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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 21, 2025 has been entered.
Detailed Action
This action is in response to the papers filed November 21, 2025 and December 2, 2025.
Amendments
Applicant's response and amendments, filed November 21, 2025 and December 2, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 5, 7-8, 14-15, 18, and 26-28, amended Claims 1 and 23, and withdrawn Claims 3-4, 6, 9-10, 19-20, and 22.
Claims 1-4, 6, 9-13, 16-17, and 19-25 are pending.
The amendment to the claims filed on November 21, 2025 and December 2, 2025 do not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The correct status of Claim 16 is (Withdrawn).
Election/Restrictions
Applicant has elected the following species, wherein:
i) the HSC is differentiated into an iNKT cell (Claim 5); and
ii) the alternative additional method step is Claim 7 (transgene encodes first TCR).
Claims 1-4, 6, 9-13, 16-17, and 19-25 are pending.
Claims 3-4, 6, 9-10, 16, 18-20, and 22 are pending but 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.
Claims 1-2, 11-13, 17, 21, and 23-25 are under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application provisional application 62/255,632 filed on October 14, 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
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 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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
1. Claims 1-2, 11, 17, and 21 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Yang et al (WO 2020/252303; filed June 12, 2020; priority to 62/860,613 filed June 12, 2019; of record) in view of Ruella et al (2016; of record), and Malide et al (August 6, 2014; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim(s) 1, Yang et al is considered relevant prior art for having disclosed a method of generating iNKT cells expressing a heterologous invariant NKTCR, the method comprising the step(s) of:
i) transducing into a population of HSCs (e.g. [0051]) a nucleic acid molecule encoding a first heterologous invariant NKTCR (e.g. [0020], “the at least one iNKT TCR is expressed from an exogenous nucleic acid”; [00263, 273, 298, 392]);
ii) in vitro differentiating the thus-transduced HSCs into iNKT cells expressing the heterologous iNKTCR (e.g. Figure 1, “in vitro differentiation”); and
iii) activating the iNKT of (ii) to produce an iNKT cell with functional heterologous TCR, as the iNKT cells can be stimulated (syn. activated) through recognizing the glycolipid antigens (alpha-galactosylceramide) directly presented by CD1d+ tumor cells or antigen-presenting cells (e.g. [0256, 299]).
Yang et al disclosed that the iNKT cells may be activated and expanded by any suitable manner [00274].
Yang et al disclosed wherein the iNKT cells are activated and expanded (e.g. [0045]) to thereby achieve the desired cell numbers (e.g. [0053]; as demonstrated in [0091], generation of iNKT TCR+TCRalphabeta through alphaGC activation and expansion; [00299, 408]).
Yang et al disclosed wherein the HSCs refers to CD34+ hematopoietic progenitor and stem cells (e.g. [00171]).
Yang et al disclosed that engineering the iNKT cells from HSCs provides for an off-the-shelf cellular therapy for use in clinical therapy, as the engineered iNKTs are suitable for allogeneic cell therapy because they are HLA negative (e.g. Abstract).
Yang et al disclosed the in vitro differentiated iNKT cells are genetically modified to express an exogenous invariant NK TCR (iNKT TCR), whereby the engineered iNKTs are differentiated from HSCs (e.g. [00263]).
Yang et al disclosed universal HSC-iNKT cells genetically modified to express an iNKT TCR, e.g. more specifically, human iNKT TCR Valpha24Jalpha18 [00349], as detected by the 6B11 antibody [0522]).
Yang et al disclosed that allogeneic HSC-iNKT cells do not express endogenous TCRs and do not cause GvHD, because the expression of the transgenic iNKT TCR gene blocks the recombination of endogenous TCRs through allelic exclusion [00271].
Yang et al disclosed an example whereby the HSCs are first transduced with the viral vector, and then the thus-transduced HSCs are then cultured to differentiate into iNKT cells (e.g. Figure 1).
Yang et al also disclosed the transgenes may be introduced into the target host cells at various stages of culture, e.g. the HSCs, the newly differentiated NK cells, or the in-expansion NK cells (e.g. [00232]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
In light of the instant specification’s working examples, the instant recitation of Claim 7, “wherein the in vitro differentiation step comprises introducing…” appears to encompass, and does not exclude, a transduction step prior to the differentiation step. Nevertheless, the specification fails to disclose an element of criticality of performing a transduction step during the differentiation step, as transduction of the HSCs before or during differentiation to iNKTs will naturally yield iNKTs expressing the heterologous TCR transgene.
While Yang et al disclosed the iNK TCR cells may further comprise a second heterologous TCR that is different than the first heterologous iNK TCR, e.g., wherein the universal HSC-differentiated iNKT cells may be further engineered to express cancer-targeting TCRs for next-generation universal TCR-iNKT therapies (e.g. [00527]), for example, universal HSC-iNKT cells transduced with a lentiviral vector encoding NY-ESO-1 TCR (Figure 11E), such is introduced into the thus-differentiated iNK TCR cells, not in combination with the iNK TCR nucleic acids transduced into the HSCs.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 1, Ruella et al is considered relevant prior art for having taught the co-transduction of a first heterologous receptor (CAR19) and a second heterologous receptor (CAR123) into the same T cell via co-transduction (e.g. pg 3822, col. 1, “cotranduce T cells”).
Malide et al is considered relevant prior art for having taught the co-transduction of HSPCs with 3 or 5 lentiviral vectors (e.g. Abstract; Introduction).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, and the creation of transgenic cells. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the method of Yang et al to comprise the step of co-transducing the first and second heterologous TCRs into the HSCs in a method of producing iNKTs genetically modified to express a first and second heterologous TCRs with a reasonable expectation of success because those of ordinary skill in the art previously recognized and successfully reduced to practice the ability to co-transduce their target cells, be they HSCs or T cells, with a first and second heterologous nucleic acids encoding the artisan’s genes of interest, including a first and second recombinant receptor useful for immunotherapy, as per Ruella et al and Malide et al. It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” Those of ordinary skill in the art would have immediately recognized that there are only two options when introducing a first heterologous TCR and a second heterologous TCR, to wit, either they are transduced separately into the target cell or co-transduced into the target cell, for which both individual transduction and co-transduction method steps were previously successfully reduced to practice.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 2, Yang et al disclosed wherein the genetically modified iNKTs are expanded (e.g. Figure 1, “in vitro expansion”).
With respect to Claim 17, Yang et al disclosed wherein the universal HSC-iNKT cells may be engineered to express cancer-targeting TCRs for next-generation universal TCR-iNKT therapies (e.g. [00527]), for example, universal HSC-iNKT cells transduced with a lentiviral vector encoding NY-ESO-1 TCR (Figure 11E).
With respect to Claim 21, Yang et al disclosed wherein the exogenous nucleic acid molecule(s) is/are introduced into the host cell via viral vectors such as lentivirus or retrovirus vectors (e.g. [00273]).
Ruella et al taught the co-transduction of lentiviral vectors (e.g. Figure 5, legend; pg 3824, col. 2, Methods).
Malide et al taught the cotransduction of HSPC with 3 or 5 lentiviral vectors (e.g. Abstract; Introduction).
With respect to Claim 11, Yang et al disclosed wherein the heterologous TCR is an engineered TCR (e.g. [00264, 268], a TCR alpha sequence from a first iNKT cell and a TCR beta sequence from a second, different, iNKT cell; modified to comprise one or more amino acid substitutions, deletions, and/or truncations).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded to and rebutted prior arguments in prior Office Actions.
2. Claims 2, 11-13, and 21 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Yang et al (WO 2020/252303; filed June 12, 2020; priority to 62/860,613 filed June 12, 2019; of record) in view of Ruella et al (2016), and Malide et al (August 6, 2014), as applied to Claims 1-2, 11, 17, and 21 above, and in further view of Jiang et al (May 7, 2015; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Yang et al do not disclose wherein the activation step occurs in the presence of APCs that present an antigen for the second TCR.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 12-13, Jiang et al is considered relevant prior art for having taught a method of producing an iNKT cell expressing at least two different TCRs, the method comprising the step(s) of:
a) transducing primary iNKT cells, which naturally express the endogenous, invariant Valpha24Jalpha18/Vbeta11 TCR (e.g. pg 8, col. 2), with a retrovirus vector encoding a heterologous TCR transgene (e.g. Abstract, Study design and methods; pg 3, col. 1, Generation of mutated TCRs, “TCR beta5/alpha9”),
wherein the genetically modified iNKT cells express the endogenous, invariant Valpha24Jalpha18/Vbeta11 TCR and the heterologous TCR transgene.
Jiang et al taught activating and expanding the thus-transduced iNKT cells (e.g. pg 3, col. 2, Methods, Transduction of iNKT cells), thereby producing an iNKT cell population with two distinct functional TCRs.
Jiang et al taught that the TCR gene-modified iNKT cells specifically killed Mtb antigen-loaded target cells directly by granule-dependent mechanisms, and simultaneously exhibited an enhanced regulating function in the early exposure of the Mtb antigen peptide through cytokine secretion (e.g. pg 9, col. 1) and suggested administering the antigen-specific TCR transgenic iNKTs into an animal model for the treatment of a disease corresponding to the antigen-specific TCR (e.g. pg 9, col. 1).
Jiang et al taught wherein the heterologous TCR is engineered to comprise a modification to prevent TCR mispairing between the first and second TCRs (e.g. pg 8, col. 2, mutations in the constant regions to comprise mouse counterpart sequences).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the second heterologous TCR of Yang et al to comprise one or more modifications to prevent TCR mispairing between the first and second TCRs, as taught by Jiang et al, with a reasonable expectation of success because Jiang et al taught that the modifications would enhance the stability of the second exogenous TCR and help prevent mispairing, which would decrease both the expression and function of the TCRs (e.g. pg 8, col. 2).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 2, Yang et al disclosed wherein the genetically modified iNKTs are expanded (e.g. Figure 1, “in vitro expansion”).
Jiang et al taught the step wherein the iNKT cells were expanded after having been transduced with the vector encoding the TCR transgene (e.g. pg 3, col. 2, Transduction of iNKT cells, “five days after transduction (syn. expansion), cells were collected”).
With respect to Claim 21, Yang et al disclosed wherein the exogenous nucleic acid molecule(s) is/are introduced into the host cell via viral vectors such as lentivirus or retrovirus vectors (e.g. [00273]).
Ruella et al taught the co-transduction of lentiviral vectors (e.g. Figure 5, legend; pg 3824, col. 2, Methods).
Malide et al taught the cotransduction of HSPC with 3 or 5 lentiviral vectors (e.g. Abstract; Introduction).
Jiang et al taught wherein the TCR transgene is introduced into the iNKTs via retroviral transduction (e.g. pg 3, col. 2, “Transduction of iNKT cells”).
With respect to Claim 11, Yang et al disclosed wherein the heterologous TCR is an engineered TCR (e.g. [00264, 268], a TCR alpha sequence from a first iNKT cell and a TCR beta sequence from a second, different, iNKT cell; modified to comprise one or more amino acid substitutions, deletions, and/or truncations).
Jiang et al taught wherein the heterologous TCR is an engineered TCR (e.g. pg 3, col. 1, Generation of mutated TCRs, “full-length TCR beta5/alpha9 in which the two TCR chains were linked with the P2A peptide sequence”).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded to and rebutted prior arguments in prior Office Actions.
3. Claims 23-25 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Yang et al (WO 2020/252303; filed June 12, 2020; priority to 62/860,613 filed June 12, 2019; of record) in view of Ruella et al (Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies, J. Clin. Investig. 126(10): 3814-3826, 2016), and Malide et al (In vivo Clonal Tracking of Hematopoietic Stem and Progenitor Cells Marked by Five Fluorescent Proteins using Confocal and Multiphoton Microscopy, J. Vis. Exp. 90: e51669, 9 pages, doi: 10.3791/51669; August 6, 2014).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim(s) 23, Yang et al is considered relevant prior art for having disclosed a method of generating iNKT cells expressing a heterologous invariant NKTCR, the method comprising the step(s) of:
i) transducing into a population of HSCs (e.g. [0051]) a nucleic acid molecule encoding a first heterologous invariant NKTCR (e.g. [0020], “the at least one iNKT TCR is expressed from an exogenous nucleic acid”; [00263, 273, 298, 392]);
ii) in vitro differentiating the thus-transduced HSCs into iNKT cells expressing the heterologous iNKTCR (e.g. Figure 1, “in vitro differentiation”);
iii) activating the iNKT of (ii) to produce an iNKT cell with functional heterologous TCR, as the iNKT cells can be stimulated (syn. activated) through recognizing the glycolipid antigens (alpha-galactosylceramide) directly presented by CD1d+ tumor cells or antigen-presenting cells (e.g. [0256, 299]); and
iv) administering the HSC-iNKT cells to a subject for the treatment of a disease or disorder, e.g. cancer (e.g. Figure 1).
Yang et al disclosed that engineering the iNKT cells from HSCs provides for an off-the-shelf cellular therapy for use in clinical therapy, as the engineered iNKTs are suitable for allogeneic cell therapy because they are HLA negative (e.g. Abstract).
Yang et al disclosed the in vitro differentiated iNKT cells are genetically modified to express an exogenous invariant NK TCR (iNKT TCR), whereby the engineered iNKTs are differentiated from HSCs (e.g. [00263]).
Yang et al disclosed universal HSC-iNKT cells genetically modified to express an iNKT TCR, e.g. human iNKT TCR alpha/beta+6B11+ ([00522]), whereby 6B11+ refers to a monoclonal antibody that specifically binds to iNKT TCR [0071], more specifically, human iNKT TCR Valpha24Jalpha18 [00349].
Yang et al disclosed that allogeneic HSC-iNKT cells do not express endogenous TCRs and do not cause GvHD, because the expression of the transgenic iNKT TCR gene blocks the recombination of endogenous TCRs through allelic exclusion [00271].
Yang et al disclosed wherein the iNKT cells are activated and expanded (e.g. [0045]) to thereby achieve the desired cell numbers (e.g. [0053]; as demonstrated in [0091], generation of iNKT TCR+TCRalphabeta through alphaGC activation and expansion; [00299, 408]).
Yang et al disclosed wherein the HSCs refers to CD34+ hematopoietic progenitor and stem cells (e.g. [00171]).
Yang et al disclosed that engineering the iNKT cells from HSCs provides for an off-the-shelf cellular therapy for use in clinical therapy, as the engineered iNKTs are suitable for allogeneic cell therapy because they are HLA negative (e.g. Abstract).
Yang et al disclosed the in vitro differentiated iNKT cells are genetically modified to express an exogenous invariant NK TCR (iNKT TCR), whereby the engineered iNKTs are differentiated from HSCs (e.g. [00263]).
Yang et al disclosed universal HSC-iNKT cells genetically modified to express an iNKT TCR, e.g. more specifically, human iNKT TCR Valpha24Jalpha18 [00349], as detected by the 6B11 antibody [0522]).
Yang et al disclosed that allogeneic HSC-iNKT cells do not express endogenous TCRs and do not cause GvHD, because the expression of the transgenic iNKT TCR gene blocks the recombination of endogenous TCRs through allelic exclusion [00271].
While Yang et al disclosed the iNK TCR cells may further comprise a second heterologous TCR that is different than the first heterologous iNK TCR, e.g., wherein the universal HSC-differentiated iNKT cells may be further engineered to express cancer-targeting TCRs for next-generation universal TCR-iNKT therapies (e.g. [00527]), for example, universal HSC-iNKT cells transduced with a lentiviral vector encoding NY-ESO-1 TCR (Figure 11E), such is introduced into the thus-differentiated iNK TCR cells, not in combination with the iNK TCR nucleic acids transduced into the HSCs.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 23, Ruella et al is considered relevant prior art for having taught the co-transduction of a first heterologous receptor (CAR19) and a second heterologous receptor (CAR123) into the same T cell via co-transduction (e.g. pg 3822, col. 1, “cotranduce T cells”).
Malide et al is considered relevant prior art for having taught the cotransduction of HSPC with 3 or 5 lentiviral vectors (e.g. Abstract; Introduction).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the method of Yang et al to comprise the step of co-transducing the first and second heterologous TCRs into the HSCs in a method of producing iNKTs genetically modified to express a first and second heterologous TCRs with a reasonable expectation of success because those of ordinary skill in the art previously recognized and successfully reduced to practice the ability to co-transduce their target cells, be they HSCs or T cells, with a first and second heterologous nucleic acids encoding the artisan’s genes of interest, including a first and second recombinant receptor useful for immunotherapy, as per Ruella et al and Malide et al. It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” Those of ordinary skill in the art would have immediately recognized that there are only two options when introducing a first heterologous TCR and a second heterologous TCR, to wit, either they are transduced separately into the target cell or co-transduced into the target cell, for which both individual transduction and co-transduction method steps were previously successfully reduced to practice.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 24-25, Yang et al disclosed wherein the HSC is autologous or allogeneic (e.g. [00267], “autologous donor…, or an allogeneic donor”).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded to and rebutted prior arguments in prior Office Actions.
Citation of Relevant Prior Art
4. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chaudhary (WO 22/178367; filed February 21, 2022, priority to February 19, 2021) is considered relevant prior art for having disclosed a method of producing a T or iNKT cell (e.g. pg 4, lines 2-3) expressing at least one heterologous nucleic acid encoding a synthetic antigen receptor, the method comprising the step(s) of introducing said heterologous nucleic acid into a hematopoietic stem cell and differentiating said HSC into a T or NK cell (e.g. pg 4, lines 4-8, iPSC… hematopoietic stem cell.… give rise to a T, NK, or NKT cell; [0042-43]), wherein the synthetic antigen receptor comprises a first TCR chain, e.g. TCRalpha, and a second TCR chain, TCRbeta (e.g. pg 309, Aspect 66; pg 380, claim 66).
The heterologous nucleic acid encoding the synthetic antigen receptor is transduced into a host cell, e.g. an iPSC or hematopoietic stem cell, said iPSC or HSC then being differentiated to produce a T or NK cell (e.g. [00689, 692, 702]; [00962], generation of HSCs engineered to express a synthetic antigen receptor, transduced with a lentiviral vector).
Chaudhary do not disclose the heterologous TCR is an iNK TCR.
Pursuant to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.), because Chaudhary is a lengthy document, 423 pages, only cited pages are provided.
Sun et al (Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional, Cytokine 72: 48-57, 2015; of record) is considered relevant prior art for having taught a method of producing an iNKT cell expressing a TCR, the method comprising:
a) conducting a process of in vitro differentiation of HSCs into iNKTs (e.g. pg 49, col. 2, Methods, Section 2.3, In vitro T cell expansion, “human HSC”, “the expanded population was stained for iNKT cells”; Section 2.6, “HSPC derived iNKT cells”),
wherein the HSC-derived iNKTs express an endogenous TCR (e.g. pg 53, col. 1, TCR gamma/delta; pg 53, col. 2, iNKT cell population (TCR Valpha24, Vbeta11)).
Sun et al taught “To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from hematopoietic stem-progenitor cells (HSPCs)” (Abstract). Sun et al successfully demonstrated the ability to in vitro differentiate iNKTs from HSPCs (e.g. Figure 5, legend, “Expansion of iNKT cells from HSPC”), and taught that “we believe that in the context of adoptive immunotherapy, the generation of iNKT cells from HSC could be utilized in combination with other tumor specific T cell types, as well as in the setting of transplantation in order to boost host immune responses. Moreover, the availability of technologies and clinical grade-reagents required for the selective expansion of iNKT cells coupled with the cost-effectiveness and versatility of the bead based-aAPC system highlights the feasibility of this therapeutic strategy” (pg 56, col. 1, Conclusion).
Wolf et al (Frontiers in Immunology 9(Article 384): pgs 1-10, doi:10.3389/immu.2018.00384, March 2, 2018; of record) is considered relevant prior art for having taught that iNKT cells may be used to express recombinant TCRs that target tumor-associated antigens (e.g. pg 6, col. 1, “recombinant TCR (rTCR-T)…to target peptides from tumor-associated…proteins”). Wolf et al taught that while GvHD is a common concern for rTCR-T cell therapy, iNKT cells have been shown in pre-clinical models to suppress, not cause, GvHD, and are associated with reduced GvHD in the clinic, making for a potentially safer therapeutic approach (pg 6, col. 2). One of the main benefits of considering iNKT cells as an ideal vector for rTCR therapies is that iNKT cells have an endogenous TCR that is confirmed to have intrinsic anti-tumor capabilities. While the “random” endogenous TCRs on a bulk polyclonal T cell preparations are unlikely to contribute to anti-tumor effects, it is likely that iNKT cells could utilize both their endogenous TCR and their rTCR to target the tumor with two different targeting moieties. Since strong TCR signaling cascades (as evidenced by potent iNKT cell antigens like α-GalCer) help cause Th1-based iNKT cell responses, having a second TCR signaling pathway engaged within the iNKT cell may help ensure that the iNKT cells remain Th1-biased in vivo. Another advantage for rTCR-iNKT cell therapies is that iNKT cells naturally migrate into non-lymphoid tissues, suggesting that they would be ideal cells to target non-lymphoid tumors (pg 6, col. 2).
Zhao et al (Extrathymic Generation of Tumor-Specific T Cells from Genetically Engineered Human Hematopoietic Stem Cells via Notch Signaling, Cancer Research 67(6): 2425-2429, 2007; of record) is considered relevant prior art for having taught a method of producing a T cell with at least two distinct TCRs, the method comprising:
a) conducting a process of in vitro differentiation of a hematopoietic stem cell (HSC) into an invariant natural killer T (iNKT) cell comprising a first T cell receptor (TCR); and
b) introducing a transgene encoding a second TCR into the HSC cell (e.g. pg 2425, col. 2, Methods; Retroviral transduction and in vitro T cell development, “transduction of HSCs”) to produce a T cell with two distinct TCRs.
Zhao et al taught wherein endogenous gamma/delta TCR rearrangements were detected in some differentiated T cells, and endogenous TCR expression is inferred (pg 2427, col. 2, “partial allelic exclusion was suggested by the observation of higher levels of CD3 and TCR surface staining..’; Figure 2D).
Zhao et al do not teach the step wherein the TCR-encoding transgene is introduced into the iNKT cell.
With respect to Claim 11, Zhao et al taught wherein the heterologous TCR is an engineered TCR (e.g. pg 2425, col. 2, Materials and Methods, NY-ESO-1-specific or human p53-specific).
With respect to Claims 14-15, the claims are considered to fail to further limit Claim 1 because it is natural law of biology that HSCs are naturally derived from pluripotent stem cells.
With respect to Claim 21, Zhao et al taught wherein the TCR transgene is introduced into the HSCs via retroviral transduction (e.g. pg 2425, col. 2, Methods; Retroviral transduction and in vitro T cell development, “transduction of HSCs”).
With respect to Claim 17, Zhao et al taught wherein the TCR transgene is directed to a cancer antigen, to wit, human p53 or NY-ESO-1 (e.g. pg 2425, col. 2, Materials and Methods).
Smith et al (Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells, Proc. Nat’l. Acad. Sci. 112(5): 1523-1528, 2015; of record) is considered relevant prior art for having taught a method of producing an iNKT cell expressing a heterologous TCR, the method comprising:
a) introducing a transgene encoding a heterologous TCR into an HSC cell (e.g. pg 1524, col. 2, Methods; Generation of clonal iNKT through genetic engineering of HSCs”, “HSC transduction”); and
b) conducting a process of in vivo differentiation of the transduced HSCs into iNKTs expressing the heterologous TCR.
Smith et al do not teach:
i) the step wherein the TCR-encoding transgene is introduced into the iNKT cell; nor
ii) the step wherein the HSCs are differentiated in vitro into iNKT cells.
With respect to Claim 11, Smith et al taught wherein the heterologous TCR is an engineered TCR (e.g. pg 1524, Figure 1D, “TCRalpha-F2A-TCRbeta”).
With respect to Claims 14-15, the claims are considered to fail to further limit Claim 1 because it is natural law of biology that HSCs are naturally derived from pluripotent stem cells.
With respect to Claim 21, Smith et al taught wherein the TCR transgene is introduced into the HSCs via retroviral transduction (e.g. pg 1524, col. 2, Methods; Generation of clonal iNKT through genetic engineering of HSCs”, “HSC transduction”; Figure 1D).
Smith et al taught that “overexpression of prerearranged αβ TCR genes in HSCs has been shown to induce allelic exclusion and block the rearrangements of endogenous TCR genes in the resulting conventional αβ T cells” (pg 1526, col. 1).
Conclusion
5. No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638