DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 2-21 are pending and under examination in the instant Office Action.
Information Disclosure Statement
The IDS dated 2/7/2024 has been considered except where lined through. Eyquem et. al. (Ref. 42), Kornete et. al. (Ref. 52), and Lombardo et. al. (Ref. 53) are lined through because a copy was not found in the instant or parent application.
Drawings
The drawings are objected to because Fig. 4 is blurry and illegible, especially for the smaller fonts under the top exon 2 and above the arrows in the bottom panel. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: The abstract appears to inadvertently recite "making a genetically cell". The Examiner believes it should read "making a genetically modified cell" .
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites a genetically modified cell comprising a heterologous promoter operably linked to a FOXP3 gene on a nucleic acid in the cell genome, wherein the heterologous promoter is: (i) downstream from a Treg-specific demethylated region (TSDR) of the FOXP3 gene; and (ii) upstream from a first coding exon of the FOXP3 gene. This is indefinite because although the heterologous promoter operably linked to a FOXP3 gene on a nucleic acid in the cell genome defines one option of a FOXP3 gene, most genomes are 2n and therefore would have at least two copies of FOXP3; additionally, insertion of a new FOXP3 gene into the genome by editing techniques such as lentiviral transduction was known in the art (Allan et. al. "Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3." Molecular Therapy 16.1 (2008): 194-202; Of record, IDS dated 2/7/2024). Thus, when the heterologous promoter is “downstream from a Treg-specific demethylated region (TSDR) of the FOXP3 gene”; and “upstream from a first coding exon of the FOXP3 gene” it creates an antecedent basis issue because downstream from a TSDR demethylated region of the FOXP3 gene suggests that the FOXP3 gene linked to the heterologous promoter has a TSDR region, but having a TSDR region is not required of the first listed “a FOXP3 gene”. Therefore, it is unclear what location is required, because it is unclear whether a promoter-FOXP3 transgene may be incorporated into the genome anywhere on the X chromosome downstream of the TSDR of the FOXP3 gene (wherein the TSDR of the FOXP3 in this case is the native genomic TSDR of the FOXP3 gene) may meet the limitations of the claim. Additionally, chimeric FOXP3 TSDR regions are known in the art and have known enhancer ability (Polansky JK, et al. (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38: 1654–1663). A person of ordinary skill in the art would not be able to discern if genetically modified FOXP3 TSDR regions could meet the limitation of the instant claims.
For the purposes of expedited prosecution, the broadest reasonable interpretation of the claim is that the gene is located downstream from a TSDR of a FOXP3 gene and upstream from a first coding exon of a FOXP3 gene. The Examiner suggests amending the claim to recite particular genomic locations or distances, or to define the relationship between the endogenous genomic copies of FOXP3 and the genetic modifications described.
Claim 2 further indefinite for the recitation of “upstream” and “downstream”. Although these terms are used in the art, the instant claims do not specify whether the positions “upstream” and “downstream” are on the coding or non-coding strands of the nucleic acid in the cell genome. Therefore, a person of ordinary skill in the art would not be able to determine the metes and bounds of the required “upstream” and “downstream” locations.
Dependent claims are rejected for failing to resolve the deficiency as described.
Claims 7 and 8 recite a “synthetic first coding exon” and a “natural first coding exon”, respectively. The metes and bounds of a “synthetic first coding exon” and a “natural first coding exon” are indefinite because the terms are not defined in the specification and there is no standard definition in the art. For example, it is unclear whether cDNA, which is derived from the mRNA and therefore is identical to the first coding exon from which the mRNA was encoded, would constitute a natural first coding exon because the sequence is identical to the natural coding sequence or a synthetic first coding exon because cDNA does not have introns and is produced in a lab. Further, it is unclear whether a correction by homologous recombination to the endogenous unmutated sequence in a cell that previously had a mutation in the first exon such as the known IPEX-disease mutations c.2T>C and p.Met1Ile (e.g. see Harbuz, R., et. al. (2010), Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome. Prenat. Diagn., 30: 1072-1078 Fig. 1(a)) would constitute a natural first coding exon because it is natural to the FOXP3 gene in general or whether it is synthetic because it represents an edited correction to the cell. Thus, an artisan would not be able to determine the metes and bounds of the claim.
Claim Rejections - 35 USC § 102
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 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.
Claims 2-5, 8, 12, 14-15, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hubbard, May 2016, Nuclease-targeted gene-editing of FOXP3 in primary T cells creates a stable and functional T phenotype, PowerPoint presentation (Of record, IDS dated 2/7/2024).
Regarding claims 2-5, Hubbard teaches editing of the Foxp3 gene in cells at a position downstream of CNDS2 (TSDR) and the 5’ UTR, in exon 2 prior to the coding sequence to insert a cassette comprising the MND promoter and GFP (p. 6). Hubbard teaches that the cells were successfully edited with a GFP integration marker indicating efficient targeting (p. 8).
Regarding claim 8, Hubbard teaches that the cells are edited to incorporate GFP before the first coding exon (reads on synthetic first coding exon) (p. 9).
Regarding claim 12, Hubbard teaches that some of the T cells are CD4+ T cells (p. 17).
Regarding claims 14 and 15, Hubbard teaches that the cells are Treg cells (p. 14) that are CD25+, CD127-, CTLA4+, and LAG3+ (p. 13).
Regarding claim 18, Hubbard teaches the cells are CD4+ regulatory T cell expressing a flu-specific TCR (p. 21).
Claims 2-5, 8, and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hubbard et. al. May 1 2016, Nuclease-targeted gene-editing of FOXP3 in primary T cells creates a stable and functional Treg phenotype, Mol. Ther. 24(Suppl. 1):S18 (ASGCT Abstract) (Of record, IDS dated 2/7/2024).
Regarding claims 2-5, Hubbard teaches editing of MND promoter upstream of the first coding exon. Regarding claim 8, Hubbard teaches that the cells are edited to incorporate GFP before the first coding exon. Regarding claims 14 and 15, Hubbard teaches that the cells are Treg cells that are CD25+, CD127-, CTLA4+, and LAG3+. See entire document.
Claims 2-4, 8, 12, and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Allan et. al. "Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3." Molecular Therapy 16.1 (2008): 194-202 (Of record, IDS dated 2/7/2024) as evidenced by Mitchell R.S., et. al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2004;2:E234. doi: 10.1371/journal.pbio.0020234.
Allan et. al. teaches design of a FOXP3 lentiviral vector under the control of the constitutive EF1a promoter “pCCLFP3” (Fig. 1a) that is upstream of the first coding exon of FOXP3 that is transduced into cells (Fig. 2a, see Methods “Retroviral and lentiviral transduction of primary and Jurkat T cells section” p. 200 right column). As evidenced by Mitchell et. al., lentiviruses such as HIV integrate throughout the human genome, including many locations on the short arm of the X chromosome (Xp11.23) where the TSDR of the FOXP3 gene is located. As explained in the 112(b) above, the metes and bounds of “downstream” of the TSDR are indefinite; however, a person of ordinary skill in the art would understand that the varied integration sites of would include cells wherein the FOXP3 lentivirus is integrated downstream of the TSDR of FOXP3. The lentiviral DNA of Allan et. al. encodes the first coding exon of the FOXP3 gene downstream of the EF1a promoter, incorporation of the lentiviral DNA at the sites as evidenced by Mitchell et. al. would naturally lead the heterologous promoter located upstream of a first coding exon of FOXP3 and downstream of a TSDR of FOXP3 as claimed.
Regarding claims 3 and 4, Allan et. al. teaches that the promoter is the constitutive EF1a promoter.
Regarding claim 8, Allan et. al. teaches that the FOXP3 gene was cloned (Materials and Methods “Construction and production of retroviral and lentiviral vectors”), which reads on synthetic first exon.
Regarding claim 12, Allan et. al. teaches that the cells are CD4+ T cells (p. 196, right column).
Regarding claims 14 and 15, Allan teaches that the cells are regulatory T cells (“EF1a-driven FOXP3 expression induce a stable population of suppressive T cells” p. 199 left column) and that they are CD25+, CD127-, and CTLA4+ (Fig. 3a).
Regarding claim 16, Allan et. al. teaches the cells express a TCR (“Expression of FOXP3 does not affect TCR diversity” p. 199 right column; Tables S1 and S2).
Claim Rejections - 35 USC §103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2-4, 6-7, 9, 10, 12, 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS dated 2/7/2024) and Torgerson TR, et. al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. 2007 May;132(5):1705-17. doi: 10.1053/j.gastro.2007.02.044. Epub 2007 Feb 23. PMID: 17484868.
Claim interpretation: Claim 2 is directed towards a genetically modified cell comprising a heterologous promoter operably linked to a FOXP3 gene on a nucleic acid in the cell genome. The Examiner notes that the word phrase “heterologous promoter” is not defined in the claims or the specification. Examples of the heterologous promoters EF-1ɑ, MND, and PGK (claim 4) are used; EF-1ɑ and PGK promoters are both promoters to mammalian genes, and therefore an artisan would not understand “heterologous” to be heterologous to the species of the cell. Therefore, the broadest reasonable interpretation of “heterologous promoter” is that the promoter is heterologous to the specific FOXP3 gene to which it is linked. The Examiner notes, therefore, that this could include editing events that fix a mutated FOXP3 gene back to an endogenous FOXP3 promoter because in that event the “wild-type” promoter would be heterologous to the endogenous copy of the FOXP3 gene in that cell.
Marson et al. describes targeted editing a genome in a cell (paragraph [0003]), the method comprising introducing into the cell: (a) a first nucleic acid comprising a heterologous regulatory element (template nucleic acid encodes a sequence that, although adjacent to or flanked by a sufficient region of homology, is entirely orthogonal to the endogenous sequence. For example, the template nucleic acid can encode an inducible promoter; paragraph [0107]); and (b) a nuclease or a second nucleic acid encoding the nuclease (cas9 nuclease; paragraph [0003]), wherein the nuclease is capable of cleaving a targeted locus within or upstream from the first coding exon of a FOXP3 gene in the cell genome, wherein the heterologous regulatory element is inserted into the cell genome, and is operably linked to the FOXP3 gene, thereby producing an engineered cell (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein. For instance, T cells containing a mutation in the FoxP3 gene, or a promoter region thereof can be rescued to treat X-linked IPEX or SLE; paragraph [0105]) (claim 2); The promoter can be inducible or constitutive. The promoter can be tissue specific. In some cases, the promoter is a U6, H1, or spleen focus-forming virus (SFFV) long terminal repeat promoter. In some cases, the promoter is a weak mammalian promoter as compared to the human elongation factor 1 promoter (EF1A). In some cases, the weak mammalian promoter is a ubiquitin C promoter or a phosphoglycerate kinase 1 promoter (PGK) (paragraph [0131])(claims 3-4) wherein the heterologous regulatory element is a heterologous promoter or a heterologous transcriptional enhancer (template nucleic acid encodes a sequence that, although adjacent to or flanked by a sufficient region of homology, is entirely orthogonal to the endogenous sequence. For example, the template nucleic acid can encode an inducible promoter; paragraph [0107]) (claim 6); wherein the heterologous promoter is an inducible promoter (template nucleic acid encodes a sequence that, although adjacent to or flanked by a sufficient region of homology, is entirely orthogonal to the endogenous sequence. For example, the template nucleic acid can encode an inducible promoter; paragraph [0107]) (claim 6); wherein the cell is a hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell (the primary hematopoietic cell is an immune cell. In some cases, the immune cell is a T cell. In some cases, the T cell is a regulatory T cell. In some cases, the regulatory T cell is a CD4+ cell; paragraph [0010]) (claims 12, 14, 18); wherein the cell is a CD25hiCD127lo regulatory T cell (paragraph [0010]) wherein the heterologous promoter is inserted upstream from a natural first coding exon of the FOXP3 gene (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein. For instance, T cells containing a mutation in the FoxP3 gene promoter region; paragraph [0105]); further comprising inserting a heterologous enhancer domain into the cell genome, wherein the heterologous enhancer domain is inserted upstream or downstream from one or more regulatory elements of the FOXP3 gene (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 9); further comprising inserting a heterologous transcriptional activation domain into the cell genome (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10); wherein the cell expresses a chimeric antigen receptor (CAR) (the primary hematopoietic cell or a primary hematopoietic stem cell is modified to express a heterologous protein before the genome of the cell is edited. In some embodiments, the heterologous protein is a chimeric antigen receptor (CAR) protein or a heterologous T-cell Receptor (TCR), including but not limited to a rearranged TCR; paragraph [0003]) (claims 16-17, 18-19); wherein the cell expresses a T cell receptor (TCR) (the primary hematopoietic cell or a primary hematopoietic stem cell is modified to express a heterologous protein before the genome of the cell is edited. In some embodiments, the heterologous protein is a chimeric antigen receptor (CAR) protein or a heterologous T-cell Receptor (TCR), including but not limited to a rearranged TCR; paragraph [0003]).
Marson et. al. teaches “a target genomic region at or near the gene encoding FOXP3 can be targeted to increase or rescue FOXP3 function and thereby treat patients suffering from an autoimmune disease such as IPEX” (paragraph [0114]).
Marson et. al. does not explicitly teach the genetically modified cell wherein the heterologous promoter operably linked to a FOXP3 gene on a nucleic acid in the cell genome is (i) downstream from a Treg-specific demethylated region of the FOXP3 gene; and (ii) upstream from a first coding exon of the FOXP3 gene, wherein the first coding exon of the FOXP3 gene is a natural first coding exon of an endogenous FOXP3 gene.
This deficiency is resolved by Torgerson et. al.
Torgerson et. al. teaches a familial form of IPEX syndrome cause by a 1388-base pair deletion (g.del-6247_-4859) of the FOXP3 gene encompassing a portion of an upstream non-coding exon (exon -1) and the adjacent intro (intron -1) (Abstract, Fig. 4). Torgerson et. al. teaches that the identified mutation leads to abnormal mRNA splicing (Fig. 4 p. 1711 right column-left column ¶1) and a decrease of functional regulatory T cells (p. 1712 left column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify the T-cells of the patients of Torgerson et. al. using the targeted gene editing technique of Torgerson et. al. by inserting a promoter and splice site in order to restore mRNA expression of FOXP3 in IPEX syndrome as taught by Marson et. al. to benefit the patients of Torgerson et. al. by providing them with Treg cells with corrected gene expression. This would result in the heterologous promoter such as the EF1a promoter or an inducible promoter as taught by Marson et. al. inserted at or downstream of the location of g.del-6247_-4859 (reads on downstream of the TSDR) and upstream of the endogenous, unmutated first coding exon of the FOXP3 gene because an artisan would understand that the exogenous promoter activity would better restore splicing if it was downstream of the mutated splice site. This would have a predictable effect because Marson et. al. teaches methods of repairing IPEX mutations using targeted editing including inserting exogenous promoters via HDR upstream of the FOXP3 gene and Torgerson et. al. teaches a particular IPEX-associated mutation that an artisan would have a reasonable expectation of repairing or improving by editing the cell as taught by Marson et. al.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Allan et. al. "Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3." Molecular Therapy 16.1 (2008): 194-202 (Of record, IDS dated 2/7/2024) as evidenced by Mitchell R.S., et. al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2004;2:E234. doi: 10.1371/journal.pbio.0020234 as applied to claim 2 above, and further in view of Zhang, Fang, et al. "Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells." Blood, The Journal of the American Society of Hematology 110.5 (2007): 1448-1457.
The teachings of Allan et. al. as evidenced by Mitchell et. al. in regards to claim 2 are in the 102 rejection above.
Allan et. al. does not teach the genetically modified cells wherein the nucleic acid further comprises a ubiquitous chromatin opening element (UCOE).
This deficiency is resolved by Zhang et. al.
Zhang et. al. teaches the use of a HNRPA2B1-CBX3 UCOE within the context of a self-inactivating lentiviral therapy for restoring immunodeficiency by overexpressing IL2RG in HSCs (Abstract) and teaches that the UCOE constructs resulted in 2.5 to 6.2-fold higher GFP expression that SFFV and CMV vector constructs, respectively. The overexpression of IL2RG in the HSCs resulted in restoration of all lineages including T cells and restored T cell proliferation (Fig. 7, Table 3). Zhang et. al. teaches that “The efficacy of gene transfer in vivo has in many cases been compromised by instability (high variability, silencing) of transgene expression from viral promoters.17,18 Furthermore, potentially mutagenic enhancer activity may be maintained even when linked promoters are silenced by DNA methylation […] We show for the first time that A2UCOE-regulated transgenes within lentiviral vectors produce a high, consistent, and homogeneous population of expressing cells that is not prone to gene silencing both in vitro (Figure 3) and more importantly within either HSCs or their progeny in vivo (Figure 4).” (Discussion, p. 1454).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to add the UCOE regulatory element to the lentiviral FOXP3 construct of Allan et. al. in order to benefit from high, consistent, and homogenous expression in hematopoietic stem cell lineages (such as T cells) as taught by Zhang et. al. when making a more stable Treg with consistently high FOXP3 expression as taught by Allan et. al. This would have a reasonable expectation of success because both Allan and Zhang show stabilization of gene expression in T cells and therefore an artisan would have a reasonable expectation that the FOXP3 expression of Allan et. al. could be stabilized by using the UCOE regulatory element of Zhang et. al.
Claims 5 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS) and Torgerson TR, et. al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. 2007 May;132(5):1705-17. doi: 10.1053/j.gastro.2007.02.044. Epub 2007 Feb 23. PMID: 17484868 as applied to claim 2 above, and further in view of De Ravin SS, et. al. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol. 2016 Apr;34(4):424-9. doi: 10.1038/nbt.3513. Epub 2016 Mar 7.
The teachings of Marson et. al. and Torgerson et. al. in regards to claim 2 are in the 103 rejection above.
Marson et. al. in view of Torgerson et. al. does not explicitly teach wherein the promoter is an MND promoter; wherein the cell is a CD4+ Treg expressing a TCR or a CAR wherein the heterologous promoter is an MND promoter; wherein the cell is a CD8+ Treg expressing a TCR or a CAR wherein the heterologous promoter is an MND promoter.
This deficiency is resolved by De Ravin et. al.
De Ravin et. al. teaches a method of gene therapy to modify human CD34+ hematopoietic stem and progenitor cells (HPSCs) using targeted integration into the human genome and a vector with an MND promoter operably linked to gp91 phox cDNA (target cDNA). De Ravin et. al. teaches “The MND (Myeloproliferative sarcoma virus MPSV enhancer, negative control region NCR deleted, d1587rev primer-binging site substituted) promoter has been shown to be suitable to drive high levels of transgene expression in HSCs19, 20. Further optimization of AAV6-donor delivery into HSCs from CGD patients to balance effects on cell growth and transfection efficiency achieved 15% gp91phox protein expression in vitro (Fig. 4a) from both the MND-gp91 donor and the SA-2A-gp91 donor [...] Despite similar TI efficiencies with both MND-91phox and SA-2A-gp91 donors, corrected cells produce significantly more gp91 from the MND promoter (MFI 107) versus from the captured PPP1R12C promoter (MFI 49)” () and that the higher levels driven by the MND promoter approached normal function. De Ravin et. al. teaches that the edited HSCs engrafted and produced engrafted progenitors (Fig. 1e).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the MND promoter of De Ravin et. al. in the place of the heterologous constitutive promoter such as EF1a as taught by Marson et. al. in view of Torgerson et. al. in order to benefit from the higher levels of expression in HSCs and the higher likelihood of restoration of gene function; this would further result in progenitor cells such as the CD4+ Tregs of Marson et. al. comprising the modification via maturation of the progenitors as taught by De Ravin. This would have a predictable effect because an artisan would expect to have similar expression benefits with a different genes expressed with the same promoter in the same cell type, and both Marson et. al. and De Ravin et. al. teach targeting the promoter to a particular locus for gene therapy. It would additionally be obvious, as taught by Marson et. al., to further modify the cells with a TCR or a CAR in order to induce antigen-specific tolerance for improvement of the outcomes in the Torgerson et. al. patients. This would have a reasonable expectation of success because an artisan would expect to be able to express a CAR or TCR in the constitutive promoter-FOXP3 cell as taught by Marson et. al. in view of Torgerson; and would expect improved FOXP3 expression from the teachings of De Ravin et. al. as described.
Claims 13, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS) and Torgerson TR, et. al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. 2007 May;132(5):1705-17. doi: 10.1053/j.gastro.2007.02.044. Epub 2007 Feb 23. PMID: 17484868. as applied to claim 2 above, and further in view of De Ravin SS, et. al. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol. 2016 Apr;34(4):424-9. doi: 10.1038/nbt.3513. Epub 2016 Mar 7 and WO2017042170 to Guillonneau effectively filed 7 September 2015.
The teachings of Marson et. al. and Torgerson et. al. in regards to claim 2 are in the 103 rejection above.
Marson et. al. in view of Torgerson et. al. does not teach wherein the T cell is a CD8 T cell, and wherein the cell is a CD8+ regulatory T cell expressing a CAR, and wherein the heterologous promoter is an MND promoter; or a pharmaceutical composition comprising the cells a pharmaceutically acceptable excipient.
This deficiency is resolved by Guillonneau and De Ravin.
De Ravin et. al. teaches a method of gene therapy to modify human CD34+ hematopoietic stem and progenitor cells (HPSCs) using targeted integration into the human genome and a vector with an MND promoter operably linked to gp91 phox cDNA (target cDNA). De Ravin et. al. teaches “The MND (Myeloproliferative sarcoma virus MPSV enhancer, negative control region NCR deleted, d1587rev primer-binging site substituted) promoter has been shown to be suitable to drive high levels of transgene expression in HSCs19, 20. Further optimization of AAV6-donor delivery into HSCs from CGD patients to balance effects on cell growth and transfection efficiency achieved 15% gp91phox protein expression in vitro (Fig. 4a) from both the MND-gp91 donor and the SA-2A-gp91 donor [...] Despite similar TI efficiencies with both MND-91phox and SA-2A-gp91 donors, corrected cells produce significantly more gp91 from the MND promoter (MFI 107) versus from the captured PPP1R12C promoter (MFI 49)” (p. 427 right column) and that the higher levels driven by the MND promoter approached normal function. De Ravin et. al. teaches that the edited HSCs engrafted and produced engrafted progenitors (Fig. 1e).
Guillonneau et. al. teaches a new subpopulation of CD8+CD45RLOW Tregs and teaches “Indeed, the highly suppressive isolated Tregs may then be expanded and pulsed with antigens of interest or genetically modified (e.g. in order to express a given chimeric antibody receptor also referred to as CAR or to express a chimeric T cell receptor (TCR)) or other types of chimeric antigen receptors in order to efficiently induce antigen- specific immune tolerance. Such expanded populations of Treg cells are of particular interest in the fields of chronic inflammation, autoimmunity, allergy, transplantation, treatment with therapeutic protein and gene therapy, to avoid degradation of self or therapeutic molecules/tissues by the immune system” (p. 1 lines 28-p. 2 line 2). Guillonneau teaches that this highly suppressive Treg population expresses FoxP3 (p. 3 lines 21-32). Regarding claim 21, Guillonneau teaches pharmaceutical compositions comprising the CD8+CD45LOW Tregs of the invention and a pharmaceutically acceptable additives, diluents or stabilizers (reads on excipient; p. 34 line 33-p. 35 line 8).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the MND promoter of De Ravin et. al. in the place of the heterologous constitutive promoter such as EF1a as taught by Marson et. al. in view of Torgerson et. al. in order to benefit from the higher levels of expression in HSCs and the higher likelihood of restoration of gene function; this would further result in progenitor cells such as the CD4+ Tregs of Marson et. al. comprising the modification via maturation of the progenitors as taught by De Ravin. This would have a predictable effect because an artisan would expect to have similar expression benefits with a different genes expressed with the same promoter in the same cell type, and both Marson et. al. and De Ravin et. al. teach targeting the promoter to a particular locus for gene therapy. It would additionally be obvious, as taught by Marson et. al., to further modify the cells with a TCR or a CAR in order to induce antigen-specific tolerance for improvement of the outcomes in the Torgerson et. al. patients. This would have a reasonable expectation of success because an artisan would expect to be able to express a CAR or TCR in the constitutive promoter-FOXP3 cell as taught by Marson et. al. in view of Torgerson; and would expect improved FOXP3 expression from the teachings of De Ravin et. al. as described.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to edit the obtain CD8+CD45RLow population as taught by Guillonneau from the HSCs of patients of modified Marson et. al. in view of Torgerson et. al. and De Ravin et. al. in order to benefit from the increased immunosuppressive properties of CD8+CDR45RLow T cells as taught by Marson et. al. to make an improved cell and pharmaceutical composition for treatment; further, an artisan would expect to be able to make an improved T cell composition for reducing the IPEX symptoms as taught by Torgerson et. al. by inducing antigen-specific tolerance to the food allergens of Torgerson et. al. by expressing a CAR as suggested by Marson and Guillonneau et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use an improved type of regulatory T cell in place of the generic regulatory T cell of Marson et. al.
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.
U.S. Patent No. 11713459
Claims 2-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11713459. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the instant claims.
The claims of the ‘459 patent teach a method of making a genetically modified CD34+ cell, the method comprising delivering to a CD34+ cell a donor template comprising a first homology arm having homology to a sequence in FOXP3 gene in the CD34+ cell, a second homology arm having homology to a sequence in the same gene or locus as the first homology arm; a promoter; and a FOXP3 cDNA sequence (claim 1; reads on instant claim 2) and that the promoter is a MPSV enhancer, MND promoter, PGK promoter, EF1a promoter, or E2F promoter (claim 5; reads on instant claims 3, 4, 5). As described in the 112(b) above, instant claim 2 does not clearly delineate the metes and bounds of the location or which strand is considered for “upstream” or “downstream”, any location within the FOXP3 locus as claimed by ‘459 would be downstream of the TSDR and the promoter-cDNA would naturally place the promoter upstream of the first coding exon of the FOXP3 gene. The examiner further notes that the spacer sequences of claim 4 of ‘459 further disclose sequences that would target particular locations in the FOXP3 gene that would be downstream of the TSDR of endogenous FOXP3 on the coding strand. Although the claims are not identical, a method of making a composition teaches the composition, and therefore the claims of ‘459 anticipate the instant claims.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11713459 as applied to claim 2 above, in further view of in view of Zhang, Fang, et al. "Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells." Blood, The Journal of the American Society of Hematology 110.5 (2007): 1448-1457.
The teachings of the ‘459 patent claims are in the NSDP rejection above.
The ‘459 patent does not teach the cell wherein the nucleic acid further comprises a UCOE.
This is resolved by Zhang. The teachings of Zhang et. al. are in the 103 rejection above. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to add the UCOE regulatory element to the lentiviral FOXP3 construct of the ‘459 claims in order to benefit from high, consistent, and homogenous expression in hematopoietic stem cell lineages (such as T cells) as taught by Zhang et. al. This would have a reasonable expectation of success because both ‘459 and Zhang show stabilization of gene expression in HSCs and therefore an artisan would have a reasonable expectation that the FOXP3 expression of ‘459 could be stabilized by using the UCOE regulatory element of Zhang et. al.
Claims 6, 9-10, 12, and 14-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11713459 as applied to claim 2 above, in further view of WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS).
The teachings of the ‘459 patent claims are in the NSDP rejection above.
The ‘459 patent does not teach the modified cell wherein the heterologous promoter is an inducible promoter.
This is resolved by Marson et. al. The teachings of Marson et. al. are in the 103 rejection above. Briefly, Marson et. al. teaches genomic editing of cells a location in the FOXP3 gene and insertion of a promoter wherein the promoter is an inducible promoter: the template nucleic acid can encode an inducible promoter; paragraph [0107]); and (b) a nuclease or a second nucleic acid encoding the nuclease (cas9 nuclease; paragraph [0003]), wherein the nuclease is capable of cleaving a targeted locus within or upstream from the first coding exon of a FOXP3 gene in the cell genome, wherein the heterologous regulatory element is inserted into the cell genome, and is operably linked to the FOXP3 gene, thereby producing an engineered cell (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the combine the method of editing a FOXP3 locus of ‘459 with the method of editing a FOXP3 locus of Marson et. al. to arrive at a CD34+ cell edited to target an inducible promoter as taught by Marson et. al. and FOXP3 cDNA as taught by ‘459. This would have a reasonable expectation of success because a person of ordinary skill in the art would be able to select a suitable promoter for their application to control FOXP3 expression and both Marson et. al. and ‘459 teach editing and insertion of a promoter into the endogenous FOXP3 gene.
Regarding claims 9 and 10, the ‘459 claims do not disclose a heterologous transcriptional enhancer domain or a heterologous transcriptional activation domain.
This is resolved by Marson et. al. As described in the 103 rejection above, Marson et. al. teaches: As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 9); further comprising inserting a heterologous transcriptional activation domain into the cell genome (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to include the enhancer elements or transcriptional activation domains of Marson et. al. in the CD34+ modified cell as taught by the ‘459 claims in order to benefit from control of promoter expression through enhancer elements or transcriptional activation domains as taught by Marson et. al. This would have a reasonable expectation of success because an artisan would be able to incorporate known enhancer and transcriptional activation elements as taught by Marson et. al. to control the expression of FOXP3 as taught by both Marson et. al. and the ‘459 claims.
Regarding claims 12, 14, and 16-19, Marson et. al. teaches the template nucleic acid can encode an inducible promoter; paragraph [0107]) (claim 6); wherein the cell is a hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell (the primary hematopoietic cell is an immune cell. In some cases, the immune cell is a T cell. In some cases, the T cell is a regulatory T cell. In some cases, the regulatory T cell is a CD4+ cell; paragraph [0010]) (claims 12, 14, 18); wherein the cell is a CD25hiCD127lo regulatory T cell (paragraph [0010]) wherein the heterologous promoter is inserted upstream from a natural first coding exon of the FOXP3 gene (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein; further comprising inserting a heterologous transcriptional activation domain into the cell genome); (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10); wherein the cell expresses a chimeric antigen receptor (CAR) (the primary hematopoietic cell or a primary hematopoietic stem cell is modified to express a heterologous protein before the genome of the cell is edited. In some embodiments, the heterologous protein is a chimeric antigen receptor (CAR) protein or a heterologous T-cell Receptor (TCR), including but not limited to a rearranged TCR; paragraph [0003])
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify a CD4+ T cell or a T regulatory cell (and further wherein the T cell is CD25hiCD127lo) as taught by Marson et. al. using the method of modifying FOXP3 as taught by ‘459, resulting in a modified regulatory T cell because CD34 is a marker of hematopoietic stem cells and Marson discloses embodiments of hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell. This would have a predictable effect because FOXP3 is a known regulator of T cell differentiation and therefore a person of ordinary skill in the art would be able to choose which type of cell (HSC, CD4+ T cell, or Treg) to modify as taught by Marson et. al.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, for the cell to further included a CAR or TCR as taught by Marson et. al. in order to benefit from a modified FOXP3-T-cell expressing a CAR or TCR as taught by Marson et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use the technique of ‘459 for modifying FOXP3 expression at the FOXP3 locus to create the CAR or TCR-expressing FOXP3-expressing HSCs or T cells as taught by Marson et. al.
Claims 13, 20, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11713459 as applied to claim 2 above, in further view of WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS) as applied to claims 17-19 above, and in further view of WO2017042170 to Guillonneau et. al. effectively filed 7 September 2015.
The teachings the ‘459 claims and the ‘459 in view of Marson et. al. are in the NSDP rejections above and are incorporated by reference herein.
As described, ‘459 in view of Marson et. al. makes obvious a CD4+ regulatory T cell expressing a CAR and wherein the heterologous promoter is an MND promoter.
‘459 in view of Marson et. al. does not make obvious a CD8+ regulatory T cell expressing a CAR and wherein the heterologous promoter is an MND promoter.
This deficiency is resolved by Guillonneau et. al.
Guillonneau et. al. teaches a new subpopulation of CD8+CD45RLOW Tregs and teaches “Indeed, the highly suppressive isolated Tregs may then be expanded and pulsed with antigens of interest or genetically modified (e.g. in order to express a given chimeric antibody receptor also referred to as CAR or to express a chimeric T cell receptor (TCR)) or other types of chimeric antigen receptors in order to efficiently induce antigen- specific immune tolerance. Such expanded populations of Treg cells are of particular interest in the fields of chronic inflammation, autoimmunity, allergy, transplantation, treatment with therapeutic protein and gene therapy, to avoid degradation of self or therapeutic molecules/tissues by the immune system” (p. 1 lines 28-p. 2 line 2). Guillonneau teaches that this highly suppressive Treg population expresses FoxP3 (p. 3 lines 21-32). Regarding claim 21, Guillonneau teaches pharmaceutical compositions comprising the CD8+CD45LOW Tregs of the invention and a pharmaceutically acceptable additives, diluents or stabilizers (reads on excipient; p. 34 line 33-p. 35 line 8).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to edit the a CD8+CD45RLow population as taught by Guillonneau using the method of Maron et. al. and ‘459 in order to obtained a CD8+ increased immunosuppressive properties of CD8+CDR45RLow T cells as taught by Marson et. al. that further expresses a CAR and FOXP3 under the control of an MND promoter as taught by ‘459 in view of Marson et. al. and to make an improved pharmaceutical composition for treatment; further, an artisan would expect to be able to make an improved T cell composition for suppressing an antigen-specific T-regulatory response by expressing a CAR as suggested by Marson and Guillonneau et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use an improved type of regulatory T cell in place of the generic or CD4+ regulatory T cell of ‘459 in view Marson et. al.
Co-pending App. No. 16981213
Claims 2-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-34, 37, 44-46, 48, 50, 52-55, and 57 of co-pending Application No. 16981213. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the ‘213 application teach a method of making modifying a lymphocytic cell, the method comprising delivering to a lymphocytic cell a donor template comprising a first homology arm having homology to a sequence in FOXP3 gene, a second homology arm having homology to a sequence in the same gene or locus as the first homology arm; a heterologous constitutive promoter; and a nucleotide sequence lacking introns and encoding a FOXP3 polypeptide sequence (claim 28; reads on instant claim 2) and delivering a gRNA spacer that is homologous to the FOXP3 gene (claim 30); and that the promoter is an MND promoter, PGK promoter, or E2F promoter, in particular an MND promoter (claim 33, claim 48; reads on instant claims 3, 4, 5). As described in the 112(b) above, instant claim 2 does not clearly delineate the metes and bounds of the location or which strand is considered for “upstream” or “downstream”, any location within the FOXP3 locus as claimed by ‘213 would be downstream of the TSDR and the promoter-cDNA would naturally place the promoter upstream of the first coding exon of the FOXP3 gene. The examiner further notes that the spacer sequences of claim 31 of ‘213 further disclose sequences that would target particular locations in the FOXP3 gene that would be downstream of the TSDR of endogenous FOXP3 on the coding strand. Although the claims are not identical, a method of making a composition teaches the composition, and therefore the claims of ‘213 anticipate the instant claims.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-34, 37, 44-46, 48, 50, 52-55, and 57 of co-pending Application No. 16981213 as applied to claim 2 above, in further view of in view of Zhang, Fang, et al. "Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells." Blood, The Journal of the American Society of Hematology 110.5 (2007): 1448-1457.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of the ‘213 application claims are in the NSDP rejection above.
The ‘213 application does not teach the cell wherein the nucleic acid further comprises a UCOE.
This is resolved by Zhang. The teachings of Zhang et. al. are in the 103 rejection above. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to add the UCOE regulatory element to the lentiviral FOXP3 construct of the ‘213 claims in order to benefit from high, consistent, and homogenous expression in hematopoietic stem cell lineages (such as T cells) as taught by Zhang et. al. This would have a reasonable expectation of success because both ‘213 and Zhang show stabilization of gene expression in HSCs or lymphocytic cells and therefore an artisan would have a reasonable expectation that the FOXP3 expression of ‘213 could be stabilized by using the UCOE regulatory element of Zhang et. al.
Claims 6, 9-10, 12, and 14-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-34, 37, 44-46, 48, 50, 52-55, and 57 of co-pending Application No. 16981213 as applied to claim 2 above, in further view of WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of the ‘213 claims are in the NSDP rejection above.
The ‘213 application does not teach the modified cell wherein the heterologous promoter is an inducible promoter.
This is resolved by Marson et. al. The teachings of Marson et. al. are in the 103 rejection above. Briefly, Marson et. al. teaches genomic editing of cells a location in the FOXP3 gene and insertion of a promoter wherein the promoter is an inducible promoter: the template nucleic acid can encode an inducible promoter; paragraph [0107]); and (b) a nuclease or a second nucleic acid encoding the nuclease (cas9 nuclease; paragraph [0003]), wherein the nuclease is capable of cleaving a targeted locus within or upstream from the first coding exon of a FOXP3 gene in the cell genome, wherein the heterologous regulatory element is inserted into the cell genome, and is operably linked to the FOXP3 gene, thereby producing an engineered cell (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the combine the method of editing a FOXP3 locus of ‘213 with the method of editing a FOXP3 locus of Marson et. al. to arrive at a CD34+ cell edited to target an inducible promoter as taught by Marson et. al. and FOXP3 cDNA as taught by ‘213. This would have a reasonable expectation of success because a person of ordinary skill in the art would be able to select a suitable promoter for their application to control FOXP3 expression and both Marson et. al. and ‘459 teach editing and insertion of a promoter into the endogenous FOXP3 gene.
Regarding claims 9 and 10, the ‘213 claims do not disclose a heterologous transcriptional enhancer domain or a heterologous transcriptional activation domain.
This is resolved by Marson et. al. As described in the 103 rejection above, Marson et. al. teaches: As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 9); further comprising inserting a heterologous transcriptional activation domain into the cell genome (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to include the enhancer elements or transcriptional activation domains of Marson et. al. in the CD34+ modified cell as taught by the ‘213 claims in order to benefit from control of promoter expression through enhancer elements or transcriptional activation domains as taught by Marson et. al. This would have a reasonable expectation of success because an artisan would be able to incorporate known enhancer and transcriptional activation elements as taught by Marson et. al. to control the expression of FOXP3 as taught by both Marson et. al. and the ‘459 claims.
Regarding claims 12, 14, and 16-19, Marson et. al. teaches the template nucleic acid can encode an inducible promoter; paragraph [0107]) (claim 6); wherein the cell is a hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell (the primary hematopoietic cell is an immune cell. In some cases, the immune cell is a T cell. In some cases, the T cell is a regulatory T cell. In some cases, the regulatory T cell is a CD4+ cell; paragraph [0010]) (claims 12, 14, 18); wherein the cell is a CD25hiCD127lo regulatory T cell (paragraph [0010]) wherein the heterologous promoter is inserted upstream from a natural first coding exon of the FOXP3 gene (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein; further comprising inserting a heterologous transcriptional activation domain into the cell genome); (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10); wherein the cell expresses a chimeric antigen receptor (CAR) (the primary hematopoietic cell or a primary hematopoietic stem cell is modified to express a heterologous protein before the genome of the cell is edited. In some embodiments, the heterologous protein is a chimeric antigen receptor (CAR) protein or a heterologous T-cell Receptor (TCR), including but not limited to a rearranged TCR; paragraph [0003])
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify a CD4+ T cell or a T regulatory cell (and further wherein the T cell is CD25hiCD127lo) as taught by Marson et. al. using the method of modifying FOXP3 as taught by ‘213, resulting in a modified regulatory T cell because CD34 is a marker of hematopoietic stem cells and Marson discloses embodiments of hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell. This would have a predictable effect because FOXP3 is a known regulator of T cell differentiation and therefore a person of ordinary skill in the art would be able to choose which type of cell (HSC, CD4+ T cell, or Treg) to modify as taught by Marson et. al.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, for the cell to further included a CAR or TCR as taught by Marson et. al. in order to benefit from a modified FOXP3-T-cell expressing a CAR or TCR as taught by Marson et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use the technique of ‘213 for modifying FOXP3 expression at the FOXP3 locus to create the CAR or TCR-expressing FOXP3-expressing HSCs or T cells as taught by Marson et. al.
Claims 13, 20, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-34, 37, 44-46, 48, 50, 52-55, and 57 of co-pending Application No. 16981213 as applied to claim 2 above, in further view of WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS) as applied to claims 17-19 above, and in further view of WO2017042170 to Guillonneau et. al. effectively filed 7 September 2015.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings the ‘459 claims and the ‘459 in view of Marson et. al. are in the NSDP rejections above and are incorporated by reference herein.
As described, ‘459 in view of Marson et. al. makes obvious a CD4+ regulatory T cell expressing a CAR and wherein the heterologous promoter is an MND promoter.
‘459 in view of Marson et. al. does not make obvious a CD8+ regulatory T cell expressing a CAR and wherein the heterologous promoter is an MND promoter.
This deficiency is resolved by Guillonneau et. al.
Guillonneau et. al. teaches a new subpopulation of CD8+CD45RLOW Tregs and teaches “Indeed, the highly suppressive isolated Tregs may then be expanded and pulsed with antigens of interest or genetically modified (e.g. in order to express a given chimeric antibody receptor also referred to as CAR or to express a chimeric T cell receptor (TCR)) or other types of chimeric antigen receptors in order to efficiently induce antigen- specific immune tolerance. Such expanded populations of Treg cells are of particular interest in the fields of chronic inflammation, autoimmunity, allergy, transplantation, treatment with therapeutic protein and gene therapy, to avoid degradation of self or therapeutic molecules/tissues by the immune system” (p. 1 lines 28-p. 2 line 2). Guillonneau teaches that this highly suppressive Treg population expresses FoxP3 (p. 3 lines 21-32). Regarding claim 21, Guillonneau teaches pharmaceutical compositions comprising the CD8+CD45LOW Tregs of the invention and a pharmaceutically acceptable additives, diluents or stabilizers (reads on excipient; p. 34 line 33-p. 35 line 8).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to edit the a CD8+CD45RLow population as taught by Guillonneau using the method of Maron et. al. and ‘213 in order to obtained a CD8+ increased immunosuppressive properties of CD8+CDR45RLow T cells as taught by Marson et. al. that further expresses a CAR and FOXP3 under the control of an MND promoter as taught by ‘213 in view of Marson et. al. and to make an improved pharmaceutical composition for treatment; further, an artisan would expect to be able to make an improved T cell composition for suppressing an antigen-specific T-regulatory response by expressing a CAR as suggested by Marson and Guillonneau et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use an improved type of regulatory T cell in place of the generic or CD4+ regulatory T cell of ‘213 in view Marson et. al.
Co-pending App. No. 18336276
Claims 2-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 4-23 of co-pending Application No. 18336276. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the ‘276 application teach a CD34+ cell, comprising a constitutive promoter operably linked to a polynucleotide sequence lacking introns and encoding a FOXP3, wherein the promoter and the polynucleotide are located in a FOXP3 gene (claim 2; reads on instant claim 2); and that the promoter is an MND promoter, PGK promoter, or E2F promoter, in particular an MND promoter (claim 4 and 13; 17; reads on instant claims 3, 4, 5). As described in the 112(b) above, instant claim 2 does not clearly delineate the metes and bounds of the location or which strand is considered for “upstream” or “downstream”, any location within the FOXP3 locus as claimed by ‘276 would be downstream of the TSDR and the promoter-cDNA would naturally place the promoter upstream of the first coding exon of the FOXP3 gene. Although the claims are not identical, the genetically edited CD34+ cells comprising the promoter in the FOXP3 gene and encoding the FOXP3 read on the instantly claimed cell as described and therefore anticipate the instant claims.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 4-23 of co-pending Application No. 18336276 as applied to claim 2 above, in further view of in view of Zhang, Fang, et al. "Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells." Blood, The Journal of the American Society of Hematology 110.5 (2007): 1448-1457.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of the ‘276 application claims are in the NSDP rejection above.
The ‘276 application does not teach the cell wherein the nucleic acid further comprises a UCOE.
This is resolved by Zhang. The teachings of Zhang et. al. are in the 103 rejection above. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to add the UCOE regulatory element to the CD34+ comprising the promoter-FOXP3 of the ‘276 claims in order to benefit from high, consistent, and homogenous expression in hematopoietic stem cell lineages (such as T cells) as taught by Zhang et. al. This would have a reasonable expectation of success because both ‘276 and Zhang show stabilization of gene expression in HSCs (CD34+ cells) and therefore an artisan would have a reasonable expectation that the FOXP3 expression of ‘276 could be stabilized by using the UCOE regulatory element of Zhang et. al.
Claims 6, 9-10, 12, and 14-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 2 and 4-23 of co-pending Application No. 18336276 as applied to claim 2 above, in further view of WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of the ‘276 claims are in the NSDP rejection above.
The ‘276 application does not teach the modified cell wherein the heterologous promoter is an inducible promoter.
This is resolved by Marson et. al. The teachings of Marson et. al. are in the 103 rejection above. Briefly, Marson et. al. teaches genomic editing of cells a location in the FOXP3 gene and insertion of a promoter wherein the promoter is an inducible promoter: the template nucleic acid can encode an inducible promoter; paragraph [0107]); and (b) a nuclease or a second nucleic acid encoding the nuclease (cas9 nuclease; paragraph [0003]), wherein the nuclease is capable of cleaving a targeted locus within or upstream from the first coding exon of a FOXP3 gene in the cell genome, wherein the heterologous regulatory element is inserted into the cell genome, and is operably linked to the FOXP3 gene, thereby producing an engineered cell (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the combine the CD34+ edited cell of ‘276 with the method of editing a FOXP3 locus of Marson et. al. to arrive at a CD34+ cell edited to target an inducible promoter as taught by Marson et. al. and FOXP3 cDNA as taught by ‘276. This would have a reasonable expectation of success because a person of ordinary skill in the art would be able to select a suitable promoter for their application to control FOXP3 expression and both Marson et. al. and ‘276 teach a cell with insertion of a promoter into the endogenous FOXP3 gene.
Regarding claims 9 and 10, the ‘276 claims do not disclose a heterologous transcriptional enhancer domain or a heterologous transcriptional activation domain.
This is resolved by Marson et. al. As described in the 103 rejection above, Marson et. al. teaches: As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 9); further comprising inserting a heterologous transcriptional activation domain into the cell genome (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to include the enhancer elements or transcriptional activation domains of Marson et. al. in the CD34+ modified cell as taught by the ‘276 claims in order to benefit from control of promoter expression through enhancer elements or transcriptional activation domains as taught by Marson et. al. This would have a reasonable expectation of success because an artisan would be able to incorporate known enhancer and transcriptional activation elements as taught by Marson et. al. to control the expression of FOXP3 as taught by both Marson et. al. and the ‘276 claims.
Regarding claims 12, 14, and 16-19, Marson et. al. teaches the template nucleic acid can encode an inducible promoter; paragraph [0107]) (claim 6); wherein the cell is a hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell (the primary hematopoietic cell is an immune cell. In some cases, the immune cell is a T cell. In some cases, the T cell is a regulatory T cell. In some cases, the regulatory T cell is a CD4+ cell; paragraph [0010]) (claims 12, 14, 18); wherein the cell is a CD25hiCD127lo regulatory T cell (paragraph [0010]) wherein the heterologous promoter is inserted upstream from a natural first coding exon of the FOXP3 gene (template nucleic acid can encode a sequence for rescuing the expression level or activity of a target endogenous gene or protein; further comprising inserting a heterologous transcriptional activation domain into the cell genome); (a promoter is defined as an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes distal enhancer elements; paragraph [0023]) (claim 10); wherein the cell expresses a chimeric antigen receptor (CAR) (the primary hematopoietic cell or a primary hematopoietic stem cell is modified to express a heterologous protein before the genome of the cell is edited. In some embodiments, the heterologous protein is a chimeric antigen receptor (CAR) protein or a heterologous T-cell Receptor (TCR), including but not limited to a rearranged TCR; paragraph [0003])
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify a CD4+ T cell or a T regulatory cell (and further wherein the T cell is CD25hiCD127lo) as taught by Marson et. al. using the method of modifying FOXP3 as taught by ‘276, resulting in a modified regulatory T cell because CD34 is a marker of hematopoietic stem cells and Marson discloses embodiments of hematopoietic stem cell, a CD4+ T cell, or a T regulatory (Treg) cell. This would have a predictable effect because FOXP3 is a known regulator of T cell differentiation and therefore a person of ordinary skill in the art would be able to choose which type of cell (HSC, CD4+ T cell, or Treg) to modify as taught by Marson et. al.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, for the cell to further included a CAR or TCR as taught by Marson et. al. in order to benefit from a modified FOXP3-T-cell expressing a CAR or TCR as taught by Marson et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use the technique of ‘276 for modifying FOXP3 expression at the FOXP3 locus to create the CAR or TCR-expressing FOXP3-expressing HSCs or T cells as taught by Marson et. al.
Claims 13, 20, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 4-23 of co-pending Application No. 18336276 as applied to claim 2 above, in further view of WO2016123578 to Marson et. al. published 4 August 2016 (Of record, cited in IDS) as applied to claims 17-19 above, and in further view of WO2017042170 to Guillonneau et. al. effectively filed 7 September 2015.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings the ‘276 claims and the ‘276 in view of Marson et. al. are in the NSDP rejections above and are incorporated by reference herein.
As described, ‘276 in view of Marson et. al. makes obvious a CD4+ regulatory T cell expressing a CAR and wherein the heterologous promoter is an MND promoter.
‘276 in view of Marson et. al. does not make obvious a CD8+ regulatory T cell expressing a CAR and wherein the heterologous promoter is an MND promoter.
This deficiency is resolved by Guillonneau et. al.
Guillonneau et. al. teaches a new subpopulation of CD8+CD45RLOW Tregs and teaches “Indeed, the highly suppressive isolated Tregs may then be expanded and pulsed with antigens of interest or genetically modified (e.g. in order to express a given chimeric antibody receptor also referred to as CAR or to express a chimeric T cell receptor (TCR)) or other types of chimeric antigen receptors in order to efficiently induce antigen- specific immune tolerance. Such expanded populations of Treg cells are of particular interest in the fields of chronic inflammation, autoimmunity, allergy, transplantation, treatment with therapeutic protein and gene therapy, to avoid degradation of self or therapeutic molecules/tissues by the immune system” (p. 1 lines 28-p. 2 line 2). Guillonneau teaches that this highly suppressive Treg population expresses FoxP3 (p. 3 lines 21-32). Regarding claim 21, Guillonneau teaches pharmaceutical compositions comprising the CD8+CD45LOW Tregs of the invention and a pharmaceutically acceptable additives, diluents or stabilizers (reads on excipient; p. 34 line 33-p. 35 line 8).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to edit the a CD8+CD45RLow population as taught by Guillonneau using the method of Maron et. al. and ‘276 in order to obtained a CD8+ increased immunosuppressive properties of CD8+CDR45RLow T cells as taught by Marson et. al. that further expresses a CAR and FOXP3 under the control of an MND promoter as taught by ‘276 in view of Marson et. al. and to make an improved pharmaceutical composition for treatment; further, an artisan would expect to be able to make an improved T cell composition for suppressing an antigen-specific T-regulatory response by expressing a CAR as suggested by Marson and Guillonneau et. al. This would have a reasonable expectation of success because an artisan would expect to be able to use an improved type of regulatory T cell in place of the generic or CD4+ regulatory T cell of ‘276 in view Marson et. al.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678