Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-4, 12, 19, 23, 33-37 and 39, drawn to a method for expanding electroporated T cells, in the reply filed on 08/14/2026 is acknowledged.
Claims 40-43, 45 and 47-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 1-4, 12, 19, 23, 33-37, 39-43, 45 and 47-48 are pending.
Claims 40-43, 45 and 47-48 are withdrawn.
Claims 1-4, 12, 19, 23, 33-37 and 39 are considered on the merits.
Priority
This application is a 371 of PCT/US2023/061765 (filed on 02/01/2023), which claims benefit from provisional application 63/267,424 (filed on 02/01/2022). The priority claim of the instant application has been granted and the earliest benefit date is 02/01/2022 from the application 63/267,424.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/13/2024 and 03/26/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Rejections - 35 USC § 102
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.
Claims 1, 3, 12, 19, 35, 36 and 39 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Singh et al., (Cancer Res. 2011; 71(10): 3516-3527).
With respect to claim 1, Singh teaches a method of producing and expanding CD19-specific T cells for adoptive immunotherapy (e.g., abstract). Singh teaches the T cells are electroporated with DNA plasmids encoding CAR transposon and SB transposase and teaches the electroporated T cells are stimulated the next day with γ-irradiated K562-aAPC and soluble recombinant human IL-21 is added beginning the day after electroporation (p. 3517, right col, para “Generation of CAR+ T cells”), thus teaches a method of expanding a population of electroporated T cells comprising culturing the electroporated T cells with a first culture medium comprising one or more cytokines (e.g., IL-21) in claim 1.
With respect to claim 3, as stated supra, Singh teaches the electroporated T cells are stimulated the next day with γ-irradiated K562-aAPC (modified to co-express mIL-15, see Fig 1 and legend), and soluble recombinant human IL-21 is added beginning the day after electroporation (p. 3517, right col, para “Generation of CAR+ T cells”), thus teaches the one or more cytokines are IL-15 and IL-21.
With respect to claim 12 directed to further culturing the T cells with a second culture medium comprising IL-21, it is noted that this limitation encompasses the second culture medium being the same as the first culture medium in claim 1. As stated supra, Singh teaches human IL-21 is added beginning the day after electroporation (p. 3517, right col, para “Generation of CAR+ T cells”), thus teaches the method further comprises culturing the electroporated T cells with a second culture medium, wherein the second culture medium comprises one or more cytokines such as IL-21.
With respect to claim 19 directed to further culturing the T cells with a third culture medium comprising IL-21, it is noted that this limitation encompasses the third culture medium being the same as the first culture medium in claim 1. As stated supra, Singh teaches human IL-21 is added beginning the day after electroporation (p. 3517, right col, para “Generation of CAR+ T cells”), thus teaches the method further comprises culturing the electroporated T cells with a third culture medium, wherein the third culture medium comprises one or more cytokines such as IL-21.
With respect to claim 35 directed to the medium further comprising an agonist of a T cell costimulatory molecule and claim 36 directed to the agonist being a CD28 agonist, as stated supra, Singh teaches the electroporated T cells are stimulated the next day with γ-irradiated K562-aAPCs that are modified to co-express CD86 and CD137L (4-1BBL) (see e.g., Fig 1 and legend). It is noted that CD86 is a ligand of T cell costimulatory molecule CD28, thus is a CD28 agonist in claims 35-36, and CD137L (4-1BBL) is a ligand of T cell costimulatory molecule 4-1BB, thus is an agonist of a T cell costimulatory molecule 4-1BB in claim 35.
With respect to claim 39 directed to culturing the T cells with feeder cells, as stated supra, Singh teaches the electroporated T cells are stimulated the next day with γ-irradiated K562-aAPCs (see e.g., Fig 1 and legend), thus teaches the electroporated T cells are cultured with feeder cells (i.e., the γ-irradiated K562-aAPCs).
Accordingly, Singh anticipates instant claims.
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.
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Singh et al., (Cancer Res. 2011; 71(10): 3516-3527).
Claim 2 is directed to the electroporated T cells being contacted with the first culture medium within 12 hours of electroporation.
As stated supra, Singh teaches the T cells are electroporated on day 0, the cells are rested for 2 to 3 hours in incomplete RPMI and subsequently cultured overnight in RPMI containing 10% FBS, and stimulated the next day (day 1) with γ-irradiated K562-aAPC. Singh further teaches soluble recombinant human IL-21 is added to the medium beginning the day after electroporation (p. 3517, right col, para “Generation of CAR+ T cells”). Thus, Singh teaches the electroporated T cells are contacted with the first culture medium beginning the day after electroporation (after overnight, i.e., about 12-16 hours after electroporation).
Although Singh does not specifically teach the electroporated T cells are contacted with the first culture medium within 12 hours of electroporation, however, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the starting time of the expansion medium to be within 12 hours of electroporation with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to stimulate the T cells from an earlier time. In addition, MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” Thus, “approaching, similar or close range” is obvious in the absence of any showing of unexpected results or criticality.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 4 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al., (Cancer Res. 2011; 71(10): 3516-3527) in view of Scheffel et al., (Cancer Res. 2016; 76(20): 6006-6016).
Claims 4 and 23 are directed to the culture medium further comprising an exogenous glutathione precursor. The instant specification discloses that “In some embodiments, the glutathione precursor is N-acetylcysteine (NAC)” (p. 1, last para.).
However, Singh is silent on the culture medium further comprising an exogenous glutathione precursor such as N-acetylcysteine (NAC) in claims 4 and 23.
Scheffel teaches the rapid in vitro expansion and repetitive stimulation of the TCR of therapeutic T cells increases DNA damage and activation-induced cell death (AICD) that leads to lack of durable complete responses in patients. “Notably, treatment with the antioxidant N-acetyl cysteine (NAC) significantly reduced upregulation of the DNA damage marker gH2AX, subsequent ATM activation, and cell death. In the Pmel mouse model of melanoma, the presence of NAC during ex vivo T-cell expansion improved the persistence of adoptively transferred cells, reduced tumor growth, and increased survival. Taken together, our results offer a preclinical proof of concept for the addition of NAC to current therapeutic T-cell expansion protocols, offering immediate potential to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics infused into patients” (e.g., abstract), related to claims 4 and 23.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of expanding electroporated CAR-T cells disclosed by Singh, by combining an exogenous glutathione precursor N-acetylcysteine (NAC) in the culture medium as suggested by Scheffel with a reasonable expectation of success. Since Singh aims to generate desired CAR+ T cells for effective immunotherapy (abstract), and since Scheffel teaches addition of NAC to therapeutic T-cell expansion protocols improves the persistence of adoptively transferred cells, reduces tumor growth, and increases survival (abstract), one of ordinary skill in the art would have had a reason to combine an exogenous glutathione precursor NAC in the expansion medium in order to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics infused into patients.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 33-37 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al., (Cancer Res. 2011; 71(10): 3516-3527) in view of Hammink et al., (ACS Appl. Mater. Interfaces. 2021; 13: 16007-16018).
Claims 33-36 are directed to the medium further comprising a CD3 agonist and a CD28 agonist. Claim 37 is directed to the medium further comprising a nanomatrix. The instant specification discloses that a nanomatrix is a multiphase material that has dimensions of less than 500 nm (p. 18 of specification).
However, although Singh teaches the medium further comprises a CD28 agonist (i.e., K562-aAPCs co-expressing CD86, see Fig 1), Singh is silent on the medium further comprising a CD3 agonist or a nanomatrix.
Hammink teaches semiflexible polyisocyanopeptide (PIC) polymer-based immunobrushes, with a length of around 400 nm (see p. 16008, left col, para 2, thus being a “nanomatrix” in claim 37), equipped with T cell activating agonistic anti-CD3 (aCD3) and aCD28 antibodies (e.g., abstract, related to claims 33-36). Hammink teaches these agonists-equipped immunobrushes demonstrate enhanced efficiency of ex vivo expansion of activated human T cells even at very low numbers of stimulating antibodies compared to rigid beads, and outperform current benchmarks by producing higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics, such as reduced exhaustion marker expression, high cytokine production, and robust expression of cytotoxic hallmarks, and have great potential in making T cell-based immunotherapies more effective (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of expanding electroporated CAR-T cells by culturing with feeder cells co-expressing costimulatory molecules and cytokines disclosed by Singh, by combining a CD3 agonist- and a CD28 agonist-equipped nanomatrix (i.e., agonists-equipped immunobrushes) in the culture medium as suggested by Hammink with a reasonable expectation of success. Since Hammink teaches these agonist-equipped immunobrushes demonstrate enhanced efficiency of ex vivo expansion of activated human T cells and outperform current benchmarks by producing higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics, such as reduced exhaustion marker expression, high cytokine production, and robust expression of cytotoxic hallmarks, and have great potential in making T cell-based immunotherapies more effective (e.g., abstract), one of ordinary skill in the art would have had a reason to combine the CD3 agonist- and CD28 agonist-equipped nanomatrix as suggested by Hammink in the expansion medium in order to take advantage of the enhanced efficiency of ex vivo expansion to produce higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics and to make T cell-based immunotherapies more effective.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 12, 19, 23, 33-37 and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-7 of US Patent No. 12,227,554 (‘554) in view of Scheffel et al., (Cancer Res. 2016; 76(20): 6006-6016) and Hammink et al., (ACS Appl. Mater. Interfaces. 2021; 13: 16007-16018). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patent claims recite a method of selectively expanding a number of T cells, the method comprising: modifying human T cells to express a TCR comprising using electroporation (reference claims 1 and 7, related to instant claim 1. One of ordinary skill in the art would have contacted the electroporated T cells with a culture medium comprising cytokines, e.g., with 10% FBS, within 12 hours of electroporation, related to instant claim 2), culturing the population of cells in a first culture, wherein the first culture comprises (i) a first population of irradiated feeder cells (reference claim 1, related to instant claim 39), (ii) one or more cytokines comprising one or more of IL-2, IL7, IL-12, IL-15, and IL-21 (reference claims 1 and 4, related to instant claims 1, 3, 12 and 19), and (iii) a first antibody, or an antigen-binding portion thereof, wherein the first antibody, or antigen-binding portion thereof, specifically binds to the murine constant region of the TCR (reference claims 1 and 6, related to instant claim 33), the method further comprising culturing the population of cells in a second culture, wherein the second culture comprises (i) a second population of irradiated feeder cells, wherein the second population of irradiated feeder cells comprise one or both of irradiated allogeneic feeder cells and irradiated autologous feeder cells, (ii) one or more cytokines, and (iii) the second antibody, or the antigen binding portion thereof, which specifically binds to the human CD3 complex (reference claim 5, related to instant claims 33-34).
However, patent claims are silent on the culture medium further comprising an exogenous glutathione precursor such as N-acetylcysteine (NAC) in claims 4 and 23.
Scheffel teaches the rapid in vitro expansion and repetitive stimulation of the TCR of therapeutic T cells increases DNA damage and activation-induced cell death (AICD) that leads to lack of durable complete responses in patients. “Notably, treatment with the antioxidant N-acetyl cysteine (NAC) significantly reduced upregulation of the DNA damage marker gH2AX, subsequent ATM activation, and cell death. In the Pmel mouse model of melanoma, the presence of NAC during ex vivo T-cell expansion improved the persistence of adoptively transferred cells, reduced tumor growth, and increased survival. Taken together, our results offer a preclinical proof of concept for the addition of NAC to current therapeutic T-cell expansion protocols, offering immediate potential to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics infused into patients” (e.g., abstract), related to instant claims 4 and 23.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the patent method of expanding T cells, by combining an exogenous glutathione precursor N-acetylcysteine (NAC) in the culture medium as suggested by Scheffel with a reasonable expectation of success. Since Scheffel teaches addition of NAC to therapeutic T-cell expansion protocols improves the persistence of adoptively transferred cells, reduces tumor growth, and increases survival (abstract), one of ordinary skill in the art would have had a reason to combine an exogenous glutathione precursor NAC in order to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics.
However, patent claims are silent on the medium further comprising a CD28 agonist or a nanomatrix in instant claims 35-37.
Hammink teaches semiflexible polyisocyanopeptide (PIC) polymer-based immunobrushes, with a length of around 400 nm (see p. 16008, left col, para 2, thus being a “nanomatrix” in instant claim 37), equipped with T cell activating agonistic anti-CD3 (aCD3) and aCD28 antibodies (e.g., abstract, related to instant claims 33-36). Hammink teaches these agonists-equipped immunobrushes demonstrate enhanced efficiency of ex vivo expansion of activated human T cells even at very low numbers of stimulating antibodies compared to rigid beads, and outperform current benchmarks by producing higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics, such as reduced exhaustion marker expression, high cytokine production, and robust expression of cytotoxic hallmarks, and have great potential in making T cell-based immunotherapies more effective (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the patent method of expanding T cells, by combining a CD3 agonist- and a CD28 agonist-equipped nanomatrix (i.e., agonists-equipped immunobrushes) in the culture medium as suggested by Hammink with a reasonable expectation of success. Since Hammink teaches these agonist-equipped immunobrushes demonstrate enhanced efficiency of ex vivo expansion of activated human T cells and outperform current benchmarks by producing higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics, such as reduced exhaustion marker expression, high cytokine production, and robust expression of cytotoxic hallmarks, and have great potential in making T cell-based immunotherapies more effective (e.g., abstract), one of ordinary skill in the art would have had a reason to combine the CD3 agonist- and CD28 agonist-equipped nanomatrix as suggested by Hammink in the expansion medium in order to take advantage of the enhanced efficiency of ex vivo expansion to produce higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics and to make T cell-based immunotherapies more effective.
Since the instant application claims are obvious over cited patent claims, in view of Scheffel and Hammink, said claims are not patentably distinct.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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