DETAILED ACTION
Claims 1-3, 7, 9-10, 12, 15-16, 18-20, 22-24, 26, 29-30, 37 and 58 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The information disclosure statement filed 7/28/2026 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following foreign documents and non-patent literature documents listed below:
(Foreign Patent Document) WO2007017201A1 Generation of Antigen Specific T cells
(Non-Patent Literature Document) International Preliminary Report (Mailed on June 8, 2023)
Drawings
The drawings are objected to because:
The legend in instant Fig. 18B is blurry and not legible, making it difficult to determine which bar corresponds to which sample.
Instant Fig. 39 is a grayscale drawing depicting the identification of other minor fraction cell types as measured by flow cytometry, wherein the legend describes cell types using different grayscale gradients (see specification page 19, ¶ [0141]). However, it is hard to interpret between the %NK cells and % monocytes based on the given gradient. Therefore, the figure is not able to be interpreted as currently drawn in grayscale.
Instant Fig. 49B is an exemplary graph of fraction of transplanted cells indicating rate of clearance of human T-cell lines modified with CRISPR to no longer express MHC class I on the cell surface in BALB/c mice, wherein each group is indicated by a black line and an open circle. This makes it impossible to interpret which group corresponds to which line on the graph. Therefore, the figure is not able to be interpreted as currently drawn in grayscale.
Instant Fig. 52B is an exemplary graph of SARS-CoV-2-specific CD8+ T cells that were measured as percentage of AIM+(CD69+CD137+) CD8+ T cells, wherein each group is indicated by a patterned circle. However, the size of the circle makes it impossible to interpret which group corresponds to which circle on the graph. Additionally, the x-axis needs to align with the vertical lines throughout the graph. Therefore, the figure is not able to be interpreted as currently drawn. This also applies to instant Fig. 53B.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). The examiner has noted that:
The specification at page 41 ¶ [0249]-[0250], page 132 ¶ [0492], and page 185, ¶ [0613] contain polylinker amino acid sequences, which need to be identified by sequence identifiers;
Tables 1-5 and 26 disclose amino acid sequences which need to be identified by sequence identifiers;
The specification at page 131, ¶ [0490], contain nucleic acid sequences, which need to be identified by sequence identifiers; and
Table 24 on pages 167-168 disclose nucleic acid sequences, which need to be identified by sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. See instant Figures 19, 20A, 20B, and 55. Amino acid sequences of 4 or more amino acids require a sequence identifier. Therefore, amendment to the drawings or Brief Description of the Drawings in the specification to include SEQ ID NOs for the sequences are required.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The use of the term NovoCyte®, GlutaMaxTM, CellGenix®, FlowJoTM, ImmunoCultTM, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such with the appropriate notation:
NovoCyte® (page 122, ¶ [0465]; page 127, ¶ [0480]; page 138, ¶ [0506]);
GlutaMaxTM (page 122. ¶ [0464]; page 173, ¶ [0580]);
CellGenix® (page 118, ¶ [0455]; page 121, ¶ [0463]; page 122, ¶ [0464], etc.);
FlowJoTM (page 122, ¶ [0465]; page 175, ¶ [0582]); and
ImmunoCultTM (page 121, ¶ [0463]; page 145, ¶ [0520]).
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 10 and 24 are objected to because of the following informalities:
Regarding instant claim 10, the amino acid sequence that describe the polylinker is missing a sequence identifier (SEQ ID NO:XX). Appropriate correction is required.
Regarding instant claim 24, “inhibitors 2 step (vii)” should read “inhibitors during step (vii)”, based on the instant specification page 186, ¶ [0626].
Claim Rejections - 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.
Claim 3 is 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.
Instant claim 3 attempts to incorporate by reference to a specific table or figure; however, such incorporation is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, there is a practical way to define the invention in words. Incorporation by reference is a necessity doctrine, not for applicant' s convenience. See MPEP 2173.05(s).
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 1-3, 7, 12, 29-30, 37, 58 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran).
Regarding instant claims 1-3, 29, 37, and 58, Tran teaches a method of generating a population of cells comprising host T cells expressing a T cell receptor (TCR) specific for a mutated KRAS peptide antigen (KRAS with the G12D mutation) (page 6, ¶ [0020]; pages 28-29, ¶ [0084]-[0086]), wherein:
Patient apheresis is thawed, washed, and then incubated;
Tandem mini-gene constructs encoding 61 mutations, among which was KRAS, were made and in vitro transcribed into RNA to identify which mutated antigen in the TMG is being recognized by the tumor infiltrating lymphocyte (TIL) cultures;
The media and non-adherent cells were removed and collected and the adherent cells (monocytes) in the flasks were then vigorously washed and incubated in DC media to differentiate into dendritic cells;
Five TMGs (e.g. TMGs 1-5) were transcribed into RNA and then electroporated into autologous antigen presenting DCs allowing for the processing and presentation of all mutations in the context of the patient's own HLA-I and HLA-II molecules; and
Twenty-four individual TIL cultures (T cells) from the patient were co-cultured with the TMG-expressing DCs;
thereby generating a population of T cells that express TCRs that specifically bind to a mutated KRAS peptide antigen (pages 37-38, ¶ [0113]-[0114], and pages 39-40, ¶ [0117]-[0119]). Tran also teaches a method of treating cancer in a mammal, comprising administering a mammal population of cells comprising the TCRs generated by the said methods described above, in an amount effective to treat cancer in the mammal (page 32, ¶ [0097]).
Regarding instant claim 7, Tran teaches that the TCR that binds specifically to the mutated KRAS peptide with the G12D mutation (hereinafter, “mutated KRAS” as disclosed in page 5, ¶ [0017]) has antigen specificity for the mutated KRAS peptide having a length of about 24 amino acids (pages 5-6, ¶ [0019]; Table 3).
Regarding instant claim 12, Tran discloses that the DC media used to differentiate isolated monocytes into dendritic cells comprises 800 IU/ml GM-CSF and 200 U/ml IL-4 (page 37, ¶ [0113]).
Regarding instant claim 30, Tran teaches that the T cels can be any type of T cells and can be of any developmental stage, including but not limited to, CD8+ T cells (page 29, ¶ [0085]).
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, 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.
Claims 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran) as applied to claim 1 above, and further in view of Sahin (Sahin et al, “Personalized RNA mutanome vaccines mobilize polyspecific therapeutic immunity against cancer”, Nature, July 5, 2017, 547:222-226; hereinafter Sahin) and D’hondt (D’hondt et al, WO2020030977A2, Priority to 8/7/2018; hereinafter D’hondt).
Regarding instant claims 9 and 10, the teachings of Tran are discussed above in the 102 rejection. Tran further teaches that for each identified mutation, a minigene encoding the mutation flanked by 12 amino acids on either side was generated and synthesized in tandem to create tandem minigene constructs, TMG 1-5 (page 38, ¶ [114]).
However, Tran does not teach that the plurality of antigens are each separated by a polylinker comprising the amino acid sequence GGSGGGSS.
The deficiency is resolved by Sahin and D’hondt.
Sahin teaches synthetic RNA constructs encoding five linker-connected 27mer peptides with a mutation in position 14 (hereinafter pentatope RNAs), wherein the linkers comprise glycine-serine linkers (page 1, left column, second paragraph-right column, first paragraph; Fig. 1b). Sahin further discloses that in order to manufacture in vitro transcribed RNA, synthetic DNA fragments coding for five putative neo-epitopes (each as 27mer with the mutation at position 14) connected by non-immunogenic glycine/serine linkers, e.g. GGSGGGGSGG, were cloned into a starting vector, containing the SP- and MITD-domains for optimized routing to HLA class I and II pathways and backbone sequence elements for improved RNA stability and translational efficiency, followed by in vitro transcription with T7 NA polymerase (page 7, §Manufacturing of in vitro transcribed RNA).
D’hondt teaches BVN22E, a synthetic protein comprised of homogeneous synthetic proteins/molecules expressing one or more epidermal growth factor (EGF) neutralizing domains, that may be useful in treating chronic disease, such as cancer. D’hondt also teaches that BVN22 includes one or more linkers or spacers that separates the synthetic EGF (sEGF) from the CT-B sequences, wherein the linkers comprise 3-14 amino acids, e.g. SSGGGGSGGGSSGGG. Furthermore, D’hondt teaches that one of skill in the art will appreciate that there are many other sequences or combinations of primarily ‘G’ and ‘S’ that would also serve as useful linker sequences (page 38, lines 4-30).
Regarding instant claims 9 and 10, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the said method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS comprising mRNA molecules comprising coding sequences for a plurality of antigens as taught by Tran wherein the antigens are separated by glycine/serine linkers comprising the amino acid sequence GGSGGGSS as taught by Sahin and D’hondt. This is obvious because, Tran teaches Tran teaches a method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS peptide antigen, wherein the minigenes encoding the mutation flanked by 12 amino acids on either side was generated and synthesized in tandem to create tandem minigene constructs, TMG 1-5, Sahin teaches synthetic RNA constructs encoding five linker-connected 27mer peptides, wherein the linkers comprise non-immunogenic glycine/serine linkers, e.g. GGSGGGGSGG, and D’hondt teaches a synthetic protein that is useful in treating chronic disease, such as cancer, comprising the linker SSGGGGSGGGSSGGG that separates the sEGF from the CT-B sequences, wherein D’hondt discloses that one of skill in the art will appreciate that there are many other sequences or combinations of primarily ‘G’ and ‘S’ that would also serve as useful linker sequences. As taught by D’hondt, selection of a particular linker sequence is a matter of routine optimization known by a skilled artisan, absent a showing of unexpected results. Also see MPEP2144.05. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein one or more mRNA molecules comprise coding sequences for a plurality of the antigens, each separated by a polylinker comprising the amino acid sequence GGSGGGSS.
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran) as applied to claim1 above, and further in view of Posch (Posch et al, “Generation of Human Monocyte-derived Dendritic Cells from Whole Blood”, J Vis Exp., December 24, 2016, 118(54968):1-6; hereinafter Posch).
Regarding instant claims 15 and 16, the teachings of Tran are discussed above in the 102 rejection. Additionally, Tran teaches that the peptides encoded in TMG-1 were synthesized and individually pulsed onto DCs overnight, followed by co-culture with TIL culture #6 (pages 37-38, ¶ [0114]; pages 39-40, ¶ [0118]).
However, Tran does not teach that substantially all of the isolated monocytes are differentiated into dendritic cells, wherein “substantially” is defined as at least about 80% of all the monocytes are differentiated into DCs (page 33, ¶ [0215]).
The deficiency is resolved by Posch.
Posch teaches the generation of human monocyte-derived cells from whole blood, wherein monocytes are isolated from whole blood samples and stimulated by IL-4 and GM-CSF for 5 days. Posch further teaches that IL4 and GM-CSF stimulation of monocytes for 5 days results in differentiation into monocyte-derived dendritic cells, and FACS analysis of monocyte-derived dendritic cells on day 5 shows a homologous population expressing high levels of CD11b, CD11c, and the C-type lectin DC-SIGN (page 3, third paragraph of §Representative Results; Fig. 4).
Regarding instant claims 15 and 16, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the said method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS comprising incubating the differentiated DCs with the mutated KRAS peptide (TMG-1) as taught by Tran to comprise that substantially all of the monocytes are differentiated into dendritic cells as taught by Posch. This is obvious because, Tran teaches a method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS peptide antigen wherein the DC media used to differentiate isolated monocytes into dendritic cells comprises 800 IU/ml GM-CSF and 200 U/ml IL-4 followed by synthesizing and individually pulsing peptides encoded in TMG-1 onto DCs overnight, and Posch teaches that GM-CSF and IL4 stimulation of monocytes for five days generated substantially all DCs from monocytes. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein substantially all of the monocytes are differentiated into DCs in step (v) of the instant method, and wherein the instant method further comprises incubating the DCs of step (v) with one or more antigen peptides associated with cancer prior to step (vii).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran) and Posch (Posch et al, “Generation of Human Monocyte-derived Dendritic Cells from Whole Blood”, J Vis Exp., December 24 2016, 118(54968):1-6; hereinafter Posch) as applied to claim 1 above, and further in view of Ali (Ali et al, “Induction of neoantigen-reactive T cells from healthy donors”, Nature Protocols, June 2019, 14:1926-1943; hereinafter Ali).
Regarding instant claim 18, the combined teachings of Tran and Posch are discussed above.
However, the combined teachings of Tran and Posch do not teach a method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the ratio of the DCs to the T cells is about 1:2 to about 1:4 after stimulating the T cells by contacting them with DCs transfected with mRNA molecules encoding one or more antigens associated with cancer.
The deficiency is resolved by Ali.
Ali teaches identifying neoepitope-specific T cells comprising transfecting monocyte-derived DCs with mRNA encoding candidate neoepitopes to prime autologous naïve CD8+ T cells (page 1926, Abstract). Ali further discloses that DCs were differentiated from monocytes by stimulating with IL-4 and GM-CSF (page 1936, Procedure Step 8), and the differentiated DCs were electroporated with the minigene M2 were cocultured with T cells at a DC:T cell ratios of 1:8, 1:4, 1:2, and 1:1, wherein there were no significant differences between cocultures with DC:T cell ratios of 1:1, 1:2, and 1:4 with respect to the induction of T cell responses to melanoma neoantigens (pages 1930-1931, §Optimizing the Interaction between…; Fig. 3d).
Regarding instant claim 18, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the said method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS wherein GM-CSF and IL4 stimulation of monocytes generated substantially all DCs from monocytes as taught by the combined teachings of Tran and Posch to further comprise that the differentiated DCs were cocultured with T cells at a DC:T cell ratio of 1:2 as taught by Ali. This is obvious because, the combined teachings of Tran and Posch teach a method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS peptide antigen wherein GM-CSF and IL4 stimulation of monocytes generated substantially all DCs from monocytes, and Ali teaches that differentiated DCs were cocultured with T cells at a DC:T cell ratios of 1:8, 1:4, 1:2, and 1:1, wherein there were no significant differences between cocultures with DC:T cell ratios of 1:1, 1:2, and 1:4 with respect to the induction of T cell responses to melanoma neoantigens. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein substantially all of the monocytes are differentiated into DCs in step (v) of the instant method, and wherein ratio of the differentiated DCs to T cells in step (vii) is about 1:2.
Claims 19-20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran), Posch (Posch et al, “Generation of Human Monocyte-derived Dendritic Cells from Whole Blood”, J Vis Exp., December 24 2016, 118(54968):1-6; hereinafter Posch), and Ali (Ali et al, “Induction of neoantigen-reactive T cells from healthy donors”, Nature Protocols, June 2019, 14:1926-1943; hereinafter Ali) as applied to claim 1 above, and further in view of Slanetz (Slanetz et al, WO2018005712A1, Priority to June 28, 2016, Published on 1/4/2018, IDS entered on 4/25/2024; hereinafter Slanetz).
Regarding instant claims 19-20 and 22, the combined teachings of Tran, Posch, and Ali are discussed above.
However, the combined teachings of Tran, Posch, and Ali do not teach a method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the T cells are stimulated in media containing cytokines, e.g. IL-7 and IL-15, and tetrameric antibodies that bind CD3, CD28 and/or CD2.
The deficiency is resolved by Slanetz.
Slanetz teaches a method for making a composition comprising T cells, wherein the method comprises a step of stimulating the cell population comprising T-cells by culturing the cell population in media comprising cytokines comprising IL-7 and IL-15 and a polyclonal stimulation that facilitate the expansion of T cells that recognize the desired target antigen(s) comprising tetrameric antibodies that bind CD3, CD28 and CD2 (pages 4-5, ¶ [0007]-[0010]).
Regarding instant claims 19-20 and 22, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the said method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS wherein differentiated DCs were cocultured with T cells at a DC:T cell ratio of 1:2 as taught by the combined teachings of Tran, Posch, and Ali to comprise that T cells were stimulated in media containing cytokines, e.g. IL-7 and IL-15, and tetrameric antibodies that bind CD3, CD28, and CD2 as taught by Slanetz. This is obvious because, the combined teachings of Tran, Posch, and Ali teach a method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS peptide antigen wherein monocyte-derived DCs were cocultured with T cells at a DC:T cell ratio of 1:2, and Slanetz teaches a method for making a composition comprising T cells, wherein the method comprises a step of stimulating T-cells by culturing the cell population in media comprising cytokines IL-7 and IL-15 and tetrameric antibodies that bind CD3, CD28 and CD2, wherein the tetrameric antibodies facilitate the expansion of T cells that recognize the desired target antigen(s). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the instant differentiated DCs are cocultured with T cells in step (vii) at a DC:T cell ratio of 1:2, and wherein the instant T cells are stimulated in media containing cytokines comprising IL-7 and IL-15 and tetrameric antibodies that bind CD3, CD28, and CD2.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran), Posch (Posch et al, “Generation of Human Monocyte-derived Dendritic Cells from Whole Blood”, J Vis Exp., December 24 2016, 118(54968):1-6; hereinafter Posch), Ali (Ali et al, “Induction of neoantigen-reactive T cells from healthy donors”, Nature Protocols, June 2019, 14:1926-1943; hereinafter Ali), and Slanetz (Slanetz et al, WO2018005712A1, Priority to June 28, 2016, Published on 1/4/2018, IDS entered on 4/25/2024; hereinafter Slanetz) as applied to claim 1 above, and further in view of Lee (Lee et al, WO2017106537A2, Priority to December 18. 2015; hereinafter Lee).
Regarding instant claim 23, the combined teachings of Tran, Posch, Ali, and Slanetz are discussed above.
However, the combined teachings of Tran, Posch, Ali, and Slanetz do not teach a method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the T cells have a deletion in the endogenous β2-micorglobulin (B2M) gene.
The deficiency is resolved by Lee.
Lee teaches compositions and methods for partial or complete inactivation or disruption of a B2M gene, and compositions and methods for introducing and expressing to desired levels of exogenous TCR transgenes in T lymphocytes, after or simultaneously with the disruption of the endogenous B2M (page 7, ¶ [0016]). Lee further teaches that expression of the B2M gene is modulated such that the cells no longer comprise a HLA class I on their cell surfaces, wherein cells modified in this manner can be used as therapeutics, for example, transplants, as the lack of B2M expression prevents or reduces an HLA-based immune response (page 17-18, ¶ [0040]).
Regarding instant claim 23, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the said method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS wherein T cells were stimulated in media containing cytokines, e.g. IL-7 and IL-15, and tetrameric antibodies that bind CD3, CD28, and CD2 as taught by the combined teachings of Tran, Posch, Ali and Slanetz to further comprise that the T cells have a deletion in the endogenous B2M gene as taught by Lee. This is obvious because, the combined teachings of Tran, Posch, Ali, and Slanetz teach a method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS peptide wherein T cells were stimulated in media containing cytokines, e.g. IL-7 and IL-15, and tetrameric antibodies that bind CD3, CD28, and CD2, and Lee teaches compositions and methods for introducing and expressing to desired levels of exogenous TCR transgenes in T lymphocytes, after or simultaneously with the disruption of the endogenous B2M gene such that the cells no longer comprise a HLA class I on their cell surfaces so that they can be used as therapeutics as the lack of B2M expression prevents an HLA-based immune response. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the instant T cells comprising a deletion in the endogenous B2M gene are stimulated in media containing cytokines comprising IL-7 and IL-15 and tetrameric antibodies that bind CD3, CD28, and CD2.
Claims 24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran et al, WO2018026691A1, Priority to August 2, 2016, IDS entered on 4/25/2024; hereinafter Tran), Posch (Posch et al, “Generation of Human Monocyte-derived Dendritic Cells from Whole Blood”, J Vis Exp., December 24 2016, 118(54968):1-6; hereinafter Posch), Ali (Ali et al, “Induction of neoantigen-reactive T cells from healthy donors”, Nature Protocols, June 2019, 14:1926-1943; hereinafter Ali), Slanetz (Slanetz et al, WO2018005712A1, Priority to June 28, 2016, Published on 1/4/2018, IDS entered on 4/25/2024; hereinafter Slanetz), and Lee (Lee et al, WO2017106537A2, Priority to December 18. 2015; hereinafter Lee) as applied to claim 1 above, and further in view of Rosen (Rosen et al, WO2017127755A1, Priority to January 20, 2016; hereinafter Rosen).
Regarding instant claims 24 and 26, the combined teachings of Tran, Posch, Ali, Slanetz, and Lee are discussed above.
However, the combined teachings of Tran, Posch, Ali, Slanetz, and Lee do not teach a method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the T cells are further exposed to an apoptosis inhibitor, such as a Rho-associated protein kinase (ROCK) inhibitor, at the initiation of stimulating the T cells.
The deficiency is resolved by Rosen.
Rosen teaches compositions and methods for modulating populations or subpopulations of immune cells, such as T cells, to improve their therapeutic potential comprising one or more compounds, e.g. Rho kinase inhibitors such as ROCK inhibitors, either alone or in combination, wherein the compound(s) modulates cell expansion, maintenance, and/or differentiation and thereby improve proliferation, cytotoxicity, cytokine response and secretion, cell recall, and/or persistence of the immune cells (pages 6-7, ¶ [00011]-[00013], [00016], [00018], [00020]; Table 1). Rosen further discloses that the sufficient length of time to treat immune cells with the compound is no less than 0.1-15 hours (page 19, ¶ [00056]).
Regarding instant claims 24 and 26, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the said method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS wherein the T cells have a deletion in the endogenous B2M gene as taught by the combined teachings of Tran, Posch, Ali, Slanetz, and Lee to comprise further exposing the T cells to ROCK inhibitors at the initiation of stimulating the T cells as taught by Rosen. This is obvious because, the combined teachings of Tran, Posch, Ali, Slanetz, and Lee teach a method of generating a population of cells comprising host T cells expressing a TCR specific for a mutated KRAS peptide wherein the T cells comprise a disruption of the endogenous B2M gene such that the cells no longer comprise a HLA class I on their cell surfaces to prevent an HLA-based immune response, Rosen teaches methods for modulating populations of immune cells, such as T cells, to improve their therapeutic potential comprising Rho kinase inhibitors, such as ROCK inhibitors, wherein ROCK inhibitors are known to improve cell expansion, viability, and survival, and the instant specification defines ROCK inhibitors as apoptosis inhibitors (instant specification page 10, ¶ [0072] and page 55, ¶0305]). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of generating a population of T cells expressing one or more TCRs that specifically bind one or more antigens, wherein the instant T cells comprising a deletion in the endogenous B2M gene are further exposed to an apoptosis inhibitor, such as ROCK inhibitors, at the initiation of step (vii).
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
