
Double Patenting
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.
Claims 45-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,152,240. The instant application is a CONTINUATION of US Patent No. 12,152,240. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious variants of the patented claims.
RESTRICTION IN PARENT PATENT 12,152,240
The examiner notes that a Restriction Requirement, of record 3/26/2019, was made during the prosecution of the parent patent, wherein the pending claims were restricted into two groups: group I, comprising compositions comprising ATRs, and group II, comprising methods of using the ATRs. Applicant elected group I without traverse on 5/27/19.
In order to advance the prosecution of the parent application (15/521,294) to allowance, the Examiner indicated that a terminal disclaimer would be required over pending application 17/963,631 (the instant application) during an interview (see, Interview Summary dated 9/20/24 in parent application). Applicant submitted a terminal disclaimer over 17/963,631 on 9/13/2024. At the time of allowance, the Examiner withdrew the restriction requirement of 3/26/2019, and the withdrawn claims to methods of using the allowable compositions comprising the ATRs were rejoined.
Because the Restriction Requirement of 3/26/2019 was withdrawn, and the instant application is a continuation of the parent patent, there is no prohibition of Nonstatutory Double Patenting Rejections under 35 USC 121, and a double patenting rejection is proper.
In addition, the prohibition of Nonstatutory Double Patenting only applies in situations where a restriction requirement, and a divisional application is filed as a result of the restriction. However, if the restriction requirement was withdrawn before the patent issues, the prohibition under 35 USC 121 do not apply, OR if a child application is filed as a divisional application where no restriction requirement is made. See, MPEP 804.01:
The following are situations where the prohibition against nonstatutory double patenting rejections under 35 U.S.C. 121 does not apply:
(A) The applicant voluntarily files two or more applications without a restriction requirement by the examiner.
(E) The requirement for restriction was withdrawn, in its entirety or in pertinent part, by the examiner before the patent issues. With the withdrawal of the restriction requirement, the non-elected claims that are no longer withdrawn from consideration become subject to examination. "The restriction requirement disappears; it is as though it had not been made. With the disappearance of the restriction requirement, the need for a divisional application and the need for the [double patenting] prohibition also disappear."In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 132 (CCPA 1971). Note that a restriction requirement in an earlier-filed application does not carry over to claims of a continuation application in which the examiner does not reinstate or refer to the restriction requirement in the parent application. Reliance on a patent issued from such a continuation application to reject claims in a later-filed divisional application is not prohibited under 35 U.S.C. 121. Bristol-Myers Squibb Co. v. Pharmachemie BV, 361 F.3d 1343, 1348, 70 USPQ2d 1097, 1100 (Fed. Cir. 2004).
Claims 1, 15 and 22 of the ‘240 patent are drawn to compositions comprising one or more artificial transcription factors (ATRs), or the nucleic acids encoding them, wherein the ATRs comprise a DNA-binding domain and different combinations of effector domains (a)-(c); wherein (a) = KREB; (b)= DNMT3A, and (c)= DNMT3L.
PNG
media_image10.png
133
545
media_image10.png
Greyscale
Claim 1 of the patent encompasses two ATRs, one of (a) and one of (b) OR two ATRs, one of (a) and one of (c):
Claim 15 of the patent encompasses one ATR comprising two domains. An ATR comprising one of (a) and one of (b) OR and ATR comprising one of (a) and one of (c):
PNG
media_image11.png
138
460
media_image11.png
Greyscale
PNG
media_image12.png
139
456
media_image12.png
Greyscale
Claim 22 of the patent encompasses two ATRs, each comprising two domains. An ATR comprising one of (a) and one of (b) AND a second ATR comprising one of (a) and one of (c):
Dependent claim 5 of the patent encompasses wherein the composition of claim 1 further comprises a separate effector protein that is not operably linked to a DNA binding domain, wherein the effector domain comprises, at least (a) KRAB, (b) DNMT3A, DNMT3B or DNMT1, or (c) DNMT3L.
Dependent claim 4 of the patent is directed to a method of gene therapy, wherein a cell is transfected with the nucleic acids encoding the ATRs ex vivo.
Dependent claim 12 of the patent is directed to a method of gene therapy wherein the ATRs are administered to a subject.
Instant claims 45, 55 and 62 are directed to methods of administering artificial transcription factors (ATRs) or the nucleic acids encoding them to a subject, wherein the ATRs comprise a DNA-binding domain and different combinations of effector domains (a)-(c); wherein (a) = KREB; (b)= DNMT3A,DNMT3B, or DNMT1, and (c)= DNMT3L.
Instant claim 45 encompasses two ATRs, one of (a) and one of (b) OR two ATRs, one of (a) and one of (c):
PNG
media_image2.png
127
538
media_image2.png
Greyscale
Instant claim 55 encompasses one ATR comprising two domains. An ATR comprising one of (a) and one of (b) OR an ATR comprising one of (a) and one of (c):
PNG
media_image3.png
146
457
media_image3.png
Greyscale
Instant claim 62 encompasses two ATRs, each comprising two domains. An ATR comprising one of (a) and one of (b) AND a second ATR comprising one of (a) and one of (c):
PNG
media_image4.png
130
454
media_image4.png
Greyscale
Instant dependent claim 48 encompasses wherein the method of claim 45 further comprises administering a separate effector protein that is not operably linked to a DNA binding domain, wherein the effector domain comprises, at least (a) KRAB, (b) DNMT3A, DNMT3B or DNMT1, or (c) DNMT3L.
Thus, the instant claims are obvious variants of the patented claims. It would have been obvious to modify the claims of the patent on compositions of ATRs with dependent claims to methods of using them, and claim the methods. In addition, it would have been obvious to include DNM3B and DNMT1 repressors with the DNMT3a repressor on the ATRs encoded in the independent claims, because the patent includes DNM3B, DNMT1 and DNMT3a repressors as a single grouping of substitutable repressors. Obvious to substitute Equivalents; Obvious to combine equivalents known for the same purpose. MPEP 2144.06.
Claims 46-54, 56-61 and 63-64 are obvious variants of patented claims 2-14, 16-21, 23-24.
Claims 45-64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45-64 of copending Application No. 18/920,058 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Both the instant application and copending Application No. 18/920,058 are continuing applications of US Patent No. 12,152,240. Thus, they share the same specification and effective filing date.
Claim 1 of the ‘058 patent is directed to a compositions comprising an artificial transcription factor (ATR), wherein the ATR comprise a DNA-binding domain and two different combinations of effector domains (a)-(c); wherein (a) = KREB; (b)= DNMT3A,DNMT3B, or DNMT1, and (c)= DNMT3L.
PNG
media_image3.png
146
457
media_image3.png
Greyscale
. The ATR comprises one of (a) and one of (b) OR the ATR comprises one of (a) and one of (c):
and optionally wherein the DNA-binding domain comprises a zinc-finger domains or a CRISPR/cas system.
Claims 57-60 of the ‘058 application are directed to embodiments wherein the ATR or nucleic acids encoding them are administered to a cell or a subject.
Instant claims 45, 55 and 62 are drawn to methods of administering artificial transcription factors (ATRs) or the nucleic acids encoding them.
PNG
media_image2.png
127
538
media_image2.png
Greyscale
Instant claim 45 encompasses two ATRs, one of (a) and one of (b) OR two ATRs, one of (a) and one of (c):
PNG
media_image3.png
146
457
media_image3.png
Greyscale
Instant claim 55 encompasses an ATR that comprises one of (a) and one of (b) OR the ATR comprises one of (a) and one of (c):
Instant claim 62 encompasses two ATRs, each comprising two domains. An ATR comprising one of (a) and one of (b) AND a second ATR comprising one of (a) and one of (c):
PNG
media_image4.png
130
454
media_image4.png
Greyscale
Claims 46, 55 and 62 additional require wherein the DNA-binding domain comprises a zinc-finger domains or a CRISPR/cas system.
.
It would have been obvious to the skilled artisan to modify the instant claims from the method of using the ART composition with optional ZFN or CRISPR, to the ART composition itself with optional ZFN or CRISPR. Claim 45 of the application is the composition comprised within method claim 55 of the instant application.
Claims 46-47 are directed to wherein the additional domains are zinc-finger domains or CRISPR/cas domains, which are obvious over claims 46, 55 and 62, for the same reasons as stated above.
Claims 52, 57-64 are obvious variants of pending claims 46-54, 56-61 and 63-64.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY A ARON whose telephone number is (571)272-2789. The examiner can normally be reached Monday-Friday 9AM-5PM.
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.
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.
KAA
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633