DETAILED ACTION
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 .
Status of the Claims
Applicant’s submission filed 28 April 2026 has been entered. Claims 1-2, 4, 7-8, 23-24, 27, 31, and 58-77 are pending. Claims 1-2, 4, 8, 24, 27, 31, and 58-60 have been amended, while claims 61-77 have been newly added. Therefore, prosecution on the merits continues for claims 1-2, 4, 7-8, 58, and 61-75 as being drawn to the elected invention, with claims 23-24, 27, 31, 59-60 and 76-77 withdrawn for reading on the non-elected invention. It is of note that new claims 76-77 are directed to methods of treating different types of cancers, and accordingly are encompassed by the invention of unelected Group III within the Restriction requirement filed 26 September 2024. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-2, 4, and 7-8 under 35 USC 103 over June et al in view of Jeevan-Raj et al
Applicant's arguments filed 28 April 2026 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 9-13 of the Remarks filed 28 April 2026 that June et al fail to teach, suggest, or motivate an ordinary artisan to utilize a transcription factor as the agent comprised within the second polynucleotide, and instead point to other CARs, checkpoint inhibitors, or cytokines. Applicant has furthered this traversal by stating that impermissible hindsight is utilized to arrive at the use of the TCF7 transcription factor as the agent comprised within the second polynucleotide. In response, the Examiner respectfully submits that June et al disclose that the agent comprised within the second polynucleotide activates the expression and/or secretion of a component that enhances the immune response or immune cell activation. See Paragraph [0216] of June et al. With that, Jeevan-Raj et al disclose that TCF7 enhances immune effector cell activation through the controlled expression of granzyme. Therefore, the ordinary artisan would have been motivated to utilize TCF7 as the inducible agent since it fits the description provided by June et al. Furthermore, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, it was within the level of the ordinary artisan at the time the claimed invention was made to recognize that TCF7 can serve as an agent that activates the expression and/or secretion of a component that enhances the immune response or immune cell activation based on the disclosure of Jeevan-Raj et al.
It is also of note that the ordinary artisan would have recognized that the recited list of agents within the disclosure of June et al are exemplary embodiments and is not an exhaustive list, as explained in Paragraph [0216] of June et al:
“The agent that enhances the immune response of an immune effector cell comprises one or more of the following characteristics: 1) targets an additional tumor antigen, e.g., a different tumor antigen targeted by the constitutively expressed, e.g., nonconditional, CAR; 2) inhibits the expression or activity of an inhibitory molecule; and/or 3) activates the expression and/or secretion of a component that enhances immune response or immune effector cell activation. Exemplary agents that enhance the immune response of the non-conditional CAR-expressing cell are further described herein.”
Applicant has further traversed the rejection, asserting in Page 13 of the Remarks filed 28 April 2026 that the ordinary artisan would not have considered simply inducing TCF7 in a cell since Jeevan-Raj et al teach that downregulation of TCF7 is needed for terminal maturation of NK cells. In response, the Examiner respectfully submits that, while Jeevan-Raj et al do teach that downregulation of TCF7 is needed for terminal maturation of NK cells, Jeevan-Raj et al also teach that TCF7 expression is required for NK cell survival during maturation and following activation by preventing excessive granzyme expression. See Pages 615-616 of Jeevan-Raj et al. Therefore, the ordinary artisan would have been motivated to inducibly express TCF7, as it required for initial survival following activation, and would have recognized that constitutive expression is not required. It is also of note that TCF7 binds a Gzmb-associated regulatory element which reduces granzyme expression and allows for an enhanced NK cell activation, thereby reading on the third characteristic of agents that enhance the immune response disclosed within June et al. See Pages 621-623 of Jeevan-Raj et al.
Applicant has lastly traversed the rejection, asserting in Page 14 of the Remarks filed 28 April 2026 that engineered cells with induced FOXO1-3A or TCF7 expression exhibit improved properties upon binding of the CAR to its target, including less differentiated status, increased proliferation, and increased activity. Applicant cites Examples 17-18 and Figures 19b, 19C, and 20 to support these asserted unexpected results. In response, the Examiner respectfully reminds Applicant that, in submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter. See MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP § 716.02(b). In the instant case, the Examiner notes that the evidence relied upon is not commensurate in scope with the pending claims. More specifically, the engineered cells of at least independent claims 1 and 66 require any engineered cell comprising a constitutively-expressed CAR or exogenous TCR and inducibly-expressed TCF7 or FOXO1-3A, while independent claims 58 and 71 require the engineered cells to be engineered T cells comprising a constitutively-expressed CAR specific for CD20 or Her2 and NFAT inducibly-expressed TCF7 or FOXO1-3A – which are each broader than the engineered T cells comprising a constitutively-expressed CAR specific for Her2 and NFAT inducibly-expressed TCF7 or FOXO1-3A within the referenced examples. Thus, the engineered cells relied upon as evidence are not of the same scope as the pending claims.
Therefore, the rejection is maintained and amended to encompass the claims as currently written.
RE: Rejection of claims 1-2, 4, 7-8, and 58 under 35 USC 103 over June et al in view of Sade-Feldman et al
Applicant has traversed the rejection, asserting in Pages 14-15 of the Remarks filed 28 April 2026 that Sade-Feldman et al teach that TCF7 acts as a biomarker for predicting responsiveness to checkpoint inhibitor therapy, and does not suggest expressing TCF7 within an immune cell. In response, the Examiner finds Applicant’s arguments persuasive.
Therefore, the rejection is withdrawn.
It is of note, however, that Applicant’s addition of new claim 61 requiring the engineered cell of instant claim 2 to be a regulatory T cell allows for the presentation of new prior art. Such prior art can read on the limitations presented in independent claim 58.
New/Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
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 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.
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 1-2, 4, 7-8, and 64 are rejected under 35 U.S.C. 103 as being unpatentable over June et al (US 2018/0044424 A1, of record on the IDS filed 23 November 2022) in view of Jeevan-Raj et al (Cell Reports, 2017, of record).
June et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 15 February 2018. Jeevan-Raj et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 1-2: June et al disclose immune effector cells engineered to constitutively express a chimeric antigen receptor (CAR) (referred to herein as a nonconditional CAR) and conditionally express an agent that enhances the immune effector response (Abstract; Paragraphs [0214]-[0215], [0219]). June et al further disclose that the agent that enhances the immune response is only substantially expressed when the non-conditional CAR-expressing cell is activated (Paragraphs [0215], [0219]).
June et al further disclose that the agent that enhances the immune response comprises an agent that activates the expression and/or secretion of a component that enhances immune response or immune effector cell activation (Paragraph [0216]).
June et al further disclose that the constitutively-expressed CAR is encoded by a first polynucleotide and that the conditionally-expressed agent is encoded by a second polynucleotide, and that both polynucleotides are comprised within a single vector (Paragraphs [0042]-[0050], [0168], [0438]-[0439]).
June et al further disclose that the engineered immune effector cell is an NK cell (Abstract; Paragraphs [0065], [0154], [0273], [0423]).
June et al do not disclose that the agent that enhances the immune response is TCF7, as required by instant claim 1.
Jeevan-Raj et al, however, disclose that Tcf1 – which is encoded by the Tcf7 gene – is essential for the development of NK cells, ensuring NK cell survival during maturation and following activation by preventing excessive granzyme expression (Abstract; Page 614, Column 1; Page 619; Page 621).
Therefore, it would have been prima facie obvious to have modified the engineered NK cell of June et al to comprise TCF7 as the inducible agent. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to have an induced expression of TCF7, as it enhances immune effector cell activation via the prevention of excessive granzyme expression according to Jeevan-Raj et al, and would have had a reasonable expectation of success based on the cell engineering protocols outline in the disclosure of June et al (Paragraphs [0042]-[0050], [0168], [0214]-[0215], [0219], [0438]-[0439]). See MPEP § 2143(I)(G).
Consequently, June et al as modified by Jeevan-Raj et al render obvious an engineered NK cell (claim 2) comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal. As the first polynucleotide and second polynucleotide are comprised within a single vector, this inherently indicates that the two polynucleotides are covalently linked to each other – see Figure 14 of the instant disclosure. This therefore renders obvious the engineered cell of instant claim 1.
Regarding claims 4 and 64: Following the discussion of claim 2, June et al further disclose that the CAR comprises an antigen binding domain, a transmembrane domain, an intracellular costimulatory domain, and an intracellular signaling domain, wherein the antigen binding domain binds to a surface tumor antigen, the intracellular costimulatory domain comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the intracellular signaling domain comprises a CD3 zeta signaling domain comprising an ITAM (claim 64) (Paragraphs [0012], [0274]-[0276], [0384], [0394]-[0400]). This therefore reads on the engineered cell of instant claim 4.
Regarding claim 7: Following the discussion of claim 2, June et al further disclose that an agent that enhances the immune response of an immune effector cell can also be an exogenous TCR or a TCR-based molecule, wherein the TCR comprises alpha and beta, or TCR gamma and delta chains (Paragraphs [0199], [0223]-[0237]).
Therefore, it would have been prima facie obvious to have substituted the first polynucleotide comprising a nucleic acid encoding a constitutively expressed CAR with a nucleic acid encoding a constitutively expressed TCR-based molecule, as doing so would have been a simple substitution of one known tumor-killing receptor for another. See MPEP § 2143(I)(B). One of ordinary skill before the effectively filing date of the invention would have recognized that the two receptors are functionally comparable, especially as the exogenous TCR-based molecule of June et al can be a fusion protein with a CAR (Paragraph [0223]), and thereby would have been able to substitute the receptors with predictable results.
Consequently, June et al as modified by Jeevan-Raj et al render obvious an engineered NK cell comprising a first polynucleotide comprising a nucleic encoding an exogenous TCR-based molecule that is operably linked to a constitutive promoter, wherein the TCR-based molecule comprises TCR alpha and beta chains, or TCR gamma and delta chains. This therefore renders obvious the engineered cell of the instant claim.
Regarding claim 8: Following the discussion of claim 1, June et al further disclose that the inducible promoter is an NFAT promoter or an NF-κB promoter (Paragraphs [0251]-[0254]). This therefore reads on the engineered cell of the instant claim.
Claims 1-2, 4, 7-8, 58, 63-64, 66-71, and 73 are rejected under 35 U.S.C. 103 as being unpatentable over June et al (US 2018/0044424 A1, of record on the IDS filed 23 November 2022) in view of Stephan et al (US 2017/0296676 A1) as evidenced by GenBank (BC021981, 2007).
June et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 15 February 2018. Stephan et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 19 October 2017.
Regarding claims 1-2: June et al disclose immune effector cells engineered to constitutively express a chimeric antigen receptor (CAR) (referred to herein as a nonconditional CAR) and conditionally express an agent that enhances the immune effector response (Abstract; Paragraphs [0214]-[0215], [0219]). June et al further disclose that the agent that enhances the immune response is only substantially expressed when the non-conditional CAR-expressing cell is activated (Paragraphs [0215], [0219]).
June et al further disclose that the agent that enhances the immune response comprises an agent that activates the expression and/or secretion of a component that enhances immune response or immune effector cell activation (Paragraph [0216]).
June et al further disclose that the constitutively-expressed CAR is encoded by a first polynucleotide and that the conditionally-expressed agent is encoded by a second polynucleotide, and that both polynucleotides are comprised within a single vector (Paragraphs [0042]-[0050], [0168], [0438]-[0439]).
June et al further disclose that the engineered immune effector cell is a T cell (Abstract; Paragraphs [0064], [0154], [0174], [0273], [0423], [0524], [0562]).
June et al do not disclose that the agent that enhances the immune response is TCF7, as required by instant claim 1.
Stephan et al, however, disclose the transient expression of a nucleic acid encoding TCF7 in T cells, wherein TCF7 binds an enhancer element and activates the CD3E gene – which is associated with T cell activation (Abstract; Paragraphs [0002], [0006]-[0007], [0022]-[0025], [0032], [0034], [0037]-[0043], [0116], [0119], [0149]; Exemplary Embodiments 11, 44, 76).
Stephan et al further disclose that the nucleic acid can further comprise a specific promoter to transiently express the encoded transcription factor (Paragraphs [0050], [0082]-[0083]).
Stephan et al further disclose that the T cells can comprise a CAR (Paragraphs [0128], [0135], [0146]-[0161]).
Therefore, it would have been prima facie obvious to have modified the engineered T cell of June et al to comprise TCF7 as the inducible agent. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to have an induced expression of TCF7, as it enhances T cell activation via the binding of an enhancer element that activates the CD3E gene according to Stephan et al, and would have had a reasonable expectation of success based on the cell engineering protocols outline in the disclosure of June et al (Paragraphs [0042]-[0050], [0168], [0214]-[0215], [0219], [0438]-[0439]) coupled with the transient expression of TCF7 outlined in Stephan et al. See MPEP § 2143(I)(G).
Consequently, June et al as modified by Stephan et al render obvious an engineered T cell (claim 2) comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal. As the first polynucleotide and second polynucleotide are comprised within a single vector, this inherently indicates that the two polynucleotides are covalently linked to each other – see Figure 14 of the instant disclosure. This therefore renders obvious the engineered cell of instant claim 1.
Regarding claims 4 and 64: Following the discussion of claim 2, June et al further disclose that the CAR comprises an antigen binding domain, a transmembrane domain, an intracellular costimulatory domain, and an intracellular signaling domain, wherein the antigen binding domain binds to a surface tumor antigen, the intracellular costimulatory domain comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the intracellular signaling domain comprises a CD3 zeta signaling domain comprising an ITAM (claim 64) (Paragraphs [0012], [0274]-[0276], [0384], [0394]-[0400]). This therefore reads on the engineered cell of instant claim 4.
Regarding claim 7: Following the discussion of claim 2, June et al further disclose that an agent that enhances the immune response of an immune effector cell can also be an exogenous TCR or a TCR-based molecule, wherein the TCR comprises alpha and beta, or TCR gamma and delta chains (Paragraphs [0199], [0223]-[0237]).
Therefore, it would have been prima facie obvious to have substituted the first polynucleotide comprising a nucleic acid encoding a constitutively expressed CAR with a nucleic acid encoding a constitutively expressed TCR-based molecule, as doing so would have been a simple substitution of one known tumor-killing receptor for another. See MPEP § 2143(I)(B). One of ordinary skill before the effectively filing date of the invention would have recognized that the two receptors are functionally comparable, especially as the exogenous TCR-based molecule of June et al can be a fusion protein with a CAR (Paragraph [0223]), and thereby would have been able to substitute the receptors with predictable results.
Consequently, June et al as modified by Stephan et al render obvious an engineered T cell comprising a first polynucleotide comprising a nucleic encoding an exogenous TCR-based molecule that is operably linked to a constitutive promoter, wherein the TCR-based molecule comprises TCR alpha and beta chains, or TCR gamma and delta chains. This therefore renders obvious the engineered cell of the instant claim.
Regarding claim 8: Following the discussion of claim 1, June et al further disclose that the inducible promoter is an NFAT promoter or an NF-κB promoter (Paragraphs [0251]-[0254]). This therefore reads on the engineered cell of the instant claim.
Regarding claim 58: As aforementioned in the discussion of claims 1 and 8, June et al as modified by Stephan et al render obvious an engineered T cell comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an NFAT-inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal, and wherein the first polynucleotide and second polynucleotide are covalently linked.
June et al further disclose that the CAR comprises an antigen binding domain that specifically binds to Her2 or CD20, a hinge region and transmembrane domain from human CD8, an intracellular costimulatory signaling domain from human 4-1BB, and an intracellular signaling domain of human CD3 zeta (Paragraphs [0023], [0028]-[0034], [0066], [0261], [0264]-[0267], [0270]-[0271], [0386], [0403]-[0404], [0446]).
This therefore renders obvious the engineered human T cell of the instant claim for the same reasons as discussed in the rejection of instant claim 1 above.
Regarding claim 63: Following the discussion of claim 2, Stephan et al further disclose that the T cell is a regulatory T cell (Paragraphs [0042], [0119]). This therefore renders obvious the engineered cell of the instant claim for the same reasons as discussed in the rejection of instant claim 1 above.
Regarding claims 66-67: June et al disclose immune effector cells engineered to constitutively express a chimeric antigen receptor (CAR) (referred to herein as a nonconditional CAR) and conditionally express an agent that enhances the immune effector response (Abstract; Paragraphs [0214]-[0215], [0219]). June et al further disclose that the agent that enhances the immune response is only substantially expressed when the non-conditional CAR-expressing cell is activated (Paragraphs [0215], [0219]).
June et al further disclose that the agent that enhances the immune response comprises an agent that activates the expression and/or secretion of a component that enhances immune response or immune effector cell activation (Paragraph [0216]).
June et al further disclose that the constitutively-expressed CAR is encoded by a first polynucleotide and that the conditionally-expressed agent is encoded by a second polynucleotide, and that both polynucleotides are comprised within a single vector (Paragraphs [0042]-[0050], [0168], [0438]-[0439]).
June et al further disclose that the engineered immune effector cell is a T cell (Abstract; Paragraphs [0064], [0154], [0174], [0273], [0423], [0524], [0562]).
June et al do not disclose that the agent that enhances the immune response is FOXO1-3A, as required by instant claim 66.
Stephan et al, however, disclose the transient expression of a nucleic acid encoding FOXO1-3A in T cells, wherein FOXO1-3A enhances the immune response via regulating factors to promote a central memory T cell-like phenotype within the T cells (Abstract; Paragraphs [0002], [0006]-[0007], [0016]-[0017], [0022]-[0025], [0032], [0034], [0037]-[0043], [0112]-[0114], [0119], [0378], [0396]-[0398]; Exemplary Embodiments 11, 44, 76).
Stephan et al further disclose that the nucleic acid can further comprise a specific promoter to transiently express the encoded transcription factor (Paragraphs [0050], [0082]-[0083]).
Stephan et al further disclose that the T cells can comprise a CAR (Paragraphs [0128], [0135], [0146]-[0161]).
Therefore, it would have been prima facie obvious to have modified the engineered T cell of June et al to comprise FOXO1-3A as the inducible agent. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to have an induced expression of FOXO1-3A, as it enhances the immune response via regulating factors to promote a central memory T cell-like phenotype within the T cells according to Stephan et al, and would have had a reasonable expectation of success based on the cell engineering protocols outline in the disclosure of June et al (Paragraphs [0042]-[0050], [0168], [0214]-[0215], [0219], [0438]-[0439]) coupled with the transient expression of FOXO1-3A outlined in Stephan et al. See MPEP § 2143(I)(G).
Consequently, June et al as modified by Stephan et al render obvious an engineered T cell (claim 67) comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding FOXO1-3A that is operably linked to an inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal. As the first polynucleotide and second polynucleotide are comprised within a single vector, this inherently indicates that the two polynucleotides are covalently linked to each other – see Figure 14 of the instant disclosure. This therefore renders obvious the engineered cell of instant claim 66.
Regarding claim 68: Following the discussion of claim 67, Stephan et al further disclose that FOXO1-3A is defined as the FOXO1 polypeptide sequence in which three key phosphorylated residues are mutated to alanine (Paragraph [0396]). Stephan et al further disclose that FOXO1 has a nucleic acid sequence set forth in BC021981 (Paragraph [0114]). When translated, this FOXO1 amino acid sequence of Stephan et al has 99.7% sequence identity to the amino acid sequence of instant SEQ ID NO: 31, with the only discrepancies being the three residues that have been mutated to alanine. See GenBank reference for translation and the corresponding sequence alignment at end of document.
Therefore, it would have been prima facie obvious to have modified the amino acid sequence of Stephan et al such that the three key phosphorylated residues that are mutated to alanine match those as detailed in instant SEQ ID NO: 31. One of ordinary artisan would have been motivated to utilize a FOXO1-3A amino acid sequence as described in Stephan et al, and would have had a reasonable
expectation of success given that (i) the substitution of key phosphorylated residues to alanine is well within the skillset of the ordinary artisan, and (ii) there is a finite number of phosphorylated residues within the translated FOXO1 sequence of Stephan et al. See MPEP § 2143(I)(E) and MPEP § 2143(I)(G), and Pages 44-45 of the instant Specification.
Consequently, June et al as modified by Stephan et al render obvious an engineered T cell comprising a second nucleic acid that encodes a FOXO1-3A polypeptide sequence as detailed in instant SEQ ID NO: 31. This therefore renders obvious the engineered cell of the instant claim.
Regarding claim 69: Following the discussion of claim 66, June et al further disclose that the CAR comprises an antigen binding domain, a transmembrane domain, an intracellular costimulatory domain, and an intracellular signaling domain, wherein the antigen binding domain binds to a surface tumor antigen, the intracellular costimulatory domain comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the intracellular signaling domain comprises a CD3 zeta signaling domain comprising an ITAM (Paragraphs [0012], [0274]-[0276], [0384], [0394]-[0400]). This therefore reads on the engineered cell of the instant claim.
Regarding claim 70: Following the discussion of claim 66, June et al further disclose that an agent that enhances the immune response of an immune effector cell can also be an exogenous TCR or a TCR-based molecule, wherein the TCR comprises alpha and beta, or TCR gamma and delta chains (Paragraphs [0199], [0223]-[0237]).
Therefore, it would have been prima facie obvious to have substituted the first polynucleotide comprising a nucleic acid encoding a constitutively expressed CAR with a nucleic acid encoding a constitutively expressed TCR-based molecule, as doing so would have been a simple substitution of one known tumor-killing receptor for another. See MPEP § 2143(I)(B). One of ordinary skill before the effectively filing date of the invention would have recognized that the two receptors are functionally comparable, especially as the exogenous TCR-based molecule of June et al can be a fusion protein with a CAR (Paragraph [0223]), and thereby would have been able to substitute the receptors with predictable results.
Consequently, June et al as modified by Stephan et al render obvious an engineered T cell comprising a first polynucleotide comprising a nucleic encoding an exogenous TCR-based molecule that is operably linked to a constitutive promoter, wherein the TCR-based molecule comprises TCR alpha and beta chains, or TCR gamma and delta chains. This therefore renders obvious the engineered cell of the instant claim.
Regarding claim 71: As aforementioned in the discussion of claim 66, June et al as modified by Stephan et al render obvious an engineered T cell comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding FOXO1-3A that is operably linked to an inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal, and wherein the first polynucleotide and second polynucleotide are covalently linked.
June et al further disclose that the CAR comprises an antigen binding domain that specifically binds to Her2 or CD20, a hinge region and transmembrane domain from human CD8, an intracellular costimulatory signaling domain from human 4-1BB, and an intracellular signaling domain of human CD3 zeta (Paragraphs [0023], [0028]-[0034], [0066], [0261], [0264]-[0267], [0270]-[0271], [0386], [0403]-[0404], [0446]).
June et al further disclose that the inducible promoter is an NFAT promoter or an NF-κB promoter (Paragraphs [0251]-[0254]).
This therefore renders obvious the engineered human T cell of the instant claim for the same reasons as discussed in the rejection of instant claim 66 above.
Regarding claim 73: Following the discussion of claim 71, Stephan et al further disclose that FOXO1-3A is defined as the FOXO1 polypeptide sequence in which three key phosphorylated residues are mutated to alanine (Paragraph [0396]). Stephan et al further disclose that FOXO1 has a nucleic acid sequence set forth in BC021981 (Paragraph [0114]). When translated, this FOXO1 amino acid sequence of Stephan et al has 99.7% sequence identity to the amino acid sequence of instant SEQ ID NO: 31, with the only discrepancies being the three residues that have been mutated to alanine. See GenBank reference for translation and the corresponding sequence alignment at end of document.
Therefore, it would have been prima facie obvious to have modified the amino acid sequence of Stephan et al such that the three key phosphorylated residues that are mutated to alanine match those as detailed in instant SEQ ID NO: 31. One of ordinary artisan would have been motivated to utilize a FOXO1-3A amino acid sequence as described in Stephan et al, and would have had a reasonable
expectation of success given that (i) the substitution of key phosphorylated residues to alanine is well within the skillset of the ordinary artisan, and (ii) there is a finite number of phosphorylated residues within the translated FOXO1 sequence of Stephan et al. See MPEP § 2143(I)(E) and MPEP § 2143(I)(G), and Pages 44-45 of the instant Specification.
Consequently, June et al as modified by Stephan et al render obvious an engineered T cell comprising a second nucleic acid that encodes a FOXO1-3A polypeptide sequence as detailed in instant SEQ ID NO: 31. This therefore renders obvious the engineered human T cell of the instant claim.
Claims 1-2, 4, 7-8, 58, and 63-73 are rejected under 35 U.S.C. 103 as being unpatentable over June et al (US 2018/0044424 A1, of record on the IDS filed 23 November 2022) in view of Stephan et al (US 2017/0296676 A1) as evidenced by GenBank (BC021981, 2007), further in view of Zhang et al (US 2007/0099251 A1).
The discussion of June et al as modified by Stephan et al regarding claims 1 and 58 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. June et al as modified by Stephan et al as evidenced by GenBank render obvious claims 1-2, 4, 7-8, 58, 63-64, 66-71, and 73. Zhang et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 17 October 2006.
Regarding claims 65 and 72: As aforementioned in the discussion of claims 1 and 58 above, June et al as modified by Stephan et al render obvious an engineered T cell comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, wherein the CAR comprises an antigen binding domain that specifically binds to Her2 or CD20, a hinge region and transmembrane domain from human CD8, an intracellular costimulatory signaling domain from human 4-1BB, and an intracellular signaling domain of human CD3 zeta, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an NFAT-inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal, and wherein the first polynucleotide and second polynucleotide are covalently linked.
The combination of June et al and Stephan et al fail to teach the encoded amino acid sequence of TCF7, as required by instant claims 65 and 72.
Zhang et al, however, disclose an encoded TCF7 polypeptide having an amino acid sequence of SEQ ID NO: 7620, which has 100% sequence identity to instant SEQ ID NO: 30 (Paragraphs [0072], [0145], [0185], [0288], [0322]; Table 1). See sequence alignment at end of document.
Therefore, it would have been prima facie obvious to have substituted the TCF7 sequence of
Stephan et al with the TCF7 sequence of Zhang et al having an amino acid sequence as set forth in SEQ ID NO: 7620, as doing so would have been a simple substitution of one TCF7 sequence for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have recognized that the TCF7 sequences are functionally comparable, and thereby would have been able to substitute the TCF7 sequences with predictable results.
Consequently, June et al as modified by Stephan et al and Zhang et al render obvious an engineered T cell comprising a second nucleic acid that encodes a TCF7 polypeptide sequence as detailed in instant SEQ ID NO: 30. This therefore renders obvious the engineered cell (claim 65) and engineered human T cell (claim 72) of the instant claims.
Allowable Subject Matter
Claims 61-62 and 74-75 are objected to as being dependent upon a rejected base claim, but
would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
It is of note that instant SEQ ID NOs: 3 and 9 are free of the prior art. Instant claim 62 is included because it is dependent upon claim 61, which requires the inducible promoter to comprise the sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 9.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
Sequence Alignment
Query Match 99.7%; Length 655; Matches 652; Conservative 2; Mismatches 1; Indels 0; Gaps 0;
Qy (INSTANT SEQ ID NO: 31) vs. Db (translated STEPHAN ET AL BC021981)
Qy 1 MAEAPQVVEIDPDFEPLPRPRSCAWPLPRPEFSQSNSATSSPAPSGSAAANPDAAAGLPS 60
||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||
Db 1 MAEAPQVVEIDPDFEPLPRPRSCTWPLPRPEFSQSNSATSSPAPSGSAAANPDAAAGLPS 60
Qy 61 ASAAAVSADFMSNLSLLEESEDFPQAPGSVAAAVAAAAAAAATGGLCGDFQGPEAGCLHP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ASAAAVSADFMSNLSLLEESEDFPQAPGSVAAAVAAAAAAAATGGLCGDFQGPEAGCLHP 120
Qy 121 APPQPPPPGPLSQHPPVPPAAAGPLAGQPRKSSSSRRNAWGNLSYADLITKAIESSAEKR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 APPQPPPPGPLSQHPPVPPAAAGPLAGQPRKSSSSRRNAWGNLSYADLITKAIESSAEKR 180
Qy 181 LTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSSWWMLN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LTLSQIYEWMVKSVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIRVQNEGTGKSSWWMLN 240
Qy 241 PEGGKSGKSPRRRAAAMDNNSKFAKSRSRAAKKKASLQSGQEGAGDSPGSQFSKWPASPG 300
|||||||||||||||:||||||||||||||||||||||||||||||||||||||||||||
Db 241 PEGGKSGKSPRRRAASMDNNSKFAKSRSRAAKKKASLQSGQEGAGDSPGSQFSKWPASPG 300
Qy 301 SHSNDDFDNWSTFRPRTSANASTISGRLSPIMTEQDDLGEGDVHSMVYPPSAAKMASTLP 360
||||||||||||||||||:|||||||||||||||||||||||||||||||||||||||||
Db 301 SHSNDDFDNWSTFRPRTSSNASTISGRLSPIMTEQDDLGEGDVHSMVYPPSAAKMASTLP 360
Qy 361 SLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGTMMQQTPCYSFAPPNTSLNSPSPN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 SLSEISNPENMENLLDNLNLLSSPTSLTVSTQSSPGTMMQQTPCYSFAPPNTSLNSPSPN 420
Qy 421 YQKYTYGQSSMSPLPQMPIQTLQDNKSSYGGMSQYNCAPGLLKELLTSDSPPHNDIMTPV 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YQKYTYGQSSMSPLPQMPIQTLQDNKSSYGGMSQYNCAPGLLKELLTSDSPPHNDIMTPV 480
Qy 481 DPGVAQPNSRVLGQNVMMGPNSVMSTYGSQASHNKMMNPSSHTHPGHAQQTSAVNGRPLP 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 DPGVAQPNSRVLGQNVMMGPNSVMSTYGSQASHNKMMNPSSHTHPGHAQQTSAVNGRPLP 540
Qy 541 HTVSTMPHTSGMNRLTQVKTPVQVPLPHPMQMSALGGYSSVSSCNGYGRMGLLHQEKLPS 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 HTVSTMPHTSGMNRLTQVKTPVQVPLPHPMQMSALGGYSSVSSCNGYGRMGLLHQEKLPS 600
Qy 601 DLDGMFIERLDCDMESIIRNDLMDGDTLDFNFDNVLPNQSFPHSVKTTTHSWVSG 655
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 DLDGMFIERLDCDMESIIRNDLMDGDTLDFNFDNVLPNQSFPHSVKTTTHSWVSG 655
Three key phosphorylated residues mutated to alanine are bolded
T24-A24
S256-A256
S319-A319
Query Match 100.0%; Length 384; Matches 384; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy (INSTANT SEQ ID NO: 30) vs. Db (ZHANG ET AL SEQ ID NO: 7620)
Qy 1 MPQLDSGGGGAGGGDDLGAPDELLAFQDEGEEQDDKSRDSAAGPERDLAELKSSLVNESE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MPQLDSGGGGAGGGDDLGAPDELLAFQDEGEEQDDKSRDSAAGPERDLAELKSSLVNESE 60
Qy 61 GAAGGAGIPGVPGAGAGARGEAEALGREHAAQRLFPDKLPEPLEDGLKAPECTSGMYKET 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GAAGGAGIPGVPGAGAGARGEAEALGREHAAQRLFPDKLPEPLEDGLKAPECTSGMYKET 120
Qy 121 VYSAFNLLMHYPPPSGAGQHPQPQPPLHKANQPPHGVPQLSLYEHFNSPHPTPAPADISQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VYSAFNLLMHYPPPSGAGQHPQPQPPLHKANQPPHGVPQLSLYEHFNSPHPTPAPADISQ 180
Qy 181 KQVHRPLQTPDLSGFYSLTSGSMGQLPHTVSWFTHPSLMLGSGVPGHPAAIPHPAIVPPS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KQVHRPLQTPDLSGFYSLTSGSMGQLPHTVSWFTHPSLMLGSGVPGHPAAIPHPAIVPPS 240
Qy 241 GKQELQPFDRNLKTQAESKAEKEAKKPTIKKPLNAFMLYMKEMRAKVIAECTLKESAAIN 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GKQELQPFDRNLKTQAESKAEKEAKKPTIKKPLNAFMLYMKEMRAKVIAECTLKESAAIN 300
Qy 301 QILGRRWHALSREEQAKYYELARKERQLHMQLYPGWSARDNYGKKKRRSREKHQESTTET 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QILGRRWHALSREEQAKYYELARKERQLHMQLYPGWSARDNYGKKKRRSREKHQESTTET 360
Qy 361 NWPRELKDGNGQESLSMSSSSSPA 384
||||||||||||||||||||||||
Db 361 NWPRELKDGNGQESLSMSSSSSPA 384
Prosecution Insights