Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/18/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
1-2, 11, 17-18, 33, and 105 are pending and under exam. Claims 35 and 53 are withdrawn from as being directed to nonelected inventions.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 102
Claims 1-2, 4, 24 and 105 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nijhuis et al (Cancer Immunol Immunother. 1990; hereinafter "Nijhuis;" See PTO-892).
The rejection is withdrawn following claim amendments to recite that the medium comprises a CD3 agonist, CD28 agonist, a 4-1BB agonist and IL2 and the medium does not comprise feeder cells.
Claim Rejections - 35 USC § 112
Claims 1-2, 11-14, 16, 22, 24, 27-28, 31, 33, and 34 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
Regarding claim 1: The rejection is withdrawn following claim amendments to indicate the specific agents in the cell culture medium.
Regarding claims 31 and 34: The rejection is withdrawn following cancellation of the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4, 11-14, 16-18, 20, 22, 24, 27-28, 31, 33-34 and 105 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Regarding claim 1: The rejection is withdrawn following amendment to recite disaggregated tumor samples comprising the TILs.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
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 and 105 are rejected under 35 U.S.C. 103 as being unpatentable over Nijhuis et al (Cancer Immunol Immunother. 1990; hereinafter "Nijhuis;" See PTO-892) in view of Teschner et al (Scand J Immunol. 2011 Aug; hereinafter “Teschner;” See PTO-892).
Niihuis disclosed that TILs can be expanded from tumor cell suspension by “[i]n the initiation phase of TIL culture immobilized anti CD3 antibodies together with anti-CD28 mAb and low dose interleukin-2 induced a rapid expansion of T cells from various human tumor tissues.” (See Nijhuis abstract). For example Nijhuis disclosed that “The combination of immobilized antiCD3 mAb with CLB-CD28/1 and low-dose IL-2, however, induced an efficient outgrowth of TIL, with expansion rates in four patients tested ranging from 4.3 to 10.4 on day 7.” (See Nijhuis, p. 247, col. 1, last para). IL-2 reads on the cytokine. It is noted that p. 4, col. 1 st para of Ye disclosed that CD3 and CD28 antibodies were agonistic antibodies. Further the CD3 agonistic antibody reads on the TCR agonist. It is further noted that tumor cell suspensions read on the claimed disaggregated tumor cells. It is noted the Nijhuis taught feeder cell-less TIL expansion. For example, Nijhuis taught that “[a]nti-CD3-coated culture wells were prepared as described. PBL or TIL (1×106/well) were cultured on the CLB-T3/3-coated wells for 3 days in a final volume of 1 ml. Where indicated 1 gg/tal CLBCD28/1, 25 IU/ml rIL-2 or a combination of both was added. After 3 days cells were harvested, counted, seeded at 2.5x105 lymphocytes/well and new culture medium with or without anti-CD28 mAb and IL-2 was added. Alliteratively, TIL were stimulated with 1000 IU/ml IL-2 on day 0. On day 7, cells were harvested and viable cells were used for further experiments. Activated lymphocytes from peripheral blood of healthy donors were restimulated with immobilized anti-CD3 antibodies and cultured for another 6 days as described above.“ (See Nijhuis p. 246, col. 1-2). Teschner taught that “expansion of tumour-reactive CD8+ CTLs over 2 weeks was more efficient using CD3⁄CD28 ⁄ CD137 beads (14.4-fold ±1.2)
compared with CD3⁄CD28 beads (10.6-fold ±0.7) (P = 0.03).” (See Teschner Abstract). Teschner taught that “the conjugation of anti-CD137 antibodies to conventional
CD3⁄CD28 beads results in a minor but significant increase in the expansion
capacity for tumour-reactive CD8+ CTLs” (See Teschner Abstract). Additionally, Teschner taught that “in vitro expansion of peripheral blood T cells over 2 weeks was clearly higher in cultures with beads and IL-2 (15.6-fold ±1.1 for CD3⁄ CD28⁄ CD137 beads; 17.4-fold ±2.3 for CD3⁄CD28 beads) versus those with IL-2 alone (2.7-fold ±1.0;
P < 0.0001).” (See Teschner p. 157, col. 1, last para).
It would have been obvious for a person of ordinary skill in the art to modify the TIL expansion method of Nijhuis to include 4-1BB costimulation as taught by Teschner. The motivation to combine arises from the fact that both references address the same general probe, namely improving expansion, proliferation and functional activity of tumor-reactive T cells for adoptive immunotherapy. At the time of invention, it was well understood that CD3 signaling provides primary T cell activation, CD28 provides essential costimulation for T cell proliferation, 4-1BB signaling enhances T cell survival proliferation and effector function. Combining multiple costimulatory signals produces additive or synergistic expansion of activated T cells. Therefore, one of ordinary skill in the art would have had a reasonable expectation that adding 4-1BB costimulation to the Nijhuis CD3/CD28/IL2 TIL expansion system would improve TIL expansion efficiency and function. The use of anti-4-1BB agonist signaling as taught by Tschner represents a routine and predictable modification of known T-cell activation protocols in view of the teachings of the prior art.
Regarding claim 2: Nijhuis disclosed that “TIL were cultured on the CLB-T3/3-coated wells for 3 days in a final volume of 1 rel. Where indicated 1 µg/ml CLB-CD28/1, 25 IU/ml rIL-2 or a combination of both was added. After 3 days cells were harvested, counted, seeded at 2.5x105 lymphocytes/well and new culture medium with or without anti-CD28 mAb and IL-2 was added.” (See Nijhuis p. 246, 1st col last para to 2nd col. 1st para). As such Nijhuis disclosed 3-day interval of cytokine addition.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Nijhuis et al (Cancer Immunol Immunother. 1990; hereinafter "Nijhuis;" See PTO-892) in view of in view of Teschner et al (Scand J Immunol. 2011 Aug; hereinafter “Teschner;” See PTO-892) and Ye et al (J Transl Med. 2011 Aug 9; hereinafter "Ye;" See IDS filed 11/08/2025).
Regarding claim 11: The teachings of Nijhuis in view of Teschner are set forth above. Nijhuis or Teschner did not teach tumor sample comprising digested tumor fragments. However, Ye taught that “TILs can be vigorously expanded directly from enzyme-digested tumor specimens ex vivo with KT64/BBL aAPCs, and display favorable phenotypic and functional attributes for the application of adoptive immunotherapy of cancer.” (See Ye p. 9, col. 2, para 1).” As such, it was known at the time of the invention that enzymatic digestion of tumor for isolation of TILs was a known and common technique. In view of the teachings of Nijhuis regarding CD3/CD28 and IL-2 mediated TIL expansion and Ye regarding arriving at a disaggregated tumor sample using digested tumor fragments, it would have been obvious for a person of ordinary skill in the art to practice the claimed invention using disaggregated tumor sample arrived at by digested tumor fragments.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Nijhuis et al (Cancer Immunol Immunother. 1990; hereinafter "Nijhuis;" See PTO-892) in view of Teschner et al (Scand J Immunol. 2011 Aug; hereinafter “Teschner;” See PTO-892) and further in view of Forget et al ( J Immunother. 2014 Nov-Dec; hereinafter "Forget;" See PTO-892).
Regarding claims 17 and 18: The teachings of Nijhuis in view of Teschner are set forth above. It is noted that Nijhuis in view of Teschner did not teach OKT3 or CD86. Forget taught that they “optimized a platform to propagate TIL to a clinical scale using K562-cells genetically modified to express costimulatory molecules such as CD86, CD137-ligand and membrane-bound IL-15 to function as artificial antigen-presenting cell (aAPC) as an alternative to using PBMC feeders.” (See Forget Abstract). It is also noted that Forget taught that “Cultured TIL were propagated by REP with anti-CD3 (OKT3, eBioscience, San Diego, CA) using pooled allogeneic irradiated PBMC feeder cells (ratio of 1 TIL to 200 feeders), which is identical to the protocol currently used for Phase II clinical trials carried out at MDACC” (See Forget p. 3, last para). IT would have been obvious to a person of ordinary skill in the art at the time of invention to modify the TIL expansion methods of Nijhuis in view of Teschner to include optimized CD3/CD28 stimulation systems as taught by Forget, including the use of OKT3 as a CD3 agonist and CD86 as a CD28 agonist, in order to enhance TIL expansion, One of ordinary skill in the art would have had a reasonable expectation of success in substituting well-known CD3/CD28 stimulation modalities as these agents were routinely used interchangeably in T-cell activation and expansion protocols.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Nijhuis et al (Cancer Immunol Immunother. 1990; hereinafter "Nijhuis;" See PTO-892) in view of Teschner et al (Scand J Immunol. 2011 Aug; hereinafter “Teschner;” See PTO-892) and Skanland et al (J. Biochem 2014; hereinafter "Skanland;" See PTO-892).
The teachings of Nijhuis in view of Teschner are set forth above. Nijhuis in view of Teschner did not teach use of CD2 agonistic antibody as required by the claim. Skanland demonstrated that “CD2 co-stimulation induces phosphorylation of the TCR-proximal signaling complex, whereas CD28 activates distal signaling molecules, including the transcription factors NF-κB (nuclear factor κB), ATF (activating transcription factor)-2, STAT3/5 (signal transducer and activator of transcription 3/5), p53 and c-Jun.” (See Skanland Abstract). Skanlan further taught that “The signaling patterns induced by CD2 and CD28 co-stimulation lead to distinct functional immune responses in T-cell proliferation and cytokine production. In conclusion, CD2 and CD28 co-stimulation induces distinct signalling responses and functional outcomes in T-cells.” (See Skanland Abstract). It would have been obvious to a person of ordinary skill in the art in view of the teachings of Nijhuis and Skanland to modify the use CD2 to the agonists taught by Nijhuis to achieve enhanced activation.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 8, 10, 11, and 24 of copending Application No. 17/802,080 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons stated below.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The following claims are anticipated by the corresponding claims in the reference application.
17/779,458; instant application
Reference application
1
1, 24
Response to Arguments: Applicants argued that the present application has an earlier effective filing date than the effective filing date, for the 17/779,458 Application. Consequently, pursuant to M.P.E.P. § 1490(VI)(D) this rejection should be withdrawn.
It is submitted that according to MPEP 804(I)(B)(1)(b)(i) and MPEP 1490(VI)(D)(2)(a), a provisional nonstatutory double patenting rejection is only withdrawn when it is the only rejection remaining in an application having the earliest effective U.S. filing date (taking into account any benefit under 35 U.S.C. 120, 121, 365(c), or 386(c) ) with respect to the conflicting claims); at which point the "provisional" nonstatutory double patenting rejection in the other (later filed) application(s) will be converted into a nonstatutory double patenting rejection when the application with the earliest U.S. effective filing date issues as a patent.
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Conclusion
No claim is allowed.
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 JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M. Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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