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 .
Applicant's reply filed on 02/06/2026 has been entered.
Claims 159, 216-230, 235 and 236 are pending and under consideration.
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.
The rejection of claims 216,225 and 226 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the clarifying amendments to the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The rejection of claim 231 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is rendered moot by the cancelation of the claim.
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.
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 Chikuma (Cancer Sci | April 2017 | vol. 108 | no. 4 | 574-580).
Applicant’s arguments have been fully considered and are not persuasive (addressed below).
‘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
(a) 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).‘674 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 (TNFα, 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, SOCS1 or BCOR as checkpoint genes.
Chikuma also discusses checkpoint inhibition in treatment of cancer and discusses PD-1, CTLA4 and SOCs1 as checkpoints. Chikuma discusses the clinical successes in blocking CTLA4 and PD-1 and focuses on SOCS family members (SOCS1, SOCS3 and CIS) as additional checkpoints as promising targets for therapeutic blockade.
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 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 its use 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 SOCS1 gene, as taught by Chikuma, 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 Beanetaught how to generate the genetically modified TILs and all requisite information to alter the SOCS1 gene was routine, available and within the skill of the ordinary artisan.
Applicant argues that the cited art fails to provide any reasonable teaching suggestion or motivation to substitute SOCS1 gene editing into ‘694’s TIL expansion method. In response, the motivation to use SOCS1 comes from the teaching of Beane and Chikuma. Beane taugh genetic modification of the PD-1 checkpoint gene in TILs and Chikuma taught SOCS1 as one aof a number of checkpoint genes with a similar role.
Applicant also argues that there wasn’t a reasonable expectation of success that SOCS1 disruption would be compatible with, or improve, the expansion process of ‘694. In response, the modification of a checkpoint gene was not to improve the expansion process but to enhance the therapeutic nature of the TILs.
Applicant argues that Chikuma expressly teaches that SOCS1 deficiency causes defective expansion which undermines any reasonable expectation that SOCS1 gene editing would succeed in the ‘694’s expansion process. In response, Chikuma says "Since deletion or suppression of SOCS1 and SOCS3 in either T cells or myeloid cells enhanced anti-tumor immunity, SOCS inhibitors could be ideal drugs that target an immune checkpointcontrolled by cytokines" p 577, col. 2. This does not negate the negative effects on expansion. However, in that regard, Chikuma references Ramanathan (The Journal of Immunology, 2010, 185: 357–366) who teaches TILs do proliferate in response to cytokines but not antigens. However, additional experiments show that inclusion of exogenous IL-2 restores the antigen-induced proliferation (page 361, col. 1). The claimed method and the method of ‘’694, performs expansion in the presence of antigen with addition of IL-2. Ramanathan states, “addition of IL-2 completely restored the gp33-induced proliferation in Socs12/2 P14 cells, with a 10-fold increase in Ag sensitivity (Fig. 5B).”
Applicant states that Beane is directed to adoptive transfer of TILs, that PD-1 is a critical inhibitory checkpoint, and that the tumor reactive TILs express PD-1. Applicant states that Beane teaches silencing PD-1 prior to adoptive cell therapy is an attractive approach to improving TIL efficiency. Applicant finds Chikuma in contrast as describing SOCS proteins as intracellular regulators of cytokine signaling, discusses SOCS1 as a checkpoint-like node, but does not provide TIL-specific ex vivo manufacturing data demonstrating SOCs1 gene editing improves outcomes. In response, this rejection is an obviousness rejection based on the art as a whole. Chikuma states, “SOCS1 is now considered to be an immune checkpoint molecule for anti-tumor immunity…” (page 576, Col. 2). It’s role as a checkpoint makes it an obvious member of a genus of checkpoint molecules that includes PD-1.
Applicant again notes that SOCS1 deficiency cause defective expansion following antigen stimulation. This was addressed above where it was taught that inclusion of IL-2 remedied this defective expansion and the claimed method also include IL-2 in this step.
Applicant discusses that ‘694 addresses checkpoint modulation through use of anti-PD1 antibodies obviating need to gene-edit TILs. In response, it was noted that gene-editing avoids toxicity associated with antibody therapy (see above). Applicant argues that the ‘694 manufacturing disclosure is expansion-centric. It appears Applicant may be arguing that the reason to use SOCS1 is supplied at a high level of generality and that ggenetic disruption of SOCS1 is not a known alternative in a REP-style expansion workflow. In response, the references taught knocking down a checkpoint with antibodies and the alternative to do so by gene modification. The art also taught alternative checkpoints, discussing SOCS1 in the same context as PD-1 (Chikima).
Applicant again addresses expectation of success given the defective expansion of SOCS1- TILs. This was addressed above. Finally Applicant argues that Chikuma discusses different means for SOCS1 inhibition but does not teach gene editing as a predictable, routine modification of a REP manufacturing process. ‘694 discusses genetic modification of TILs (para 347, for example) and Beane taught genetic modification to eliminate PD-1 checkpoint expression.
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.
Claims 159 and 216-231, 235 and 236 remain 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 Chikuma (Cancer Sci | April 2017 | vol. 108 | no. 4 | 574-580). 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, SOCS1 or BCOR as checkpoint genes. However, However, Chikuma taught inhibition of checkpoint molecules in treatment of cancer as the checkpoint proteins act to de-escalate the immune response by T-cells. Chikuma discusses PD1 as one of the most studied checkpoints, which is also taught by ‘779. Chikuma also teaches the SOCS family, including the claimed SOCS1, and teaches that SOCS1 can inhibit nearly all cytokines and negatively regulates signaling of IFN-g and IL-12, which are essential for anti-tumor immunity. Chikuma also teaches that shRNA inhibition of SOCS1 in T cells has been shown to have therapeutic anti-tumor effects.
It would have been obvious to make genetically modified TILs to lack a functional SOCS1 gene, as taught by Chikuma, 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 Chikuma taught the effectiveness of knocking downs SOCS1 expression enables necessary cytokine signaling for anti-tumor immunity. One would have had a reasonable expectation of success in making the combination as all requisite information to alter the SOCS1 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
THIS ACTION IS MADE FINAL. 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 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.
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/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632