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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/23/2026 has been entered.
Claims 159, 216-230, 235 and 236 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/926,147, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. ‘147 fails to provide support for gene editing of TOX, ANKRD11 or BCOR as recited in claim 1. The claims are given the earliest effective filing date of PCT/US2020/057135 which is 10/23/2020.
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 rejection of claim(s) 159, 216-231 and 235-236 under 35 U.S.C. 103 as being unpatentable over USPGPUB 2018/0282694 (published 10/04/2018, filed 01/05/2018) in view of Beane (2015, Molecular Therapy, vol. 23 no. 8, 1380-1390) and further in view of Chikuma is withdrawn in light of Applicant’s amendments removing SOCS1 from the breadth of encompassed checkpoint genes.
Claim(s) 159, 216-231 and 235-236 remain rejected under 35 U.S.C. 103 as being unpatentable over USPGPUB 2018/0282694 (published 10/04/2018, filed 01/05/2018) in view of Beane (2015, Molecular Therapy, vol. 23 no. 8, 1380-1390) and further in view of Wang (J. Hepatol. 2019, 71, 731–741, online 6/5/2019, http://dx.doi.org/10.1016/j.jhep.2019.05.015) and Seo (Journal of Immunology, 202:1, page 134.3, May 2019) and Khan (11 July 2019 | Vol 571 | Nature | 211-218).
'694 meets the limitations of claim 159 as previously established with the exception that '694 did not teach gene-editing the immune checkpoint genes recited in claim 159. More
specifically, the teachings of '694 as they relate to claim 159 are interspersed within the text of claim 159, below.
Claim 159 is drawn to a population of expanded TILs obtainable by a method comprising
adding tumor digests or fragments obtained from a tumor resected from a patient into a sterile cell culture system to obtain a first population of TILs; See '694, para 120, Step (a)
(b) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2, and optionally OKT-3, to produce a second population of TILs, wherein the first expansion is performed in a first container wherein the first expansion
is performed for about 3-14 days to obtain the second population of TILs, see paragraph 122 Step (c) (about 3-14 days), see para 29, in some embodiments 12 days
(c) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, optionally OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-12 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the second expansion is performed in a second container; para 123 Step (d) (about 7-14 days), see para 29, in some embodiments 12 days
(d) harvesting the therapeutic population of TILs obtained from step (d); See para 124 Step (e)
(e) transferring the harvested TIL population from step (d) to an infusion bag; See para 125, Step (f)
(f) optionally cryopreserving the infusion bag comprising the harvested TIL population from step (e) using a cryopreservation process; and
Claim 216 requires the first period in step (b; first expansion) and the second period in step (d; harvesting, presumed to be referring to step c, second expansion) are each individually performed within a period of 10,11, or 12 days. This is met by '694, see para 29, In some embodiments, the first period and the second period are each individually performed within a period of 10 days, 11 days, or 12 days. Claim 217 requires steps a-e are performed within 10-22 days which is met by 2, 11 day expansions. Claims 218-219 require the first and second container be gas permeable, which is taught by '694 at para 671. With regard to closed system Claims 220-223, '694 teaches Xuri cell bags (para 695) and gas permeable bioreactor bags (para 674-675). With regard to claim 224, '694 teaches culture with 4-1BB stimulation, see para 163.
'694 does not teach genetic modification of a checkpoint gene but does teach checkpoint modulation with anti-CTLA4 and anti-PD-1 (for example para 180, 486,2296). '694 does discuss use of checkpoint inhibitor therapies (i.e. anti-PD-1 antibodies; in combination with treatments using the genetically modified TILs. PD-1 is a checkpoint gene but is not one of the checkpoint genes listed in claim 159.
Beane teaches the use of zinc finger nucleases (claim 235-236) to gene-edit melanoma tumor infiltrating lymphocytes to decrease the expression of the checkpoint gene PD-1 (claims 232-233). Beane teaches, "Thus, the ability to permanently silence PD-1 in TIL manipulated ex vivo, prior to ACT, represents an attractive approach to improving the efficacy of TIL, while avoiding the toxicities associated with the long-term administration of a systemic anti-PD-1 antibody," and states, " the PD-1 gene edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNFa, GM-CSF, and IFNγ) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500-2,000-fold in vitro." (Abstract). Beane teaches genetically modifying PD-1 following stimulation and first expansion. Beane does not teach any of TOX, ANKRD11, or BCOR as checkpoint genes.
Wang also discusses checkpoint inhibition in treatment of cancer and discusses PD-1, CTLA4 and TOX as checkpoint molecules that promote T-cell exhaustion. Wang discusses that TOX supports the action of PD1 and that anti-PD1 and TOX knockdown each enhance T cell antitumor immunity and inhibits tumor growth.
Wang also taught that when TOX was completely deleted in activated T-cells, proliferation increased and apoptosis decreased, which led to anti-tumor immunity (Discussion). Wang also discusses limits of anti-PD1 therapy and suggests TOX downregulation as a new strategy to maximize immunotherapeutic efficacy in cancer patients (page 740, last para).
Additionally, Seo taught TIL deficient for TOX and TOX2 suppressed tumor growth and prolonged survival of tumor-bearing mice. Seo states that disruption of TOX expression could be a promising strategy for cancer immunotherapy. Similarly, Khan taught that in the absence of TOX, exhausted T cells do not form.
It would have been obvious to make genetically modified TILs to lack a functional PD-1 gene in place of the checkpoint inhibitor therapy in conjunction with TIL therapy discussed by '694 to arrive at the invention as claimed. One would have been motivated to make such a substitution as Beane taught not only the effectiveness of knocking out PD-1 expression in TILs
but also that use of gene editing in place of anti-PD-1 antibodies avoids the toxicities associated with that treatment. It would have been obvious to make genetically modified TILs to lack a functional TOX gene, as taught by Wang and by Seo and by Khan, in place of the gene-editing to reduce the checkpoint protein PD-1 in conjunction with TIL therapy discussed by '694 and Beane to arrive at the invention as claimed. One would have had a reasonable expectation of success in making the combination as Beane taught how to generate the genetically modified TILs and all requisite information to alter the TOX gene was routine, available and within the skill of the ordinary artisan.
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 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.
The rejection of claims 159 and 216-231, 235 and 236, on the ground of nonstatutory double patenting as being unpatentable over the claims of the U.S. Patents and copending applications listed below in view of Chikuma (Cancer Sci | April 2017 | vol. 108 | no. 4 | 574-580) is withdrawn in view of Applicant’s amendments to the claims removing SOCS1 from the breadth of the claims.
Claims 159 and 216-231, 235 and 236 are rejected, or provisionally rejected in the case where the reference is a pending application, on the ground of nonstatutory double patenting as being unpatentable over the claims of the U.S. Patents and copending applications listed below in view of Wang (J. Hepatol. 2019, 71, 731–741, online 6/5/2019, http://dx.doi.org/10.1016/j.jhep.2019.05.015) and Seo (Journal of Immunology, 202:1, page 134.3, May 2019) and Khan (11 July 2019 | Vol 571 | Nature | 211-218).
Although the claims at issue are not identical, they are not patentably distinct from each other because in each case they claim either:
Methods of expanding tumor infiltrating lymphocytes comprising successive culturing steps, wherein there are at least two consecutive steps of culturing in media for a total of 22 days
or less, Cells and compositions comprising such cells made by those culturing methods, wherein the cells are suitable for treating cancer, and/or methods of treating subjects with cancer comprising administering such TILs or compositions. These reference applications did not teach TOX, ANKRD11, or BCOR as checkpoint genes.
However, Wang taught inhibition of checkpoint molecules in treatment of cancer as the checkpoint proteins act to de-escalate the immune response by T-cells. Wang discusses PD1, CTLA4 and TOX checkpoints whose reduction enhances anti-tumor immunity.
Wang also taught that when TOX was completely deleted in activated T-cells, proliferation increased and apoptosis decreased, which led to anti-tumor immunity (Discussion). Wang also discusses limits of anti-PD1 therapy and suggests TOX downregulation as a new strategy to maximize immunotherapeutic efficacy in cancer patients (page 740, last para).
Additionally, Seo taught TIL deficient for TOX and TOX2 suppressed tumor growth and prolonged survival of tumor-bearing mice. Seo states that disruption of TOX expression could be a promising strategy for cancer immunotherapy. Similarly, Khan taught that in the absence of TOX, exhausted T cells do not form.
It would have been obvious to make genetically modified TILs to lack a functional TOX gene, as taught by Wang, in place of the gene-editing to reduce other checkpoint genes in conjunction with TIL therapy to arrive at the invention as claimed. One would have been motivated to make such a substitution as Wang, Seo and Khan each taught the effectiveness of knocking down TOX enhances anti-tumor immunity of T cells. One would have had a reasonable expectation of success in making the combination as all requisite information to alter the TOX gene was routine, available and within the skill of the ordinary artisan.
Issued U.S. Patents
10130659
10166257
10272113
10363273
10398734
10420799
10537595
10463697
10537595
10639330
10646517
10653723
10695372
10894063
10905718
10918666
10925900
10933094
10946044
10946045
10953046
10953047
11007225
11007226
11013770
11026974
11040070
11052115
11052116
11168303
11168304
11058728
11083752
11123371
11141438
11179419
11202803
11202804
11220670
11241456
11254913
11266694
11273180
11273181
11291687
11293009
11304979
11304980
11311578
11337998
11344579
11344580
11344581
11351197
11351198
11351199
11364266
11369637
11384337
11401507
11433097
11517592
11529372
11541077
11026974
10517894
11351198
11351199
11357841
11384337
11433097
11517292
11529372
11713446
11857573
11865140
11819517
11969444
11975028
11998568
12121541
11939596
12031157
11384337
12024718
12031157
11857573
U.S. Patent Applications
16969362
17110179(allowed)
17041305 (allowed)
17147080 (allowed)
17147096 (allowed)
17147412 (allowed)
17817217 (allowed)
17817226 (allowed)
17817232 (allowed)
17817239 (allowed)
17817247 (allowed)
17817273 (allowed)
17856793 (allowed)
17050552 (allowed)
17819909 (allowed)
17823419 (allowed)
17823448 (allowed)
17856806 (allowed)
17819909 (allowed)
17856793 (allowed)
17856806 (allowed)
18410900 (allowed)
17817207
17823454
17810540
17817276
17053344
17829087
17838127
17997648
17997731
18247878
18256421
18256798 (claims 8 and 20)
18256853
18262365
18291536 (Claims 2-5)
18411991
18551138
18551586 (see claim 32)
18555513 (see claim 2)
18619119
18661510
18674755 (see claim 2)
18693508
18707719
18745958
18781928 (see claim 12)
18832493 (see claim 2)
18832901
18886988 (see claim 14)
19011427
Newly added: 18962995 (see claim 3)
In the interest of compact prosecution, Applicant is invited to indicate whether or not the differences between the instant and each of the copending sets of claims are obvious as they read on method of treating cancer comprising administering to the subject expanded TILs and expanded TIL composition that was obtained by the same method as in the instantly claimed product by process claims, i.e. in closed system with the shortened time period and at least two expansions protocols
This rejection as it relates to pending applications is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Applicant argues, similar to above, that because the reference claims do not recite the now-recited checkpoint molecules and because removal of SOCS1 has negative effects on expansion, the obviousness cannot be sustained. In response, as set forth above, both the claims and the art support that the inclusion of IL-2 restores expansion in the presence of antigen. Thus, Applicant’s argument is not persuasive.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached on M-F 6AM-2:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/VALARIE E BERTOGLIO/
Primary Examiner, Art Unit
1632
Prosecution Insights