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
Claims 1 - 20 are currently pending in the instant application.
Status of Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on April 21, 2026. Claims 1 – 20 are currently pending. Claims 1 and 4 have been amended in the Applicant’s amendment filed April 21, 2026. No claims have been added or canceled in the Applicant’s amendment filed April 21, 2026.
Applicant had previously elected, without traverse in the reply filed 11 September, 2025 of Group I, claims 1 - 12, directed to a method producing modified young T cells; and the following election of Species, without traverse, is acknowledged:
Species (A): the TCR gene encodes for a TCR that recognizes a patient derived tumor antigen (Claim 8), and
Species (B): wherein the population of modified young T cells comprises T cells that are ….CD127+ (Claim 11) and
Species (C) . “wherein the final formulation comprises at least about 20% of memory T
stem cells (Tmsc) and central memory T cells (Tcm). collectively’ (claim 15).
Claims 13 - 20 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claim 9 and 12 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was still deemed proper and was therefore made FINAL.
The claims were examined insofar as they read on the elected species.
Therefore, claims 1-8 and 10 - 11 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed 28 September, 2021, is a CON of PCT/US2020/025758, filed 30 March, 2020, which claims the benefit of Provisional Application 62/826,824, filed 29 March, 2019.
Therefore, the earliest priority date is 29 March, 2019.
Withdrawn Objections/Rejections
Claim Rejections - 35 USC § 112(a) - Written Description
The rejection of claims 1, 4, and 5 is withdrawn under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to describe the structure of the HR template.
In view of the withdrawn rejection, Applicants argument is moot.
Claim Rejection - 35 USC § 112(b)
The rejection of claims 4 and 5 is withdrawn under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 has been amended to no longer be indefinite.
In view of the withdrawn rejection, Applicant’s arguments are moot.
Claim Rejections - 35 USC § 102
The rejection of claims 1 – 3, 5 - 8, and 10 - 11 under 35 U.S.C. 102 (a)(1)/(a)(2) as being anticipated by Nicholson et al. (hereinafter referred to as “Nicholson”) (US 20180289741 A1, published October 11, 2018) is withdrawn.
Applicant has amended claim 1 by incorporating the limitations of claim 4 into claim 1. (Please note: Nicholson was not previously rejected as being anticipated by Nicholson). Nicholson does not teach the limitations of amended claim 1.
In view of the withdrawn rejection, Applicant’s arguments are moot.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The rejection of claims 1, 4, and 5 is maintained, and claims 2 – 3, 6 – 8, and 10 – 11 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the Specification, while being enabling for introducing into a TCRα locus cell a HR template nucleic acid sequence comprising
First and second homology arms to first and second target nucleic acid sequences,
A TCR Vβ and Cβ2 gene sequence positioned between the first and second homology arms,
A first P2A coding sequence positioned upstream of the TCR gene sequence and a second P2A coding sequence positioned downstream of the TCR gene sequence, wherein the first and second P2A coding sequences are codon-diverged relative to each other,
A sequence coding for the amino acids GSG is positioned immediately upstream of the
A Furin cleavage site positioned upstream of the second P2A coding sequence;
A HGH signal sequence positioned between the first 2A coding sequence and the TCR gene sequence,
does not reasonably provide enablement for introducing the nucleic acid at any locus in the T cell, introducing any other TCR genes into the cell, using any other construct, second TCR sequence positioned between the second P2A coding sequence and second homology arm; and a second HGH signal sequence positioned between the second 2A coding sequence and second TCR gene sequence. Please note: This rejection has been amended by the response filed April 21, 2026.
The Specification does not enable any person skill in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The claims, when given the broadest possible interpretation, encompass a method of producing a population of modified young T cells, comprising
Introducing via electroporation into a T cell a HR template nucleic acid sequence comprising
First and second homology arms homologous to first and second target nucleic acid sequences
A TCR gene sequence positioned between the first and second homology arms
A first P2A coding sequence positioned upstream of the TCR gene sequence and a second P2A coding sequence positioned downstream of the TCR gene sequence, wherein the first and second P2A coding sequences are codon-diverged relative to each other,
A sequence coding for the amino acids GSG is positioned immediately upstream of the first P2A coding sequences
A Furin cleavage site positioned upstream of the second P2A coding sequence;
Recombining the HR template nucleic acid into an endogenous TCR gene locus; and
Culturing the T cell in the presence of IL2, IL7, or IL15.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The invention encompasses a method of producing a population of modified young T cells, comprising
Introducing via electroporation into a T cell a HR template nucleic acid sequence comprising
First and second homology arms homologous to first and second target nucleic acid sequences
A TCR gene sequence positioned between the first and second homology arms
Recombining the HR template nucleic acid into an endogenous TCR gene locus; and
Culturing the T cell in the presence of IL2, IL7, or IL15.
Scope of the invention. The invention encompasses a method of producing a population of
modified young T cells for the eradication of solid and liquid tumors.
Number of working examples and guidance. In the instant case, Applicant provides one
relevant working example. The as-Filed Specification teaches example 1, wherein constructs containing genes of interest were inserted into endogenous loci with the use of homologous repair templates (Paragraph [0285]). The gene of interest was sandwiched between 2A peptides, a protease cleavage site that is upstream of the 2A peptide, and a GSG linker was inserted before each 2A peptide (Paragraph [0285]). There is also a Furin site that is inserted before the second 2A peptide (Figure 2B – see below).
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This example and figure teach this specific order and construct is necessary for the translation and processing of the gene of interest. It is important to note that TCR Vβ and Cβ2 gene sequence positioned between the first and second homology arms.
The disclosure also teaches that FIG. 2A shows a schematic representing the general targeting strategy used for integrating neoantigen-specific TCR constructs (neoTCRs) into the TCRα locus (Paragraph [0081]). The disclosure does not teach integrating the TCR constructs into any other TCRα loci.
Further, the as-Filed Specification does not teach that the HR template further comprises a second TCR sequence.
State of the art. Although the field of producing a population of modified young T cells using
homologous recombination is highly developed, the method of using the construct comprising two 2A sequences, a GSG sequence, a Furin cleavage site, and a HGH signal together is not as well known. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known in the art that the cleavage efficiency of the 2A peptide motif is affected by the preceding peptide sequence and the upstream protein, and that the inclusion of a Gly-Ser-Gly (GSG) linker between the upstream cistron and the 2A peptide nullified this variable, as evidenced by Szymcak et al. (Szymczak-Workman et al. . Design and construction of 2A peptide-linked multicistronic vectors. Cold Spring Harb Protoc. 2012 Feb 1;2012(2):199-204. doi: 10.1101/pdb.ip067876. PMID: 22301656.) (pg. 201, Incorporation of a GSG linker paragraph). Szymcak et al teaches that the insertion of a furin cleavage site between the protein and the 2A sequence has been shown to result in the removal of this 2A tag (pg. 200, A 2A “Tag” Attached to upstream protein paragraph).
Additionally, it was known in the art that single transcript expression and separated protein production is possible via the use of 2A viral peptides, but detailed characterization to assess their suitability and applications is needed, as evidenced by Souza-Moreira et al. (Souza-Moreira et al., Screening of 2A peptides for polycistronic gene expression in yeast, FEMS Yeast Research, Volume 18, Issue 5, August 2018) (Abstract). Souza-Moreira et al. teaches that only 3 out of the 22 2A sequences tested yielded high cleavage efficiency (Abstract).
Further, it was known that the counter indications to using 2A peptides are poor cleavage efficiency of the translated polypeptide and disruption of function of the upstream protein by the residual 2A peptide that remains fused to its C-terminus, which leads to accumulation of significant amounts of uncleaved protein and the formation of toxic protein aggregates in cells expressing the transgene, as evidenced by Verrier et al. (Verrier JD. Et al. Bicistronic lentiviruses containing a viral 2A cleavage sequence reliably co-express two proteins and restore vision to an animal model of LCA1. PLoS One. 2011;6(5):e20553. doi: 10.1371/journal.pone.0020553. Epub 2011 May 27. PMID: 21647387; PMCID: PMC3103589.) (pg. 8, right column, last paragraph).
Please note: HGH signal sequences are not commonly used in such P2A constructs (as the Examiner was not able to find relevant prior art).
Amount of Experimentation Required. Given the unpredictability of the art, the poorly
developed state of the art with to the use of HGH signal sequences, the variability of cleavage efficiency of the 2A sequences, which can lead to accumulation of significant amounts of uncleaved protein and the formation of toxic protein aggregates in cells expressing the transgene, and the importance of the linking the inclusion of a Gly-Ser-Gly (GSG) linker between the upstream cistron and the 2A peptide along with a furin site, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the template as described in the instant claims to produce a population of modified young T cells. Further, due to the lack of specific guidance in the specification for using a construct comprising a second TCR sequence, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Response to Arguments as they apply to rejection of claims 1, 4 and 5 under 35 USC § 112(b)
Applicant’s arguments filed April 21, 2026 have been fully considered but they are not persuasive. Applicant essentially asserts (a) that there is support for HR template comprising a first TCR gene sequence and a second TCR gene sequence (Remarks, pg. 6, second paragraph).
Regarding (a), Applicant cites paragraph [0289], which teaches that the “the encoded NeoTCRa and NeoTCRB polypeptides are also unliked from each other through cleavage,” and argus that there is support for a first TCR gene sequence and a second TCR gene sequence. However, this argument is not found persuasive.
It is unclear whether the HR template comprises two complete TCR gene sequences or two separate parts of a single gene sequence (i.e. TCRα and TCRβ sequence).
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Specifically, as seen in Figure 2A, the patient cells have been engineered with a neoE-TCR DNA that comprises a neo-TCRβ and TCRα. The examiner suggests amending the claims to clarify exactly what is enclosed within the homology arms of the HR template.
Conclusion
Claims 1 – 8 and 10 - 11 remain rejected.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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