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 .
DETAILED ACTION
Claim status
Claims 1-6, 12-13, 16-18, 20-21, 23, 25, 29, 37, 39-40, 42, 47-48, 69, 112-113, 134-135 are pending
Claims 42, 47-48, 69, 112-113, 134-135 are withdrawn
Claims 1-6, 12-13, 16-18, 20-21, 23, 25, 29, 37, 39, and 40 are under examination
Election/Restrictions
Applicant’s election of the following invention without traverse in the reply filed on 10/28/2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Group I, claims 1-6, 12-13, 16-18, 20-21, 23, 25, 29, 37, 39-40, and 42, drawn to a method of genetically modifying an immune cell.
Claims 47-48, 69, 112-113, 134-135 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Applicant’s election of the following species is acknowledged.
T cells as the species of immune cell.
Claim 42 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic claim.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/22/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 the transgene is under the control of the endogenous gene’s promoter (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 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):
PNG
media_image1.png
160
1367
media_image1.png
Greyscale
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.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ARTHUR S LEONARD/Examiner, Art Unit 1631