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 .
Election/Species
A telephone call was made to Susan J. Myers Fitch on 03 September 2026 to request an oral election of species, but did not result in an election being made.
Claim Status
Claims 1-20 are currently amended and claims 1-20 have been considered on their merits.
Claim Objections
Claims 2-20 are objected to because of the following informalities: Claims 2-20 ultimately depend from claim 1 and for proper form should start with the phrase “The mammalian synthetic chromosome …” rather than “A mammalian synthetic chromosome …”.
Appropriate correction is required.
Claim Interpretation
Claim 1 is directed to a mammalian synthetic chromosome, this term is defined on page 46 of the instant specification as: “Synthetic chromosomes” (also referred to as “artificial chromosomes”) are nucleic acid molecules, that stably replicate and segregate alongside endogenous chromosomes in cells and are subject to the host cell's native DNA replication and repair mechanisms, thereby providing optimal integrity. A “mammalian synthetic chromosome” refers to chromosomes that have an active mammalian centromere(s). Thus, any modified mammalian chromosome reads on the mammalian synthetic chromosome of claim 1. Since the genes encoding chemokine receptors are present in the lymphocyte genome, even if they are not expressed on the cells surface (Stengel, para. [0006]). Therefore, a lymphocyte with a modified chromosome would read on the limitations of claim 1, as lymphocyte chromosomes inherently possess nucleic acids encoding the chemokine receptors.
Claim 13 recites the intended use of a mammalian synthetic chromosome for cellular homing. Claims 17-18 recite the intended use of a cell comprising a mammalian synthetic chromosome according to claim 1. These intended use statements are not limiting because they do not add structure to the product. It has been held that when the body of a claim fully and intrinsically sets forth all limitations of the claimed invention, such as all the components of a composition, and the preamble merely states the intended use of the invention, rather than any distinct definition of the any of the claimed invention’s limitations, the preamble is not considered a limitation and is of no significance to claim construction. See MPEP § 2111.02.
Claim 14 is recited as an independent claim comprising a mammalian synthetic chromosome. The remaining limitations following “for use” read as an intended use of a product. Therefore, this claim is interpreted as any mammalian synthetic chromosome
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 1-11 and 13-20 are rejected under 35 U.S.C. 102(a)(1)/a)(2) as being anticipated by Stengel (WO 2019/113132 A1, published 13 June 2019) as evidenced by Hughes et al. (The FEBS Journal 285 (2018) 2944-2971).
Regarding claims 1-3 and 15, Stengel teaches modified lymphocytes that express an endogenous gene of interest, such as a gene encoding a chemokine cell surface receptor (Abstract). Stengel teaches there is a need for lymphocytes that are modified to express cell surface endogenous genes normally silent or transcriptionally repressed, in order to target lymphocytes to a particular tumor or tumor microenvironment (para. [0008]). Stengel teaches the lymphocyte comprises a modification whereby at least one endogenous chemokine receptor-encoding gene in the lymphocyte genome is expressed, wherein the at least one endogenous chemokine receptor-encoding gene is not expressed in a naturally occurring lymphocyte, and further wherein the modification does not comprise an engineered insertion of the at least one chemokine receptor encoding gene into the lymphocyte cell genome (para. [0009]). Stengel teaches the endogenous chemokine receptor-encoding gene to include CCR4 (claim 3), CXCR3, and CXCR4 (claim 2) (para. [0011]). Stengel teaches the method comprising introducing into the lymphocyte an artificial transcription factor (ATF) complex comprising a catalytically inactive polynucleotide binding domain and an effector domain, wherein the complex targets and binds to a nucleic acid target sequence proximal to a transcriptional start site (TSS) of a selected endogenous chemokine receptor-encoding gene in the genome of the lymphocyte to promote expression of the gene (para. [0013]). Stengel teaches expression cassettes can be introduced into a wide variety of organisms including mammalian cells (para. [00132]). The chromosomes within the modified cell read as a mammalian synthetic chromosome according to the claim interpretation above, as the chromosomes have been modified to induce expression of a chemokine receptor. Therefore, the modified lymphocyte of Stengel reads as a cell (claim 15) comprising a mammalian synthetic chromosome comprising a nucleic acid sequence encoding a chemokine receptor (claim 1).
Regarding claim 4, Stengel teaches although the number of chemokines and cognate chemokine receptors is large, each lymphocyte type expresses only a limited set of chemokine receptors on their surface, despite the fact that the genes encoding these receptors are present in the lymphocyte genome (para. [0006]). Therefore, the synthetic chromosome within the modified lymphocyte of Stengel would necessarily comprise two or more nucleic acid sequences encoding two or more chemokine receptors as the lymphocyte encodes all of the chemokine receptors.
Regarding claim 5, Stengel teaches lymphocytes use cell surface chemokine receptors to sense cognate chemokines secreted by cells for directed horning on their target sites (para. [0006]). Stengel teaches although the number of chemokines and cognate chemokine receptors is large, each lymphocyte type expresses only a limited set of chemokine receptors on their surface, despite the fact that the genes encoding these receptors are present in the lymphocyte genome (para. [0006]). Therefore, the modified lymphocyte of Stengel would necessarily encode both CCR4 and CCR6.
Regarding claims 6-8, Stengel teaches polynucleotides encoding one or more of the various components are operably linked to an inducible promoter (claim 7), a repressible promoter, or a constitutive promoter (claim 8) (para. [00130]). The promoters taught by Stengel read as independently controlling expression of one or more chemokine receptor (claim 6).
Regarding claim 9, Stengel teaches a mammalian synthetic chromosome comprising a constitutive promoter and the inducible expression of chemokine receptors is considered an inherent property of leukocytes as evidenced by Hughes, see below. It is noted for the record that the language of claim 9 does not require the promoters to promote expression of said encoded chemokine receptors.
Hughes teaches memory CD4+ T cells, regulatory T cells, γδ T cells (thymus), and thymic epithelial cells all express both CCR4 and CCR6 (p. 2952). Hughes teaches the most studied function of the chemokine network is cell migration, particularly of leukocytes (p. 2949). Hughes teaches a wide variety of other biological processes can be induced by the activation of common chemokine receptors (cCKRs) on leukocytes, including proliferation, survival, differentiation, cytokine production, degranulation, and respiratory burst (p. 2949). Hughes teaches cCKR switching is also prominent during CD4+ and CD8+ T-cell activation and differentiation, and cCKRs are reported to directly contribute to T-cell costimulation (p. 2955). Hughes teaches when CD4+ T cells encounter antigen, they can differentiate into one of many functionally distinct T cell types, including effector T cells (Th1, Th2, and Th17), follicular T cells (Tfh and Tfr), induced regulatory T cells (iTreg), and memory T cells (Tcm and Tem) (p. 2955). Hughes teaches Th2 cells preferentially display CCR3 and CCR4 and Th17 are often CCR6+ (p. 2955). The teaching of Hughes regarding differentiation of CD4+ T cells following antigen exposure suggests the expression of chemokine receptors are inherently inducible depending on the desired immunological function of the T cells.
Thus, the mammalian synthetic chromosome of Stengel would necessarily possess at least two promoters wherein one is inducible and another is constitutive.
Regarding claim 10, the expression of CCR6 would be considered inducible in the modified lymphocyte of Stengel, as the cell would comprise the gene encoding CCR6 and the expression of chemokine receptors are considered inducible as evidenced by Hughes.
Regarding claim 11, Stengel teaches the endogenous chemokine receptor-encoding gene to include CCR4 (para. [0011]) and Stengel teaches polynucleotides encoding one or more of the various components are operably linked to an inducible promoter, a repressible promoter, or a constitutive promoter (para. [00130]). Thus, Stengel teaches a mammalian synthetic chromosome encoding the chemokine receptor CCR4 and expression of CCR4 is constitutive.
Regarding claim 13, as discussed in the claim interpretation above, claim 13 is interpreted the same as claim 1 and is rejected for the same reasons. Cellular homing would also be considered an inherent property of a cell expressing a chemokine receptor.
Regarding claim 14, as discussed in the claim interpretation above, claim 14 is interpreted as requiring a mammalian synthetic chromosome. The teachings of Stengel read on the limitations of the claim as discussed in the rejection of claim 1 above.
Regarding claim 16, a lymphocyte is a type of leukocyte, therefore, the lymphocyte of Stengel reads on the limitations of the claim.
Regarding claims 17 and 18, as discussed in the claim interpretation above, these claims recite the intended use of a cell comprising a mammalian synthetic chromosome according to claim 1. Therefore, are rejected for the same reasons as claim 15. However, even if the intended use statements were considered limiting, Stengel teaches the modified lymphocytes can be used in to enhance (claim 18) cancer treatment (para. [00124]). Cancer treatment reads as for medical use (claim 17).
Regarding claims 19 and 20, Stengel teaches the compositions comprising the modified lymphocyte may include one or more additional agents, such as other medications used to treat a subject for the cancer in question (para. [00156]). Additional agents read as an additive.
Thus, the reference anticipates the subject matter of claims 1-11 and 13-20.
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.
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.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Stengel (WO 2019/113132 A1, published 13 June 2019) as evidenced by Hughes et al. (The FEBS Journal 285 (2018) 2944-2971) as applied to claims 1-11 and 13-20 above, and further in view of Praznovszky (Methods in Molecular Biology, vol. 738, Chapter 10, 2011) as evidenced by Gaszner et al. (Nature Reviews, Genetics, Volume 7, September 2006).
Stengel anticipates the subject matter of claims 1-11 and 13-20, and thus also renders them obvious.
Regarding claim 12, Stengel is silent to a mammalian synthetic chromosome comprising one or more insulators.
However, Praznovszky teaches chromosome engineering with the artificial chromosome expression (ACE), lambda-integrase mediated recombination system (Abstract). Praznovszky teaches gene of interest are cloned into targeting vector (ATV), and site-specific loading of genes onto Platform ACE is facilitated by ACE-integrase mediated recombination and ACE system is suitable for multiple or subsequent loading of useful genes onto the same chromosome vector (Abstract). Praznovszky teaches site-specific loading of a transgene onto the Platform ACE, wherein the satellite DNA-based artificial chromosome generated by large-scale amplification contains multiple integration sites, the recombination acceptor sites for the ACE-integrase, attP is located between a selectable marker gene and its promoter, and the ACE targeting vector (ATV) carries a gene of interest bordered with insulator sequences, and the attB integrase specific site upstream a promoterless selectable marker gene (Figs. 1 and 2). Praznovszky teaches the ATV contains the target gene cassette, which consists of gene(s) of interest flanked by insulators and a 5’ upstream CX promoter (chicken β-actin promoter and CMV immediate/early enhancer), a well-known constitutive promoter (p. 221-222). Praznovszky teaches multiple copies of the same gene or more than one gene can be placed into the ATV and loaded on to the Platform ACE (p. 222). Praznovszky teaches the site-specific recombination is mediated by the transiently expressed ACE Integrase, a mutant version of the lambda phage integrase that has been genetically engineered to function in mammalian cells without bacterial cofactors and catalyze the recombination between donor and acceptor sites (p. 222 and Fig. 2).
Therefore, it would have been obvious to one of ordinary skill in the art to include insulators in the mammalian synthetic chromosome with a reasonable expectation of success because Praznovszky teaches artificial chromosome designs include an ATV carrying a gene of interest bordered with insulator sequences and Stengel one method of introducing chromosome modifications are via artificial chromosome. One would have been motivated to include insulators in the mammalian synthetic chromosome because insulators are DNA sequence elements that prevent inappropriate interactions between adjacent chromatin domains, as evidenced by Gaszner (Abstract) which would facilitate proper expression of the desired gene.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Fagin et al. (Arthritis Research & Therapy 2012, 14:R73)
Fagin teaches chemokine receptors play an important role in mediating the recruitment of T cells to inflammatory sites, wherein CCR4 and CCR6 expression could also be implicated in T cell recruitment to inflamed sites. Fagin teaches investigation of the expression of CCR4 and CCR6 on T cells and its association with T cell diversity and polarization. Fagin teaches the chemokine receptors for peripheral tissue migration are CCR4 and CCR6. Fagin suggests CCR4 and CCR6 could be involved in the recruitment of different T cell subsets, including cytokine-producing cells.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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