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 .
Amendments
In the reply filed 4/14/2026, Applicant has made no amendments.
Claims 42, 47-48, 69, 112-113, 134-135 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-6, 12-13, 16-18, 20-21, 23, 25, 29, 37, 39, and 40 are under consideration.
Maintained Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-6, 12-13, 16-18, 21, 23, 25, 37, 39, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Sadelain et al., (2019/0119638, filed 4/14/2017, published 4/25/2019, see IDS)
In regard to claim 1, Sadelain teaches methods of genetically modifying T cells, comprising introducing a transgene such as a CAR inserted within an endogenous gene locus of the cells such that “expression of the transgene is under the control of an endogenous promoter of the T cell” (Abstract). Specifically, Sadelain teaches the gene locus with the endogenous promoter is IL-13 ([0066, 0115, 0192, 0210, 0233], see also Table 1, pg. 27).
However, Sadelain is silent to a preferred embodiment of a method for producing genetically modifying T cells, comprising introducing a CAR under the control of the endogenous IL-13 gene’s promoter.
Nevertheless, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to practice said method to produce a the modified T cell because each of the individual elements of the instant claims are independently presented by Sadelain as embodiments and are taught that they can be combined in various embodiments; therefore a combination of all the elements into a single embodiment would be apparent to an artisan skilled in CART cell therapy in light of the Supreme Court’s KSR decision (see MPEP 2143 Exemplary Rationale (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of filing of the invention. Each of the elements (CAR transgenes, IL-13 promoter, targeting methods and T cell gene modifications) are taught by Sadelain and further they are taught in various combinations and are shown to be used in a method for genetically modified T cells with a CAR transgene operably linked to an endogenous promoter. It would have been therefore predictably obvious to use a combination of these elements in said method.
In regard to claim 2, as stated supra, Sadelin teaches the transgene is under the control of the endogenous IL-13 promoter.
In regard to claim 3, although Sadelain is silent to changes in expression of the endogenous IL-13 gene, Sadelain teaches the transgene is inserted into the first exon and/or in frame with the endogenous gene (i.e., IL-13) ([0013, 0051-0054, 0064, 0216-0217, 0676], see Fig. 7B). Thus, it would have been expected to reduce the expression of the endogenous IL-13 gene.
In regard to claims 4-6, as stated supra, Sadelain teaches the transgene is a CAR.
In regard to claims 12 and 13, Sadelain teaches the CAR transgene is operably linked to a 5’ self-cleaving 2A peptide and a 3’ polyadenylation sequence [0205, 0213].
In regard to claims 16-18, Sadelain teaches the transgene insertion into the endogenous gene locus is mediate by a CRISPR Cas9 nuclease and as stated supra, the guide RNA is to target the first exon or 5’ end of the endogenous gene’s promoter region such that it is in frame with the endogenous gene (i.e., IL-13) ([0013, 0051-0054, 0064, 0216-0217, 0676], see Fig. 7B).
In regard to claims 21 and 23, Sadelin teaches the promoter-less CAR transgene is introduced to the cell as a single stranded donor nucleotide in an AAV vector [0134, 0192] .
In regard to claim 25, Sadelin teaches the donor nucleotide comprises 5’ and 3’ homology arms targeting the endogenous gene’s promoter region (i.e., IL-13 gene locus) [0205, 0217].
In regard to claims 37, 39 and 40, Sadelain teaches the IL-13 promoter is activated when the T cell is a Th2 (T helper cell type 2) phenotype ([0055, 0084, 0142], Table 2). Specifically in regard to claim 37, Sadelain teaches that inducible endogenous promoters such as IL-13 are induced by activation of the T cell [0017, 0036], thus it would have naturally followed that a transgene operably linked to said inducible promoter would increase in expression upon activation of the IL-13 promoter.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 20 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Sadelain et al., (2019/0119638, filed 4/14/2017, published 4/25/2019, see IDS), in view of Gilbert et al., (US 11,254,933, filed 7/14/2017, patented 2/22/2022).
As stated supra, Sadelain suggests a method of genetically modifying a T cell with a CAR transgene inserted at the IL-13 gene locus so as to be operably linked to the IL-13 promoter.
However, although Sadelain teaches that a CRISPR/Cas9 system can be used with gRNA that target the first exon and/or the transcriptional start site of the endogenous gene, and that the T cells comprising the transgene operable linked to the IL-13 promoter are human T cells [0030, 0050, 0062], they are silent with respect to the gRNA of SEQ ID NO:17, which targets the first exon at the transcription start site of the human IL-13 gene.
In regard to claims 20 and 29, Gilbert teaches methods of genetically modifying cells comprising a CRISPR/Cas9 system and a gRNA that targets the transcriptional start site (TSS) of an endogenous gene (col 2, 3rd para.,col 22, 4th para.). Specifically, Gilbert teaches SEQ ID NO:82999, which is 100% identical to SEQ ID NO:17 (see SCORE search 12/30/2025, rni.file, result #1).
Accordingly, in regard to claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of CRISPR/Cas9 mediated insertion a CAR transgene into the first exon/in frame of the IL-13 gene such that it is operably linked to the IL-13 promoter as taught by Sadelain and choose the gRNAs that target the first exon of the IL-13 gene as taught by Gilbert with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Sadelain because the gRNA would cut the IL-13 gene in exon 1 at its start codon (see alignment below of reverse complement of SEQ ID NO:17 with human IL-13 genomic sequence with “ATG” in bold and PAM highlighted):
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Since, CRISPR/Cas9 cut the target sequence 3-4 nucleotides adjacent to the PAM sequence, the use of the gRNA of Gilbert would have allowed an in-frame insertion of the CAR transgene using the transcriptional start site of the endogenous IL-13 gene.
However, in regard to claim 29, Sadelain is silent to a homology arm that comprises a sequence at least 80% identical to the 400 nucleotide SEQ ID NO:14.
Nevertheless, Sadelain teaches a right and/or left homology arm that flank the sequence to be targeted in the endogenous gene, and Sadelain provides an embodiment where the homology arms are 1.9 kb in length (Example 1, [0678], see also Fig. 5A).
Accordingly, in regard to claim 29, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to practice a method of CRISPR/Cas9 mediated insertion of a CAR transgene with a gRNA that targets the first exon/in frame of the IL-13 gene such that it is operably linked to the IL-13 promoter as suggested by Sadelain and Gilbert, and choose a 5’ homology arm of 1.9 kb, which encompasses a sequence at least 80% identical to SEQ ID NO:14 with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Sadelain and Gilbert because the length and position of the 5’ homology are taught by the prior art and using the corresponding IL-13 gene sequence would have merely required simple cloning and well-established molecular biology techniques.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 4/14/2026 are acknowledged.
Applicant argues that the Examiner’s motivations to reconstruct the claimed method were based on impermissible hindsight, and there that there was no reasonable expectation of success in making the claimed immune cell.
Specifically, in regard to the lack of motivation, Applicant argues that Sadelain teaches a laundry list of potential endogenous promoters to choose from, and the mentioning of IL-13 is purely generic. Sadelain does not target the IL-13 locus, specifically suggest disrupting IL-13 expression, nor provide any IL-13 specific guide RNA or donor design. Furthermore, the Examiner concedes that the preferred embodiments of Sadelain are directed to inserting a CAR transgene into a TRAC or B2M locus.
In regard to the reasonable expectation of success for doing so, Applicant argues that instant specification confirms that the IL-13 locus is materially different from the TRAC or B2M loci. Specifically, when a promoter-less cassette is integrated into the TRAC locus it is expressed in a constitutive manner, with high knock-in efficiencies (average 38%) and robust expression of the transgene such as IL-15 or GFP. By contrast, IL-13 has an activation-dependent promoter, that allows an inducible system controlled by T cell activation. Thus, methods applicable to TRAC knock-ins were not predictive of the inducible properties of a IL-13 knock-in. Furthermore, Applicant argues that the exchange of TRAC/B2M for IL-13 locus was not a simple substitution but were fundamentally different with respect to not only locus behavior, but promoter strength and chromatin context.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In instant case, Sadelain explicitly teaches the IL-13 promoter is to be used as the endogenous promoter [0115, 0233].
Furthermore, the fact that Sadelain teaches the IL-13 gene within a list of known options of T cell related promoters used for the same purpose does not render its selection any less obvious. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (“That the ʼ813 patent discloses a multitude of effective combinations does not render any particular formulation less obvious. This is especially true because the claimed composition is used for the identical purpose.”); see also In re Susi, 440 F.2d 442, 445 (CCPA 1971) (obviousness rejection affirmed where the disclosure of the prior art was “huge, but it undeniably include[d] at least some of the compounds recited in appellant’s generic claims and [was] of a class of chemicals to be used for the same purpose as appellant’s additives”); In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009) (“[W]here a skilled artisan merely pursues ‘known options’ from a ‘finite number of identified, predictable solutions,’ obviousness under § 103 arises.” (quoting KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007)).
Moreover, although Sadelian does not provide a preferred embodiment of a modified IL-13 gene, the MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. In instant case, using the IL-13 endogenous promoters appear both in the specification and in the Tables of Sadelain. Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
In regard to Applicant’s second arguments that there was no reasonable expectation in practicing the claimed method based on the teachings of the prior art, as a first matter, arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements regarding the unpredictability of the prior art to target other loci beyond TRAC and B2M in immune cells, are not evidence without a supporting declaration.
Moreover, in regard to the reasonable expectation of success, Sadelain clearly teaches targeting the IL-13 promoter. Furthermore, contrary to Applicant’s assertion, Sadelain was well aware that the IL-13 promoter was a regulated promoter in T cells. Specifically, Sadelain teaches the IL-13 promoter is regulated by activity induced transcriptions factors such as GATA-3 and c-MAF, and can be induced with Th2 commitment (Table 1 of Sadelain). Thus, one of ordinary skill following the guidance of Sadelain would have understood that the IL-13 promoter behaved differently than the constitutive TRAC promoter. Moreover, Sadelain in view of Gilbert teaches the guide RNAs for doing so that would target the start codon of the human IL-13 gene, and one of ordinary skill in the art could have turned to the related art at the time of filing to make an IL-13 modified immune cell. Finally, the genetic modified of the IL-13 locus and regulated expression was well known in the art before the time of filing. Importantly, in order to complete the art of record and to rebut Applicant's arguments, Applicant is directed to the prior art of Monk et al., (US2005/0065327, filed 7/15/2004, published 3/24/2005), which demonstrate that well before the time of invention it was known that the IL-13 could be successfully targeted (albeit in a mouse stem cell) where the mouse IL-13 gene was replaced from “start to stop codon” with the relevant portion of the human IL-13 gene. This mouse strain expressed human IL-13, rather than mouse IL-13, in response to the same stimuli as the wild-type mouse, as the endogenous IL-13 promoter and IL-13 pA tail remained unchanged (Example 17, [0383-0384]).
Thus, any conclusions of unpredictability have to be made in the context of this particular in vitro method of modifying a known gene in a common cell type. Furthermore, the Federal Circuit found that the claims at issue would have been obvious since there had been ample suggestion in the prior art that the claimed method would have worked. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
Conclusion
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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