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 Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on December 11, 2025. Claims 1-2, 4, 8, 10 – 12, 14 – 15, 18 – 21, 24, and 26 are currently pending. Claims 1, 2, 4, 8, 10, 11, 14 – 15, and 18 – 20 have been amended and claims 7, 9, 13, 16 – 17 have been canceled in the Applicant’s amendment filed December 11, 2025. No claims have been added in the Applicant’s amendment filed December 11, 2025.
Applicant's election, in the reply filed 29 June, 2025 of Group I, claims 1, 2, 4, and 7 - 20, directed to a method of producing an expanded population of TILs was previously acknowledged.
Claims 21, 24, and 26 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
The restriction requirement was previously made FINAL.
Please Note: Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election of invention has been treated as an election without traverse (MPEP § 818.03(a)).
Therefore, claims 1-2, 4, 8, 10 – 12, 14 – 15, 18 – 20 are under consideration to which the following grounds of rejection are applicable.
The examiner acknowledges receiving the Declaration under 37 C.F.R. § 1.63 filed on August 20, 2024, and executed by Micah Benson, Noah Jacob Tubo, Nicholas John Colletti, Robert Andrew LaMothe, Gregory V. Kryukov, Michael R. Schlabach, and Sean Philip Learly Arlaukas.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 11, 2025 has been considered. An initialed copy of the IDS accompanies this Office Action.
Priority
The present application filed 24 August, 2022 is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/019861, filed 26 February, 2021, which claims the benefit of Provisional Application 63/144,855, filed 2 February, 2021, which claims the benefit of Provisional Application 63/074,841, filed 4 September, 2020, which claims the benefit of Provisional Application 62/983,416, filed 28 February, 2020.
Therefore, the earliest priority date is 28 February 2020.
Withdrawn Objections/Rejections
Claim Rejection - 35 USC § 103
The rejection of claims 1 – 2, 4, 7 – 10 and 12 - 20 under 35 U.S.C. 103 as being unpatentable over Lotze et al. (hereinafter referred to as “Lotze”) (WO/2018/129332, published 12 July, 2018), and further in view of Benson et al. (hereinafter referred to as “Benson”) (US20190284553 A1, published 19 September, 2019) are withdrawn.
Lotze and Benson do not teach culturing the disaggregated tumor sample in a culture medium comprising a CD28 agonist, a CD3 agonist, and IL-15 (amended claim 1).
In view of the withdrawn rejection, Applicant’s arguments are moot.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(b)
The rejection of claims 3 and 19 are maintained under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 is indefinite for the recitation of “the culture medium does not comprise IL-2, IL-21, or IL-7” in lines 1 – 2. It is unclear if that is intended to be a Markush group, or all 3 of the cytokines do not have to present. Thus, the metes and bounds of the claim cannot be determined.
Claim 18 is indefinite for the recitation of “the culture medium is changed or supplemented with IL-15” in lines 1 – 2. It is unclear if the culture medium is “changed” as in replaced, or if the culture medium is “changed” to just have IL-15. Thus, the metes and bounds of the claim cannot be determined.
New Objections/Rejections
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 – 2, 4, 8, 10 – 12, 14 – 15, and 18 – 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the Specification, while being enabling for
A method of producing an expanded population of engineered TILs, the method comprising culturing a disaggregated tumor sample in a final concentration of IL-2 at a final concentration at 5 ng/mL, and adding IL-15 at a final concentration of 1000 ng/mL, followed by culturing the TILs using an anti-CD3/anti-CD2/anti-CD28 antibody or colloidal polymeric nanomatrix covalently attached to humanized recombinant agonists against human CD3 and CD28, thereby producing an expanded population of TILs, and modifying an endogenous SOCS1 gene, or modifying an endogenous SOCS1 gene and an endogenous ZC3H12A gene wherein the modifications are made using a CRISPR-Cas9 system and sgRNAs targeting the specific genes, in TILs of the expanded populations of TILs, thereby producing an expanded population of engineered TILs.
Does not reasonably provide enablement for introducing the CD28 agonist, CD3 agonist, and IL-15 together, introducing any concentration of IL-15, not culturing the TILs in IL-2, and using any method to modify the endogenous SOSC1 and ZC3H12A gene . This is a new rejection necessitated by the response filed December 11, 2025.
The Specification does not enable any person skill in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The claims, when given the broadest possible interpretation, encompass a method of producing expanded population of engineered TILs, comprising culturing the disaggregated tumor sample in a culture medium comprising a CD28 agonist, a CD3 agonist, and IL-15, thereby producing an expanded population of TILs, and modifying an endogenous SOCS1 gene, a SOCS1 gene and a ZC3H12A gene in the expanded population of TILs, thereby producing an expanded population of engineered TILs. The Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses encompass a method of producing expanded population of engineered TILs, comprising culturing the disaggregated tumor sample in a culture medium comprising a CD28 agonist, a CD3 agonist, and IL-15, thereby producing an expanded population of TILs, and modifying an endogenous SOCS1 gene, a SOCS1 gene and a ZC3H12A gene in the expanded population of TILs, thereby producing an expanded population of engineered TILs.
Scope of the invention. The invention encompasses a method of producing an expanded population of engineered TILS.
Number of working examples and guidance. In the instant case, Applicant provides many examples of expanding TILs. Specifically, the Applicant notes that for all five TIL expansion methods outlined above, a common protocol was followed at discrete time intervals, wherein IL-2 was added to each well, for a final concentration of 6,000 U/ml, assuming consumption to the corresponding wells, and IL-15 was added at a final concentration of 1000 ng/ml to the corresponding wells assuming consumption (Paragraph [0883]). The Applicant also teaches an expansion method of TILS using IL7/1L15 feeder-free methods, wherein the TILs were supplemented with 10-1000 ng/ml IL-7 and/or 10-1000 ng/ml IL-15 (Paragraph [0865]). Then, the TILs were cultured with Anti-CD3/anti-CD2/anti-CD28 tetrameric antibody complex (TAC) or a colloidal polymeric nanomatrix covalently attached to humanized recombinant agonists against human CD3 and CD28 (Paragraph [0865]). Throughout the specification, the Applicant notes that there are specific concentrations and a specific order in which the TILs are being cultured using IL-7, IL-2 and/or IL-15. The Applicant also teaches particular CD3 and CD28 agonists that being used to expand the TILs.
Note: the as-Filed Specification teaches that the final concentration of IL-2 in the cell culture
media is 0.51 ng/mL to 10,000 ng/mL (Paragraph [0251]).
Further, the as-Filed Specification teaches examples wherein the TILs were genetically engineered using CRISPR-Cas9, specifically in Example 15 and 19 (Paragraph [0905]) and [0941], respectively). In these examples, there are sgRNAs for the SOCS1 gene and the ZC3H12A gene, and Cas9 that is added to the cells to genetically engineer the TILS (0941]).
State of the art. Although the field of TILs are highly developed, the method of producing an
expanded population of engineered TILs using a CD28 agonist, CD3 agonist, and IL-15, and then genetically modifying the expanded TILs expressing is not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known in the art that TILs are rapidly expanded by activating 500,000 TILs with 26×106 allogeneic, irradiated (5000cGy) PBMC feeder cells in 20 mL TIL media+20 mL of Aim-V media (Invitrogen)+30 ng/mL OKT3 mAb. 48 hours later (Day 2), 6000 U/mL IL-2 is added to the cultures, as evidenced by Benson et al. (US20190284553 A1, published September 19, 2019). (Paragraph [0501]). This protocol teaches that the IL-2 is added later, and does not require the use of IL-15.
Further, it was known in the art that TILs can be rapidly expanded in gas permeable container in the presence of IL-2 or IL-15, using a non-specific T cell receptor stimulus including an anti-CD3 antibody (OKT-3) (Paragraph [001055]). Lotze also teaches that for expansion, the IL-2 and/or IL-15 is administered at 300 IU/mL, or upto 100 ng/mL of IL-15 (Paragraph [001055]). This reference does not require IL-15 for the expansion of the TILs, and teaches particular concentrations for the rapid expansion of TILs.
Powell teaches that the fresh enzyme-digested tumors were incubated in the presence of recombinant human IL-7 and IL-15 (50 ng/ml each) or IL-2 cytokine (50 IU/ml) (US 20160215262 A1, published July 28, 2016) (Paragraph [0139]).
These references teach that there is a lot of variation in the method of expanding TILs.
Amount of Experimentation Required. Given the unpredictability of the art, the poorly
developed state of the art regarding producing an expanded population of engineered TILs using a CD28 agonist, CD3 agonist, and IL-15, and the variability in the art regarding the method and components used to expand the TILs, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the expanded population of engineered TILs.
Conclusion
Claims 1-2, 4, 8, 10 – 12, 14 – 15, 18 – 20 remain rejected.
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 extension fee 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 VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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