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.
Restriction/Election
Applicant's election, 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Claims 13 - 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claim 9 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.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 is still deemed proper and is therefore made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1-8and 10 - 11 are under consideration to which the following grounds of rejection are applicable.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 30 September, 2021 has been considered. An initialed copy of the IDS accompanies this Office Action.
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.
Claim objection
Claims 4 is objected to because of the following informalities: abbreviations such as P2A should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim Rejection - 35 USC § 112(b)
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 and 5 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.
Claim 4 is indefinite for the recitation of “furin cleavage site positioned upstream of the P2A coding sequence” in line 8. It is unclear whether the furin is located immediately upstream of the second P2A coding sequence, or slightly more upstream of the second P2A coding sequence, i.e. in front of the GSG sequence. Thus, the metes and bounds of the claim cannot be determined.
Claim 5 is indefinite insofar as they ultimately depend from claim 4.
Claim Rejections - 35 USC § 112(a) - Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112, first paragraph:
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, and 5 are rejected 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.
Claims 1,4, and 5 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
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.
Overall, what these statements indicate is that the Applicant must provide adequate description of such core structure and function related to that method such that the Artisan could determine the desired effect. Hence, the analysis below demonstrates that Applicant has not determined the core structure and function for full scope of the claimed method.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail such that the Artisan can reasonably conclude that the inventors had possession of the claimed invention. Such possession may be demonstrated by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and/or formulae that fully set forth the claimed invention. Possession may be shown by an actual reduction to practice, showing that the invention was "ready for patenting", or by describing distinguishing identifying characteristics sufficient to show that Applicant was in possession of the claimed invention (January 5, 2001 Fed. Reg., Vol. 66, No. 4, pp. 1099-11). MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. Moreover, MPEP 2163 states: [A] biomolecule sequence described only by a functional characteristic, without any known or disclosed characteristic, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.
In analyzing whether the written description requirement is met for the claimed method, it is first determined whether the examples describe 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.
The instant claims encompass a population of modified young T cells with the contemplated use of treating cancer. There is not structure/function correlation for the claimed genus of cells. In the instant case,
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. Further, the as-Filed Specification does not teach that the HR template further comprises a second TCR sequence.
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).
There is no structure/function correlation for all the claimed components of the template used to make the modified young T cells. In the instant case, Applicant does not disclose any relevant examples that teach a construct comprising a second TCR sequence. These claims are termed "reach through claims" and rejection is proper on the grounds that the applicants do not possess the method, comprising all laimed components.
Therefore, the specification does not contain a written description of the invention, and a manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains can make and use the same, nor does it set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. This limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of the method of culturing natural killer cells as recited in the instant claims.
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, and 5 are 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 T cell a HR template nucleic acid sequence comprising
First and second homology arms 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 Gly Ser Gly (GSG) positioned immediately upstream of the first and second P2A coding sequences
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 any other HR template nucleic acid sequences; a
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.
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
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. 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.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 – 3, 5 - 8, and 10 - 11 are rejected 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).
Regarding claim 1, Nicholson teaches the introducing an exogenous nucleic acid sequence, comprising an EagI restriction site, into the genome of human T cells at the TRC 1-2 recognition sequence via homologous recombination (Paragraph [00356]) (interpreted as recombining the HR template nucleic acid into an endogenous TCR). Nicholson teaches the AAV405 plasmid generally comprises sequences for a 5′ ITR, a CMV enhancer and promoter sequence, a 5′ homology arm, a nucleic acid sequence comprising the EagI restriction site, an SV40 poly(A) signal sequence, a 3′ homology arm, and a 3′ ITR (Paragraph [0357] (interpreted as a first and second homology arms, and a TCR gene sequence, positioned between the first and second homology arms). Nicholson teaches that the TRC 1-2 recognition sequence (SEQ ID NO:3) spans nucleotides 187-208 of the human T cell receptor alpha constant region (Paragraph [0086]). Nicholson teaches genetically-modified cells that comprise an exogenous polynucleotide sequence exogenous TCR coding sequence inserted into the human TCR alpha constant region gene, which simultaneously disrupts expression of the endogenous T cell receptor at the cell surface. (“The present inventors are the first to teach genetically-modified cells that comprise an exogenous polynucleotide sequence (e.g., a chimeric antigen receptor or exogenous TCR coding sequence) inserted into the human TCR alpha constant region gene, which simultaneously disrupts expression of the endogenous T cell receptor at the cell surface.” Paragraph [0012]). Nicholson teaches that when the genetically-modified cell is a genetically-modified human T cell (or a cell derived therefrom), pharmaceutical compositions of the invention can further include biological molecules, such as cytokines (e.g., IL-2, IL-7, IL-15, and/or IL-21), which promote in vivo cell proliferation and engraftment (Paragraph [0320]) (interpreted as culturing in the presence of IL-7).
Regarding claims 2 and 3, cytokines (e.g., IL-2, IL-7, IL-15, and/or IL-21) are used to promote in vivo cell proliferation and engraftment (Paragraph [0320]).
Regarding claim 6, Nicholson teaches that homology arms were either “short” (200 bp on the 5′ homology arm and 180 bp on the 3′ homology arm) to mimic the self-complimentary AAV vectors, or “long” (985 bp on the 5′ homology arm and 763 bp on the 3′ homology arm) to mimic the single strand AAV vectors (Paragraph [0407]).
Regarding claim 7, Nicholson teaches a plasmid DNA encoding an exogenous nucleic acid sequence can be digested by one or more restriction enzymes, such that the circular plasmid DNA is linearized prior to transfection into the cell (Paragraph [0316]) (interpreted as HR template is circular).
Regarding claim 8, Nicholson teaches that the expression of an exogenous TCR on an immune effector cell can confer specificity for a specific epitope or antigen (e.g., an epitope or antigen preferentially present on the surface of a cancer cell or other disease-causing cell or particle) (Paragraph [0276]). Nicholson teaches the use of T cells, wherein “human T cell” or “T cell” refers to a T cell isolated from a human donor (Paragraph 0287]).
Regarding claim 10, Nicholson teaches meganucleases that can be engineered to recognize and cleave recognition sequences within human TRAC region, and further allow for homologous recombination of exogenous nucleic acid sequences directly into the TCR alpha constant region gene (Paragraph [0290]).
Regarding claim 11, although Nicholson does not specifically exemplify the specific markers taught in instant claim 11, Nicholson does teach the method of producing a population of T cells as required by claim 1, and that such that the modified T cells taught by Nicholson will inherently express the markers taught in instant claim 11 (See; MPEP 2112.1, 2112.01(II) and MPEP 2112(V)).
Conclusion
Claims 1 – 8, and 10 – 11 are rejected.
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