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 .
Status of the Claims
Claims 4, 19, 25-29, and 36-40 are pending.
Claim 25-27 and are newly amended.
Claims 4, 19, 25-29, and 36-40 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The previous rejections of claims 4, 19, 25, and 38 under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) as evidenced by Lantelme et al. (Molecular Immunology, 2008), Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025), and Zhong et al. (Proceedings of the National Academy of Sciences, 1997) is withdrawn in order to readdress the claims.
The previous rejections of claims 26, 36, and 39 are under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013) as evidenced by Lantelme et al. (Molecular Immunology, 2008), Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025), and Zhong et al. (Proceedings of the National Academy of Sciences, 1997) is withdrawn in order to readdress the claims.
The previous rejections of claims 28-29 are under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013), as evidenced by Lantelme et al. (Molecular Immunology, 2008), Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025), and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claims 25 and 26 above and further in view of del Banco et al. (PNAS, 2015) is withdrawn in order to readdress the claims.
The previous rejections of claim 37 is under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Hawwari et al. (Journal of Experimental Medicine, 2005) as evidenced by Lantelme et al. (Molecular Immunology, 2008), Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025), and Zhong et al. (Proceedings of the National Academy of Sciences, 1997) is withdrawn in order to readdress the claims.
The previous rejections of claim 40 is under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013), as evidenced by Lantelme et al. (Molecular Immunology, 2008), Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025), and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claims 25 and 39 above and further in view of Kamala (Scandinavian Journal of Immunology, 67) is withdrawn in order to readdress the claims.
Claim Rejections - 35 USC § 112(b) - maintained
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 4, 19, 25-29, and 36-40 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.
It is noted that claim 25 is the independent claim.
Claim 25 recites the limitation “a known TCR or CAR gene” (line 7) and “the known TCR or Car gene”.
A claim may be rendered indefinite by reference to subjective term (see MPEP 2173.05(b), IV). Specifically, the phrase “a known TCR or CAR gene” is subjective and renders the claim indefinite. The phrase “a known TCR or CAR gene” (or “the known TCR or CAR gene) is not defined by the claim, the specification does not provide a standard for some standard for measuring the scope of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
In particular, because the claim hinges on what is known, the metes and bounds of the claim change depending on that knowledge.
A claim that requires the exercise of subjective judgment without restriction (i.e., what is known to one person may not be known to another) may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014) (holding the claim phrase "unobtrusive manner" indefinite because the specification did not "provide a reasonably clear and exclusive definition, leaving the facially subjective claim language without an objective boundary”).
For compact prosecution, the phrase has been interpreted for allowing for any TCR or CAR gene.
It is noted that in as much as Applicant intends the limitation to be maximally broad in regards to any TCR or CAR gene, “a TCR or CAR gene” would still achieve this intend without hinging on requiring subjective knowledge about a TCR or CAR gene.
Claims 4, 19, 26-29, and 36-40 are rejected under 35 U.S.C. 112(b) for their dependence on claim 25.
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 4, 19, 25, and 38 rejected under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997).
It is noted that claim 25 is the independent claim and therefore, has been addressed first.
In regards to claim 25, Kawamoto discloses a methods of introducing TCR genes (thus, exogenously) into induced pluripotent stem (iPS) cells (Abstract; claims 1-3; p4 paragraph 7). Kawamoto discloses that these cells can express these endogenous genes (p5, first paragraph).
In regards to step (1), Kawamoto discloses that these exogenous TCR genes can be inserted into the (endogenous) TCR locus by “replacement” (p5, second paragraph). As it well known in the art that re-arrangement of the TCR locus occurs during the development of T cells in the thymus. Moreover, as disclosed by Kawamoto, not only can iPS cells can be derived from somatic cells from any site (thus, from non-T cell) (p4, paragraph 4), but also that in embodiments Rag1 or Rag2 genes may be knocked out to avoid “reconstitution” of the endogenous TCR (p5, paragraph 6). As a result, a person of ordinary skill in the art would have immediately envisioned that non-rearranged TCR loci fall within the disclosure of Kawamoto.
Additionally, Kawamoto discloses that in embodiments the TCR gene can comprise a TCRα gene primed by SEQ ID NO: 1 (p6, paragraph 7), which as evidenced by Leiden is part of a rearranged TCR alpha chain V-region (whole document), and therefore, the exogenous TCR itself is rearranged.
In regards to the composition of the exogenous TCR, as evidenced by Zhong, the TCRα gene as disclosed by Kawamoto comprises from upstream to downstream a V region promoter locus and C region enhancer locus (Fig. 1, p5220; p5219, right column).
In regards to the locus between V and C regions, the sequences of the TCRα gene itself (which is between the V region promoter locus and C region) is a “known TCR gene” which reads on the limitation.
In regards to the distance between the V region promoter and C region enhancer, as the iPS cells were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene by “the T cell receptor control system”.
In regards to step (2), in regards to the step of replacing “a known TCR . . . gene”, it is noted that the plain language of the claim suggests that the endogenous TCR gene itself can be a known TCR gene, and the claim does not necessarily require that the known TCR gene be the same known TCR gene as in step (1) (i.e., the step (2) of replacing a TCR gene does not require replacing the same TCR gene as in step (1)). Since the method of Kawamoto replaces the endogenous TCR in a cell with an exogenous TCR, it therefore, replaces a known TCR with an exogenous TCR.
In regards to claim 4, Kawamoto discloses that the TCR gene can be introduced by genome editing technology (p5, second paragraph).
In regards to claim 19, Kawamoto discloses that the TCR gene can comprise TCRα and TCRβ chains (p7, second paragraph). Since the cells are at least exposed to anti-CD3 antibody, they would be expected to be rearranged as discussed above.
In regards to claim 38, Kawamoto discloses that the iPS cells can be differentiated to T cells (p5, paragraph 3).
Therefore, Kawamoto anticipates the invention as claimed.
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.
Claims 26, 36, and 39 are under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997).
Kawamoto anticipates claim 25 as discussed above.
In regards to claim 26, Kawamoto teaches that the TCR gene may be introduced with a vector comprising a drug resistance gene cassette comprising a first drug resistance gene (p5, first paragraph; Figs. 1-2). Kawamoto teaches that the vector may comprises necessary promoters (p5, first paragraph), and a person of ordinary skill in the art would have recognized that the drug resistance gene would be linked to a promoter and could be expressed in the cell.
Kawamoto does not explicitly teach a first (i) upstream or second (ii) different downstream target sequence for a first recombinase. However, a person of ordinary skill in the art would have been motivated to include these sequences because Li teaches that technologies that employ recombinases (such as dual-recombinase mediated cassette exchange (dual RMCE) allows for TCR gene replacement at a single site in the genome and is therefore more reliably safe than other methods (Abstract). As taught by Li dual RMCE targets first upstream and second downstream sequences (Fig. 1). Furthermore, because Li teaches that TCR genes may successfully be exchanged with engineered genes utilizing dual RMCE technology (Abstract, Fig. 1), and Kawamoto and Li are in the same technical field of producing engineering TCRs, it could have been done with predictable results and a reasonable expectation of success.
In regards to a second drug resistance gene, according to MPEP 2144(VI)(B), it is prima facie obvious to duplicate parts absent evidence of unexpected results. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a “web” which lies in the joint, and a plurality of “ribs” projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.)
Additionally, in the instant case, a person of ordinary skill in the art would have been motivated to include multiple drug resistance genes in order to provide greater selectivity of transfected cells. Furthermore, because Voziyanova teaches that dual RCME can utilize two recombinases directed to different targets (Abstract, p1; Fig. 3), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (b), as above, Kawamoto teaches that vectors can be successfully knocked in (transfected) and that genes are expressed (Fig. 5), which indicates that the distance between the V region promoter and C region enhancer must have been sufficiently close to allow expression of this gene.
In regards to step (c), Kawamoto teaches that transduced cells can be selected for (p6, second to last paragraph). A person of ordinary skill in the art would have been motivated to select cells in the presence of the first drug resistance gene in order to eliminate non-transduced cells. Furthermore, because Kawamoto teaches that cells can be engineered to be resident to drugs (p5, first paragraph), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 36, which further comprises step (2), it is noted that this is a second step that introduces a second vector (in this case TCR or CAR gene cassette exchange vector) which replaces the sequences of the drug resistance gene cassette introduced in claim 26.
A person of ordinary skill in the art would have been motivated to motivated introduce a TCR or CAR gene in the site of the drug resistance cassette in order to, as taught by Li, safely introduce tumor-antigen-specific TCR molecules which can then be used for clinical anti-tumor T cell immunotherapies (Abstract). Furthermore, because Li teaches that technologies such as RMCE can be used to introduce exogenous TCRs to generate antigen-specific TCR molecules and Kawamoto and Li are in the same technical field of engineering TCRs it could have been done with predictable results and a reasonable expectation of success.
In regards to step (d), in regards to the ordering of the TCR or CAR gene cassette exchange vector, as above, a person of ordinary skill in the art would have been motivated to incorporate target sequences for a first recombinase at the ends in order to the entire TCR or CAR gene cassette exchange vector into the TCR locus (see Fig. 1 of Li).
They would have been motivated to incorporate the second recombinase target sequence between the first recombinase target sequences in order to allow for secondary editing of the gene.
Furthermore, because Voziyanova teaches that dual RCME can utilize two recombinases directed to different targets (Abstract, p1, Fig. 3, p5) and because, as above, Li teaches that dual RCME technology can be used for engineering the TCR locus, it could have been done with predictable results and a reasonable expectation of success.
In regards to placement of the exogenous TCR or CAR gene or a promoter, it is noted that a person of ordinary skill in the art the TCR gene comprises multiple promoters within that gene, and therefore would be arranged in the order of an exogenous rearranged TCR or CAR gene and a promoter.
In regards to step (e), as above, a person of ordinary skill in the art would have been motivated introduce a TCR or CAR gene in the site of the drug resistance cassette in order to, as taught by Li, safely introduce tumor-antigen-specific TCR molecules which can then be used for clinical anti-tumor T cell immunotherapies (Abstract). They would have been motivated to apply a first recombinase in order to effect the exchange of the an engineered TCR (see Fig. 1 of Li). It is noted that replacing the flanked sequences is the expected result of using RMCE technology.
Furthermore, because Li teaches that RMCE technology can be effectively used to specifically introduce exogenous TCRs at the TCR locus (Fig. 1; claim 1), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (f), a person of ordinary skill in the art would have been motivated to apply the second drug resistance gene in order to positively select transformed cells. Furthermore, because as above, Li teaches that TCR-RMCE displaced cells can be selected for with the drug hygromycin (p7, seventh paragraph), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (g), a person of ordinary skill in the art would have been motivated to apply the second recombinase in order to eliminate drug resistance in transformed cells and improve their safety. Furthermore, because as above, Voziyanova teaches that dual RCME can utilize two recombinases directed to different targets (Abstract, p1; Fig. 3) and because, as above, Li teaches that dual RCME technology can be used for engineering the TCR locus, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 39, as above, in regards to step (1), Kawamoto teaches that the TCR gene is inserted into (and thus, alters) the TCR locus of iPS cells (p5, second paragraph).
In regards to the limitation of a “non-rearranged” TCR locus, it is noted that it is well-known in the art that TCR rearrangement is a T cell phenomenon. As taught by Kawamoto, the iPS cells can be derived from somatic cells from any site (thus, from non-T cell) (p4, paragraph 4). Thus, inserting an exogenous TCR into the TCR locus of an iPS cell not derived from a T cell would be in a non-arranged locus.
Also, as above, Kawamoto teaches that in embodiments the TCR gene can comprise a TCRα gene (p6, paragraph 7), which as evidenced by Zhong comprises from upstream to downstream a V region promoter locus and C region enhancer locus (Fig. 1, p5220; p5219, right column).
In regards to the locus between V and C regions, the sequences of the TCRα gene itself (which is between the V region promoter locus and C region) is a “known TCR gene” which reads on the limitation.
As above, Kawamoto teaches that the iPS cells can be differentiated to T cells (p5, paragraph 3).
In regards to step (2), similarly to as above, a person of ordinary skill in the art would have been motivated to replace the exogenous TCR by means of RMCE because Li teaches dual RMCE allows for TCR gene replacement at a single site in the genome and is therefore more reliably safe than other methods (Abstract). As taught by Li dual RMCE targets first upstream and second downstream sequences (Fig. 1). Furthermore, because Li teaches that TCR genes may successfully be exchanged with engineered genes utilizing dual RMCE technology, and Kawamoto and Li are in the same technical field of producing engineering TCRs, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Kawamoto, Li, and Voziyanova renders obvious the invention as claimed.
Claims 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013), as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claims 25 and 26 above and further in view of del Banco et al. (PNAS, 2015).
In regards to claims 27-29, while Kawamoto is silent as to the exact of vector knock-in, del Banco teaches that the Tcra enhancer is essential for germ-line transcription and primary Vα-to-Jα recombination during TCR rearrangement (Abstract, pE1744). Additionally, as evidenced by Zhong, as discussed above, the most upstream region of the TCR gene is V region (which comprises the various V region promoters) with the C region enhancer (Eα) being the most downstream, with the D and J regions being in the middle (Fig. 1, p5220).
Therefore, a person of ordinary skill in the art would have been motivated to knock this vector into the DJ region (as in claims 27 and 28) or between V and C regions (as in claims 27 and 29), in order to preserve promoter and enhancer interactions, which is essential for Vα-to-Jα recombination during TCR rearrangement. Furthermore, because, as above, Kawamoto teaches that the TCR gene is inserted into (and thus, alters) the TCR locus of iPS cells (p5, second paragraph) and because as above, teaches that technologies that employ recombinases (such as dual-recombinase mediated cassette exchange (dual RMCE) allows for TCR gene replacement at a single site in the genome (Abstract), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Kawamoto, Li, Voziyanova, and del Banco renders obvious the invention as claimed.
Claim 37 is under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Bassing et al. (PNAS 2003) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997).
Kawamoto anticipates claim 25 as discussed above.
In regards to claim 37, in regards to the distance between the V region promoter and the C region enhancer, while Kawamoto is silent as to the distance between these two region, a person of ordinary skill in the art could have arrived at a distance of about 8 to 32kbp by routine optimization, and the disclosure does not point to a criticality in this amount.
According to 2144.05(II)(A), Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
In the instant case, because Belmont broadly teaches that
Bassing teaches that the TCRα enhancer has transcriptional activity at distances of about 100 kb to the promoters of assembled VDJ segments (Introduction, p2598) whichis greater than the amount of about 8 to 32 kbp, a person of ordinary skill in the art could have arrived at a distance of about 8 to 32 kbp by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Kawamoto and Bassing renders obvious the invention as claimed.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013), as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claims 25 and 39 above and further in view of Kamala (Scandinavian Journal of Immunology, 67).
In regards to claim 40, Kawamoto does not explicitly teach a step of removing unsuccessfully changed (non-transformed) cells with an antibody. However, a person of ordinary skill in the art would have been motivated to remove unusually changed cells in order to obtain a pure population of cells. They would have been motivated to do so with antibodies because Kamala teaches that antibodies allow for negative selection of unwanted T cells (Abstract, p285). Furthermore, because Kamala teaches that unwanted cells (unsuccessfully changed or non-transformed cells) can be removed with antibodies (Abstract, p285), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Kawamoto, Li, Voziyanova, and Kamala renders obvious the invention as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 4, 19, 25, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,194,083B2 in view of Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997).
Claims 26, 36, and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,194,083B2 in view of Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claim 25 above, and further in view of Li et al. (CN105316362A, 2016, on IDS 04/29/2021) and Voziyanova et al. (Nucleic Acids Research, 2013).
Claims 27-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,194,083B2 in view of Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021), Li et al. (CN105316362A, 2016, on IDS 04/29/2021), and Voziyanova et al. (Nucleic Acids Research, 2013) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claims 25 and 26 above, and further in view of del Banco et al. (PNAS, 2015).
Claims 26, 36, and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,194,083B2 in view of Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claim 25 above, and further in view of Bassing et al. (PNAS 2003).
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,194,083B2 in view of Kawamoto et al. (WO2016010154A1, on IDS 04/29/2021) and Bassing et al. (PNAS 2003) as evidenced by Leiden et al. (GenBank: M15565.1, 1986, retrieved from NCBI 11/21/2025) and Zhong et al. (Proceedings of the National Academy of Sciences, 1997), as applied to claims 25 and 39 above, and further in view of Kamala (Scandinavian Journal of Immunology, 67).
Although the conflicting claims of U.S. Patent No. 12,194,083B2 are not identical to the currently prosecuted claims 4, 19, 25-29, and 36-40, they are not patently distinct because said claims of both invention are drawn to methods for producing cells that express an exogenous re-arranged TCR or CAR.
In regards to the specific steps of claim 25 (which is noted, is the independent claim), these were all disclosed by Kawamoto before the effective filing date.
As discussed above, Kawamoto discloses a methods of introducing TCR genes (thus, exogenously) into induced pluripotent stem (iPS) cells (Abstract; claims 1-3; p4 paragraph 7). Kawamoto discloses that these cells can express these endogenous genes (p5, first paragraph).
Kawamoto discloses that these exogenous TCR genes can be inserted into the (endogenous) TCR locus by “replacement” (p5, second paragraph). As it well known in the art that re-arrangement of the TCR locus occurs during the development of T cells in the thymus. Moreover, as disclosed by Kawamoto, not only can iPS cells can be derived from somatic cells from any site (thus, from non-T cell) (p4, paragraph 4), but also that in embodiments Rag1 or Rag2 genes may be knocked out to avoid “reconstitution” of the endogenous TCR (p5, paragraph 6). As a result, a person of ordinary skill in the art would have immediately envisioned that non-rearranged TCR loci fall within the disclosure of Kawamoto.
Additionally, Kawamoto discloses that in embodiments the TCR gene can comprise a TCRα gene primed by SEQ ID NO: 1 (p6, paragraph 7), which as evidenced by Leiden is part of a rearranged TCR alpha chain V-region (whole document), and therefore, the exogenous TCR itself is rearranged.
In regards to the composition of the exogenous TCR, as evidenced by Zhong, the TCRα gene as disclosed by Kawamoto comprises from upstream to downstream a V region promoter locus and C region enhancer locus (Fig. 1, p5220; p5219, right column).
In regards to the locus between V and C regions, the sequences of the TCRα gene itself (which is between the V region promoter locus and C region) is a “known TCR gene” which reads on the limitation.
In regards to the distance between the V region promoter and C region enhancer, as the iPS cells were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene by “the T cell receptor control system”.
In regards to step (2), in regards to the step of replacing “a known TCR . . . gene”, it is noted that the plain language of the claim suggests that the endogenous TCR gene itself can be a known TCR gene, and the claim does not necessarily require that the known TCR gene be the same known TCR gene as in step (1) (i.e., the step (2) of replacing a TCR gene does not require replacing the same TCR gene as in step (1)). Since the method of Kawamoto replaces the endogenous TCR in a cell with an exogenous TCR, it therefore, replaces a known TCR with an exogenous TCR.
In regards to claim 4, Kawamoto discloses that the TCR gene can be introduced by genome editing technology (p5, second paragraph).
In regards to claim 19, Kawamoto discloses that the TCR gene can comprise TCRα and TCRβ chains (p7, second paragraph). They are rearranged as discussed above.
In regards to claim 38, Kawamoto discloses that the iPS cells can be differentiated to T cells (p5, paragraph 3).
A person of ordinary skill in the art would have been motivated to utilize these steps because Kawamoto indicates that the method is useful for generating cells which can be used for introducing TCR genes with desired antigen specificity into pluripotent stem cells for use in immunotherapy (Technical field, p2), and because Kawamoto is the same inventor as the patent (and indeed is the prior art WIPO publication of the patent, and therefore, are embodiments envisioned by the patent), a person of ordinary skill in the art could have performed the claimed method steps, based on the disclosure of Kawamoto with predictable results and a reasonable expectation of success.
In regards to claim 26, Kawamoto teaches that the TCR gene may be introduced with a vector comprising a drug resistance gene cassette comprising a first drug resistance gene (p5, first paragraph; Figs. 1-2). Kawamoto teaches that the vector may comprises necessary promoters (p5, first paragraph), and a person of ordinary skill in the art would have recognized that the drug resistance gene would be linked to a promoter and could be expressed in the cell.
Kawamoto does not explicitly teach a first (i) upstream or second (ii) different downstream target sequence for a first recombinase. However, a person of ordinary skill in the art would have been motivated to include these sequences because Li teaches that technologies that employ recombinases (such as dual-recombinase mediated cassette exchange (dual RMCE) allows for TCR gene replacement at a single site in the genome and is therefore more reliably safe than other methods (Abstract). As taught by Li dual RMCE targets first upstream and second downstream sequences (Fig. 1). Furthermore, because Li teaches that TCR genes may successfully be exchanged with engineered genes utilizing dual RMCE technology (Abstract, Fig. 1), and Kawamoto and Li are in the same technical field of producing engineering TCRs, it could have been done with predictable results and a reasonable expectation of success.
In regards to a second drug resistance gene, according to MPEP 2144(VI)(B), it is prima facie obvious to duplicate parts absent evidence of unexpected results. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a “web” which lies in the joint, and a plurality of “ribs” projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.)
Additionally, in the instant case, a person of ordinary skill in the art would have been motivated to include multiple drug resistance genes in order to provide greater selectivity of transfected cells. Furthermore, because Voziyanova teaches that dual RCME can utilize two recombinases directed to different targets (Abstract, p1; Fig. 3), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (b), as above, Kawamoto teaches that vectors can be successfully knocked in (transfected) and that genes are expressed (Fig. 5), which indicates that the distance between the V region promoter and C region enhancer must have been sufficiently close to allow expression of this gene.
In regards to step (c), Kawamoto teaches that transduced cells can be selected for (p6, second to last paragraph). A person of ordinary skill in the art would have been motivated to select cells in the presence of the first drug resistance gene in order to eliminate non-transduced cells. Furthermore, because Kawamoto teaches that cells can be engineered to be resident to drugs (p5, first paragraph), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 36, which further comprises step (2), it is noted that this is a second step that introduces a second vector (in this case TCR or CAR gene cassette exchange vector) which replaces the sequences of the drug resistance gene cassette introduced in claim 26.
A person of ordinary skill in the art would have been motivated to motivated introduce a TCR or CAR gene in the site of the drug resistance cassette in order to, as taught by Li, safely introduce tumor-antigen-specific TCR molecules which can then be used for clinical anti-tumor T cell immunotherapies (Abstract). Furthermore, because Li teaches that technologies such as RMCE can be used to introduce exogenous TCRs to generate antigen-specific TCR molecules and Kawamoto and Li are in the same technical field of engineering TCRs it could have been done with predictable results and a reasonable expectation of success.
In regards to step (d), in regards to the ordering of the TCR or CAR gene cassette exchange vector, as above, a person of ordinary skill in the art would have been motivated to incorporate target sequences for a first recombinase at the ends in order to the entire TCR or CAR gene cassette exchange vector into the TCR locus (see Fig. 1 of Li).
They would have been motivated to incorporate the second recombinase target sequence between the first recombinase target sequences in order to allow for secondary editing of the gene.
Furthermore, because Voziyanova teaches that dual RCME can utilize two recombinases directed to different targets (Abstract, p1, Fig. 3, p5) and because, as above, Li teaches that dual RCME technology can be used for engineering the TCR locus, it could have been done with predictable results and a reasonable expectation of success.
In regards to placement of the exogenous TCR or CAR gene or a promoter, it is noted that a person of ordinary skill in the art the TCR gene comprises multiple promoters within that gene, and therefore would be arranged in the order of an exogenous rearranged TCR or CAR gene and a promoter.
In regards to step (e), as above, a person of ordinary skill in the art would have been motivated introduce a TCR or CAR gene in the site of the drug resistance cassette in order to, as taught by Li, safely introduce tumor-antigen-specific TCR molecules which can then be used for clinical anti-tumor T cell immunotherapies (Abstract). They would have been motivated to apply a first recombinase in order to effect the exchange of the an engineered TCR (see Fig. 1 of Li). It is noted that replacing the flanked sequences is the expected result of using RMCE technology.
Furthermore, because Li teaches that RMCE technology can be effectively used to specifically introduce exogenous TCRs at the TCR locus (Fig. 1; claim 1), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (f), a person of ordinary skill in the art would have been motivated to apply the second drug resistance gene in order to positively select transformed cells. Furthermore, because as above, Li teaches that TCR-RMCE displaced cells can be selected for with the drug hygromycin (p7, seventh paragraph), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (g), a person of ordinary skill in the art would have been motivated to apply the second recombinase in order to eliminate drug resistance in transformed cells and improve their safety. Furthermore, because as above, Voziyanova teaches that dual RCME can utilize two recombinases directed to different targets (Abstract, p1; Fig. 3) and because, as above, Li teaches that dual RCME technology can be used for engineering the TCR locus, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 39, as above, in regards to step (1), Kawamoto teaches that the TCR gene is inserted into (and thus, alters) the TCR locus of iPS cells (p5, second paragraph).
In regards to the limitation of a “non-rearranged” TCR locus, it is noted that it is well-known in the art that TCR rearrangement is a T cell phenomenon. As taught by Kawamoto, the iPS cells can be derived from somatic cells from any site (thus, from non-T cell) (p4, paragraph 4). Thus, inserting an exogenous TCR into the TCR locus of an iPS cell not derived from a T cell would be in a non-arranged locus.
Also, as above, Kawamoto teaches that in embodiments the TCR gene can comprise a TCRα gene (p6, paragraph 7), which as evidenced by Zhong comprises from upstream to downstream a V region promoter locus and C region enhancer locus (Fig. 1, p5220; p5219, right column).
In regards to the locus between V and C regions, the sequences of the TCRα gene itself (which is between the V region promoter locus and C region) is a “known TCR gene” which reads on the limitation.
As above, Kawamoto teaches that the iPS cells can be differentiated to T cells (p5, paragraph 3).
In regards to step (2), similarly to as above, a person of ordinary skill in the art would have been motivated to replace the exogenous TCR by means of RMCE because Li teaches dual RMCE allows for TCR gene replacement at a single site in the genome and is therefore more reliably safe than other methods (Abstract). As taught by Li dual RMCE targets first upstream and second downstream sequences (Fig. 1). Furthermore, because Li teaches that TCR genes may successfully be exchanged with engineered genes utilizing dual RMCE technology, and Kawamoto and Li are in the same technical field of producing engineering TCRs, it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 27-29, while Kawamoto is silent as to the exact of vector knock-in, del Banco teaches that the Tcra enhancer is essential for germ-line transcription and primary Vα-to-Jα recombination during TCR rearrangement (Abstract, pE1744). Additionally, as evidenced by Zhong, as discussed above, the most upstream region of the TCR gene is V region (which comprises the various V region promoters) with the C region enhancer (Eα) being the most downstream, with the D and J regions being in the middle (Fig. 1, p5220).
Therefore, a person of ordinary skill in the art would have been motivated to knock this vector into the DJ region (as in claim 28) or between V and C regions (as in claim 29), in order to preserve promoter and enhancer interactions, which is essential for Vα-to-Jα recombination during TCR rearrangement. Furthermore, because, as above, Kawamoto teaches that the TCR gene is inserted into (and thus, alters) the TCR locus of iPS cells (p5, second paragraph) and because as above, teaches that technologies that employ recombinases (such as dual-recombinase mediated cassette exchange (dual RMCE) allows for TCR gene replacement at a single site in the genome (Abstract), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 37, in regards to the distance between the V region promoter and the C region enhancer, while Kawamoto is silent as to the distance between these two region, a person of ordinary skill in the art could have arrived at a distance of about 8 to 32kbp by routine optimization, and the disclosure does not point to a criticality in this amount.
According to 2144.05(II)(A), Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
In the instant case, because Bassing teaches that the TCRα enhancer has transcriptional activity at distances of about 100 kb to the promoters of assembled VDJ segments (Introduction, p2598) whichis greater than the amount of about 8 to 32 kbp, a person of ordinary skill in the art could have arrived at a distance of about 8 to 32 kbp by routine optimization with predictable results and a reasonable expectation of success.
In regards to claim 40, Kawamoto does not explicitly teach a step of removing unsuccessfully changed (non-transformed) cells with an antibody. However, a person of ordinary skill in the art would have been motivated to remove unusually changed cells in order to obtain a pure population of cells. They would have been motivated to do so with antibodies because Kamala teaches that antibodies allow for negative selection of unwanted T cells (Abstract, p285). Furthermore, because Kamala teaches that unwanted cells (unsuccessfully changed or non-transformed cells) can be removed with antibodies (Abstract, p285), it could have been done with predictable results and a reasonable expectation of success.
Response to Arguments
In regards to the rejections under 35 USC 112(b), Applicant argues that the phrase “a known TCR or CAR gene” is not indefinite (Remarks, p6). Specifically, Applicant argues that, “Once a TCR or CAR is identified” a person of ordinary skill in the art can obtain an antibody or tetramer specific to the TCR or CAR (Remarks, p6). Applicant further argues that as discussed in the specification (paragrpah [0089]), where the material cells for the introduction of an exogenous antigen receptor gene have a known TCR or CAR gene, the known TCR or CAR gene introduced may be replaced with an exogenous TCR or CAR gene (Remarks, p6). Therefore, Applicant concludes that any “known TCR or CAR gene” can be used to conduct the claimed method, and therefore, this phrase does not render the claim indefinite (Remarks, p6).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
As noted by Applicant, the metes and bounds of the claim require specific identification by a person of ordinary skill in the art. Since the metes and bounds require specific knowledge or identification of a TCR or CAR gene, it is unclear of genes which are not yet identified as or known as TCR or CAR genes are included within the scope of the claims.
Therefore, as above, the limitation is indefinite because it requires the exercise of subjective judgment without restriction (i.e., what is known to one person may not be known to another) may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014) (holding the claim phrase "unobtrusive manner" indefinite because the specification did not "provide a reasonably clear and exclusive definition, leaving the facially subjective claim language without an objective boundary”).
Furthermore, as above, it is noted that in as much as Applicant intends the limitation to be maximally broad in regards to any TCR or CAR gene, “a TCR or CAR gene” would still achieve this intend without hinging on requiring subjective knowledge about a TCR or CAR gene.
Applicant argues that claim 27 as amended, overcomes the written description rejection under 35 USC 112(a) (Remarks, p6-7).
Applicant’s arguments, see p6-7, filed 04/02/2026, with respect to the rejection under 35 USC 112(a) have been fully considered and are persuasive. The rejection under 35 USC112(a) of claim 27 has been withdrawn.
Applicant argues that Kawamoto fails to disclose each and every element of the claims and therefore does not anticipate the claims (Remarks, p7-8).
Specifically, Applicant argues that in the claimed method the endogenous V-region promoter and C-region enhancer at the TCR locus function together as part of the TCR control system to regulate expression of the introduced exogenous arranged TCR or CAR, and therefore, cells generated in this manner contain a site-specific insertion within the TCR locus rather than a random genomic insertion (Remarks, p7-8). Citing the specification (paragraph [0002]), Applicant argues that the method avoids the risk associated with introducing exogenous rearranged TCR or CAR genes by retroviral or lentiviral vectors (Remarks, p8).
As further argued by Applicant, per the Declaration under 37 CFR 1.132 filed 04/02/2026, the cited art does not disclose altering a non-rearranged TCR locus such that the V-region promoter and C-region enhancer are positioned sufficiently close to exert the endogenous TCR control system (Remarks, p8; Repeated in arguments traversing rejection under 35 USC 103, p9-10). Specifically, Applicant argues that the method of Kawamoto, instead of being under the control of the TCR locus V region promoter as claimed was under control of a recombinant UbC promoter introduced by the lentiviral vector (Remarks, p8).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
Kawamoto discloses each and every limitation, and therefore, anticipates the invention.
Kawamoto discloses a methods of introducing TCR genes (thus, exogenously) into induced pluripotent stem (iPS) cells (Abstract; claims 1-3; p4 paragraph 7). Kawamoto discloses that these cells can express these endogenous genes (p5, first paragraph).
In regards to step (1), Kawamoto discloses that these exogenous TCR genes can be inserted into the (endogenous) TCR locus by “replacement” (p5, second paragraph). As it well known in the art that re-arrangement of the TCR locus occurs during the development of T cells in the thymus. Moreover, as disclosed by Kawamoto, not only can iPS cells can be derived from somatic cells from any site (thus, from non-T cell) (p4, paragraph 4), but also that in embodiments Rag1 or Rag2 genes may be knocked out to avoid “reconstitution” of the endogenous TCR (p5, paragraph 6). As a result, a person of ordinary skill in the art would have immediately envisioned that non-rearranged TCR loci fall within the disclosure of Kawamoto.
Additionally, Kawamoto discloses that in embodiments the TCR gene can comprise a TCRα gene primed by SEQ ID NO: 1 (p6, paragraph 7), which as evidenced by Leiden is part of a rearranged TCR alpha chain V-region (whole document), and therefore, the exogenous TCR itself is rearranged.
In regards to the composition of the exogenous TCR, as evidenced by Zhong, the TCRα gene as disclosed by Kawamoto comprises from upstream to downstream a V region promoter locus and C region enhancer locus (Fig. 1, p5220; p5219, right column).
In regards to the locus between V and C regions, the sequences of the TCRα gene itself (which is between the V region promoter locus and C region) is a “known TCR gene” which reads on the limitation.
In regards to the distance between the V region promoter and C region enhancer, as the iPS cells were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene by “the T cell receptor control system”.
In regards to step (2), in regards to the step of replacing “a known TCR . . . gene”, it is noted that the plain language of the claim suggests that the endogenous TCR gene itself can be a known TCR gene, and the claim does not necessarily require that the known TCR gene be the same known TCR gene as in step (1) (i.e., the step (2) of replacing a TCR gene does not require replacing the same TCR gene as in step (1)). Since the method of Kawamoto replaces the endogenous TCR in a cell with an exogenous TCR, it therefore, replaces a known TCR with an exogenous TCR.
In regards to Applicant’s arguments that the method of Kawamoto, instead of being under the control of the TCR locus V region promoter as claimed was under control of a recombinant UbC promoter introduced by the lentiviral vector (Remarks, p8), it is noted that the claim only requires that the distance between the V region promoter and the C region enhancer is sufficiently close to each other to exert the T cell receptor control system to express the intervening gene. This limitation is broad, and does not necessarily suggest that expression of the exogenous TCR or CAR is specifically driven by the V region promoter, only that they ae sufficiently close that the T cell receptor control system expresses the intervening gene. As discussed above, since TCRα gene, as disclosed by Kawamoto comprises a V region promoter and a C region enhancer, and since Kawamoto alters a non-rearranged TCR locus in a material cell genome and since iPSCs were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene by the “T cell receptor control system.”
Applicant argues that Lantelme fails to cure the deficiencies of Kawamoto, and specifically does not disclose a method for insertion of an exogenous rearranged TCR or CAR, wherein a V region promoter and the C region enhancer are sufficiently close to each other to exert the T cell receptor control system to drive expression of an inserted gene (Remarks, p8-9).
Applicant’s arguments filed 04/02/2026 have been fully considered but moot because Lantelme is not relied upon for any teaching in the instant rejection.
Applicant argues that Leiden fails to cure the deficiencies of Kawamoto and does not disclose any method for insertion of an exogenous TCR (Remarks, p9; repeated, p11).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
As discussed above, Leiden is only relied upon to provide evidence that the exogenous TCR genes as disclosed by Leiden are rearranged.
Applicant argues that Zhong fails to cure the deficiencies of Kawamoto and does not disclose utilizing a TCR locus in a material cell genome wherein a V region promoter and the C region enhancer are sufficiently close to each other to exert the T cell receptor control system to drive expression of an inserted gene (Remarks, p9, repeated p11).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
As discussed above, Zhong is only used to provide evidence that the TCRα gene comprises a V region promoter locus and C region enhancer locus upstream to downstream.
In regards to closeness of the V region promoter and C region enhancer to exert the T cell receptor control system to drive expression of an inserted gene, as discussed above, since the iPS cells were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene.
Applicant argues that the claimed method produces different cells and has uniform TCR expression after differentiation across different iPSC lines from those of Kawamoto citing Exhibit A, Fig. 1 of the Declaration under 37 CFR 1.132 filed 04/02/2026 (Remarks, p10).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., specific cell phenotypes and uniform TCR expression) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that none of Li, Voziyanova, del Banco, or Kamala cures the deficiencies of Kawamoto, and does not teach a V region promoter and the C region enhancer are sufficiently close to each other to exert the T cell receptor control system to drive expression of an inserted gene (Remarks, p11-12, 14).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
As discussed above, Li is relied upon to provide motivation to utilize a dual RMCE technique to introduce a an exogenous TCR to the TCR locus.
Furthermore, as discussed above, del Banco is relied upon to provide motivation to knock-in the vector into a DJ region of the non-rearranged TCR locus.
Additionally, as discussed above, Kamala is relied upon to provide motivation to remove unsuccessfully transformed cells with an antibody.
In regards to closeness of the V region promoter and C region enhancer to exert the T cell receptor control system to drive expression of an inserted gene, as discussed above, since the iPS cells were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene.
Applicant argues that Hawwari does not cure the deficiencies of Kawamoto, and does not teach a V region promoter and the C region enhancer are sufficiently close to each other to exert the T cell receptor control system to drive expression of an inserted gene (Remarks, p12-13). Specifically, Applicant argues that Hawwari is about the regulation of TCR α and ß repertories and the rearrangement of TCR loci, and does not teach or suggest expressing an exogenous TCR under an endogenous TCR locus promoter-enhancer control system (Remarks, p12-13). Rather, Applicant argues that Hawwari discusses the distance over which the TCR α enhancer can regulate chromatin structure in recombination of TCR gene segments, and therefore, the Office's reasoning equivocates the existence of endogenous enhancer function during recombination to suggest that promoter-enhancer spacing needed for engineering exogenous TCR gene expression would have been obvious, but these are different biological contexts effectuating different results (Remarks, p12-13).
In regards to Applicant’s arguments that Hawwari does not teach or suggest expressing an exogenous TCR under an endogenous TCR locus promoter-enhancer control system, this specifically taught by Kawamoto as discussed above.
Applicant’s arguments filed 04/02/2026 have been fully considered but moot because Hawwari is not relied upon for any teaching in the instant rejection.
In regards to the non-statutory double patenting rejections, Applicant argues that none of the cited patent claims nor cited art teach or suggest a V region promoter and the C region enhancer are sufficiently close to each other to exert the T cell receptor control system to drive expression of an inserted gene (Remarks, p11-12, 14).
Applicant’s arguments filed 04/02/2026 have been fully considered but are not found persuasive.
As discussed above, although the conflicting claims of U.S. Patent No. 12,194,083B2 are not identical to the currently prosecuted claims 4, 19, 25-29, and 36-40, they are not patently distinct because said claims of both invention are drawn to methods for producing cells that express an exogenous re-arranged TCR or CAR.
In regards to the specific steps of claim 25 (which is noted, is the independent claim), these were all disclosed by Kawamoto before the effective filing date.
As discussed above, Kawamoto discloses a methods of introducing TCR genes (thus, exogenously) into induced pluripotent stem (iPS) cells (Abstract; claims 1-3; p4 paragraph 7). Kawamoto discloses that these cells can express these endogenous genes (p5, first paragraph).
Kawamoto discloses that these exogenous TCR genes can be inserted into the (endogenous) TCR locus by “replacement” (p5, second paragraph). As it well known in the art that re-arrangement of the TCR locus occurs during the development of T cells in the thymus. Moreover, as disclosed by Kawamoto, not only can iPS cells can be derived from somatic cells from any site (thus, from non-T cell) (p4, paragraph 4), but also that in embodiments Rag1 or Rag2 genes may be knocked out to avoid “reconstitution” of the endogenous TCR (p5, paragraph 6). As a result, a person of ordinary skill in the art would have immediately envisioned that non-rearranged TCR loci fall within the disclosure of Kawamoto.
Additionally, Kawamoto discloses that in embodiments the TCR gene can comprise a TCRα gene primed by SEQ ID NO: 1 (p6, paragraph 7), which as evidenced by Leiden is part of a rearranged TCR alpha chain V-region (whole document), and therefore, the exogenous TCR itself is rearranged.
In regards to the composition of the exogenous TCR, as evidenced by Zhong, the TCRα gene as disclosed by Kawamoto comprises from upstream to downstream a V region promoter locus and C region enhancer locus (Fig. 1, p5220; p5219, right column).
In regards to the locus between V and C regions, the sequences of the TCRα gene itself (which is between the V region promoter locus and C region) is a “known TCR gene” which reads on the limitation.
In regards to the distance between the V region promoter and C region enhancer, as the iPS cells were induced to encode a TCR (Fig. 5), the distance between these regions must have been sufficiently close to allow expression of this gene by “the T cell receptor control system”.
Response to Declaration under 37 CFR 1.132
Applicant declares that none of the references cited by the Office disclose a method of utilizing the TCR locus in a material cell genome wherein a V region promoter and the C region enhancer are sufficiently close to each other to exert T cell receptor control system to drive expression of an inserted gene as required by claim 25 (paragraph 5).
The Declaration under 37 CFR 1.132 filed 04/02/2026 is insufficient to overcome the rejection of the claims based upon 35 USC 102 as set forth in the last Office action because: they do no establish facts which overcome the instant rejection.
As discussed above, since in the method of Kawamoto, as the iPS cells were induced to encode a TCR (Fig. 5), the distance between V and C regions must have been sufficiently close to allow expression of this gene by “the T cell receptor control system”.
Applicant declares that the claimed method avoids the risk of introducing exogenously rearranged TCR or CAR genes by retroviral or lentiviral vectors (paragraph 6, citing p1, paragraph [0002] of the instant specification.
The Declaration under 37 CFR 1.132 filed 04/02/2026 is insufficient to overcome the rejection of the claims based upon 35 USC 102 as set forth in the last Office action because: they are not commensurate in scope with the claims.
Specifically, the claims do not disallow introducing exogenously rearranged TCR or CAR genes my retroviral or lentiviral vectors.
Thus, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
While claim 26 utilizes first and second recombinases, it was known in the art before the effective filing date that other methods could be used to introduce exogenous genes into single sites in the genome (see Li, as above).
Specifically, a person of ordinary skill in the art would have been motivated to introduce exogenous TCR genes with dual recombinase technologies because that technologies that employ recombinases (such as dual-recombinase mediated cassette exchange (dual RMCE) allows for TCR gene replacement at a single site in the genome and is therefore more reliably safe than other methods including retroviruses specifically (Abstract).
Furthermore, because Li teaches that TCR genes may successfully be exchanged with engineered genes utilizing dual RMCE technology (Abstract, Fig. 1), and Kawamoto and Li are in the same technical field of producing engineering TCRs, it could have been done with predictable results and a reasonable expectation of success.
Applicant declares that experiments (Exhibit A) conducted after the filing of the instant Application verify differences between Applicant’s claimed method and that of Kawamoto, and therefore, Kawamoto neither anticipates or renders obvious the claimed method (paragraphs 7-10).
In regards to Exhibit A, Specifically, Applicant declares that unlike the method of Kawamoto, which utilizes a lentiviral vector to knock in an exogenous TCR gene in iPSC lines, and obtains one or three copies of the inserted TCR gene, the instantly claimed method result in cells with a single copy insertion of the foreign TCR into the TCRβ chain (Declaration, p4-6). Applicant also sites numerous specific methodological steps as taught by Kawamoto (e.g., differentiation induction using an EB method, etc.) (Declaration, p4-6).
The Declaration under 37 CFR 1.132 filed 04/02/2026 is insufficient to overcome the rejection of the claims based upon 35 USC 102 as set forth in the last Office action because: they are not commensurate in scope with the claims.
Specifically, the claims do not require a cell with a single copy insertion of a foreign TCR in the TCRβ chain, not does it disallow methodological steps as taught by Kawamoto.
Thus, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Legut et al. (Gene Therapy, 311).
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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