DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10-01-2025 has been entered.
Status of the Claims
Claims 1,19,70-73,82-83,96-97 and 213-215 are currently pending in the Application with claim 214 currently withdrawn. Therefore claims 1,19,70-73,82-83,96-97 and 213, 215 are examined on the merits below.
Response to Arguments - Claim Rejections - 35 USC § 103
In reply to previously applied rejection the Applicant traverses. Applicant initially considers each reference individually and provides that there is no motivation to combine the provided references and/or arrive at the claimed invention if the references are combined.
As presented previously the disclosure of Wardell describes the particular process of producing a TIL population as is instantly claimed. The disclosure further describes that one may want to genetically modify the TIL population for a variety of purposes including the final “therapeutic” TIL population as described in the rejection(s) of record. The disclosure of Roybal further provides that TIL populations would benefit from genetic modification procedures and conceptually provides a variety of modifications such as orthogonal cytokine receptor/ cytokine pairs. As presented previously the motivation to combine references does not need to be explicit. The further disclosure of Sockolosky does not explicitly describe that TIL cells may be modified with an orthogonal IL-2/IL2RB pair. However the disclosure clearly indicates that the system disclosed may have broader application other than the model which is instantly utilized. Therefore the disclosure indicates that “selective potentiation” of engineered adoptively transferred T cells is conceptually a relevant application of the technology (abstract). Furthermore the disclosure describes “Our results constitute an approach to redirect the specificity of IL-2 toward engineered T cells using orthogonal IL-2 cytokine-receptor pairs, which enables the selective expansion of desired T cell subsets in settings of adoptive cell therapy, but with limited off-target activity and negligible toxicity”. Thus an artisan of ordinary skill in the art, as a non-automaton, reading the disclosure of Roybal and further Sockolosky would realize the utility of providing an orthologous IL2RB chain TIL population that may be prepared ex-vivo for further in-vivo infusion that would allow for utilization of an orthogonal IL-2 molecule to provide selective stimulation of adoptively transferred genetically modified T cells. This is the protocol the Applicant instantly claims. The motivation would be to provide in-vivo stimulation while limiting toxicity of conventional IL-2 therapeutic administration.
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.
Claim 1,19,70-73,82-83,96-97 and 213, 215 are rejected 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 1 is amended to describe that step (b) is performed by culturing the first population of TILs in a cell culture medium comprising IL-2. OKT-3 and APC are not included in the culture conditions. However the step (c) describes that the number of APC in the REP step is “at least twice the number of APCs present in the cell culture medium in step (b). As amended step (b) does not comprise any APC as limited by the consisting of delimiter in the preamble of the claim 1. As 2 times 0 = 0 it is not clear what Applicant intends to include as APC in the second expansion step (b). Appropriate clarification or correction is required. For purposes of examination the Examiner interprets the claim to mean that the second expansion step comprises any number of APC as any number would be greater than the zero APC of claim 1(b).
Claim 97 refers to the “method of claim 97”. Applicant appears to have renumbered previous claims 97 and 98 as 96 and 97 respectively causing confusion. Appropriate correction is required.
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.
Claims 72, 213 and 215 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The instant claim 1 is closed as indicated by the introduced “consisting of” phraseology of the preamble. However the dependent claims 72, 213, 215 (and withdrawn claim 214) describe additional elements thereby failing to further limit the claim(s). Claim 72 requires addition of PBMC-APC, claim 213 (and 214) requires a different step in which orthogonal IL-2RB engineering is performed, claim 215 requires an additional substitution of orthogonal IL-2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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 1,19,70-73,82-83,96-97 and 213, 215 are rejected under 35 U.S.C. 103 as being unpatentable over Wardell (US20180325954A1) and further in view of Roybal (Annual Review of Immunology, 2017, 35: 229-253) and Sockolosky (Science 359, 1037-1042, 2 March 2018).
With respect to the claim 1(a) the disclosure of Wardell describes a process of obtaining TILs wherein a population of TILs is obtained through processing a tumor resection from a subject into multiple tumor fragments (0007).
With regards to claim 1(b) the population is utilized in a first expansion wherein the cells are cultured 3-14 days or alternatively any time period of 1 day to 14 days (0435) or for about 11 days (0423) in a container providing a gas permeable surface area (0009) to provide bulk TIL cultures. The population of cells may be thereby cultured with IL-2 at a variety of concentrations (0427).
As in step 1(c) the cells may thereby be subjected to a second expansion step that may proceed in some embodiments for 7-14 days in the presence of IL-2, anti-CD3 (OKT3) and APC for example PBMC (0447)(0454) in a gas permeable container (0448). Regarding the limitation that APC are added to the culture at least 2X the number of the culture in step(a) as explained in 112b rejections the addition of any amount of APC is qualifying to result in 2X the number of (0) APC added in step 1(b).
With regards to the instant claim 1(d) “harvesting” the disclosure of Wardell indicates that cells are “harvested” as a therapeutic cell population (0011)(0057)(0081)(0487-0493).
Step “(e)” is concerned with the engineering of TILs to express “orthogonal” IL-2 receptor Beta. As further described above Applicant indicates that the engineering of the TILs to express the orthogonal IL-2RB (although indicated in claim 1 as step “(e)” ) is performed “between steps (b) and (c)” as in claim 213 for example or after the pre-REP (1st expansion) expansion step as opposed to the indicated step “(e)”. With regards to introduction of orthologous IL-2RB, the disclosure of Wardell further describes that method of producing TILs of the disclosure may include an additional “step” in which TILs that are derived from first or second or subsequent expansion step may be subjected to “genetic modifications” for suitable treatments (0720)(0440). As such the disclosure of Wardell suggests genetic modification of cells at timepoints after the first or the second expansion steps. Wardell does not describe that the genetic modification is specifically expression of an “orthogonal” IL-2RB molecule for example.
However the limitation of engineering T cells to comprise an orthogonal IL-2RB is provided by the disclosure of Sockolosky as described below with the disclosure of Roybal further supporting that one would be motivated to provide this orthogonal construct to T cells (TILs) as the “genetic modification” of Wardell.
With regards to the limitation that the TILs are engineered to express an orthogonal cytokine receptor the disclosure of Roybal describes that TILs are a population of cells that could benefit from further engineering during “ex-vivo processing as response rates could be improved through arming the cells to combat the often refractory tumor microenvironment” concluding thereby that TILs are “thus an important test bed for synthetic biology approaches discussed below” (p234, “tumor-infiltrating lymphocytes”). The disclosure thereby further describes “below” a variety of techniques available in the synthetic biology “toolkit” for programming immune cells (p236-p237). Included in this “toolkit” are “nonnatural and synthetic cytokine and cytokine receptor platforms” (p239-p240). Roybal further describes that “the development of completely orthogonal cytokines that provide privileged channels of communication between therapeutic cells are of much interest”. The further disclosure of Sockolosky provides a reduction to practice of this very concept through production of an ortholog IL-2/ IL-2RB pair ( as instantly claimed) which functions to transmit native IL-2 signals but is completely insulated from the endogenous IL-2 cytokine/ receptor signalling system (abstract, Figure 1). Thus the authors conclude that the results describe an approach to redirect (restrict) the specificity of IL-2 (beneficial signalling) toward engineered T cells while limiting off-target activity in settings of adoptive cell therapy (which TIL therapy is a species). It would thus be obvious to utilize (engineer) the orthogonal IL-2/IL-2RB pair of Sockolosky in a TIL population for the beneficial properties thereby imparted in the cells as described by both the disclosure of Sockolosky and Roybal.
Claim 19 further reiterates that the process results in an expansion of TILs from the first to the second expansion step final products. The expansion may be from 1.5x-100x as indicated. The disclosure of Wardell in aspects describes that TILs of a second population expanded from a first expansion may result in a 50-fold expansion (0055)(0332)(0122) Furthermore the disclosure of Wardell describes that expansion phases may result in increases of at least about 3 fold to at least about 100-fold over a seven day period for example. It would therefore be obvious through routine optimization to arrive at an expansion of about 1.5-100 x the original population of cells through optimization of the multiple variable inputs of APC/TIL ratio, IL-2 amount , culture time period, OKT3 amount.
With regards to claims 70 and 71 the disclosure of Wardell indicates that for example APC utilized in the invention may preferably comprise irradiated allogeneic PBMC, (also “feeder cells”) (0003, 0015, 0088). It would be obvious therefore obvious to utilizes the claimed feeder cell population as specifically disclosed by Wardell.
Claim 72 describes that in the first expansion the number of PBMC added to the culture media is 2.5x10E8. In as much as this appears to be a value related in the method to the number of TILs that are seeded in the initial culture conditions, as above the disclosure of Wardell indicates that an appropriate ratio of TIL-PBMC added to a culture may comprise 1:100 cells for instance . If one were starting with 5 x 10E6 cells (see claim 12 above) for example it would be obvious to add for example add PBMC feeder cells at a disclosed ratio of 1:50 to arrive at 2.5x10E8 PBMC cells added (0457).
Claim 73 describes that the total number of PBMC added to the culture system is 5x10E8 cells. The disclosure of Wardell indicates that for example 5x10E6 TIL and 5x10E8 PBMC feeder per GREX-100M flask may be provided at the initiation of a “REP” for example providing a 1:100 ratio as disclosed above (see figure 84, “REP” 1C embodiment). It would be obvious therefore if one started the process with 5x10E6 TIL to seed a GREX 100 with the claimed number of feeder cells as previously disclosed as effective.
Claims 82 and 83 relate to particular IL-2 concentrations utilized in cell culture supernatants. The disclosure of Wardell describes in particular embodiments that IL-2 may be present in tissue culture supernatants at an amount of specifically 6000 IU/ml (0423, 0427) and alternatively within the range of 10000-5000 IU/ML (0427).
With regards to claims 96 and 97 the disclosure of Wardell likewise indicates that therapeutically effective dosages of TILs administered to subjects may be for example 2.3x10E10 to 13.7x10E10 cells total. (0498) It would be obvious to administer said population of cells to a subject for the purposes of treating a target condition effectively as a therapeutically effective dosage.
With regards to the instant claims 213, 215, the combined disclosure of Wardell, Sockolosky, and Roybal make obvious utilization of an orthogonal IL-2RB construct in tumor infiltrating lymphocytes (Roybal, Sockolosky), a construct which may be introduced at any point in the culture process (Wardell). With regards to the disclosure that orthogonal IL-2 is substituted for the generic IL-2 of the claim 1(c) the disclosure of Sockolosky indicates that a particular orthogonal IL-2RB/IL-2 pair may be utilized to selectively target for proliferation cells which comprise the orthogonal receptor (transduced). It would be obvious therefore to target cells for proliferation (transduced TILs) which would respond to the IL-2 and thereby be selectively provided with growth and survival benefits. The selectively proliferated TILs would then be selectively utilized for further in-vivo treatment protocols.
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.
To the extent that the claims in the conflicting patents or applications are drawn to methods of treatment or the TILs cell cultured, as opposed to the now-claimed methods of expanding TILs the underlying specifications disclose the same method of expanding as instantly claimed. See MPEP 804(Il)(B)(l).
Claims 1,19,70-73,82-83,96-97 and 213, 215 are rejected on the ground of nonstatutory double patenting as being unpatentable over :
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,,11052116,11168304,11058728,11083752,11123371,11141438,11179419,11202803,11202804,11220670,11241456,11254913,11266694,11273180,11273181,11291687,11293009,11304979,11304980,11311578,11337998,11344579,11344580,11344581,11351197,11351198,11351199,11364266,11369637,11384337,11401507,11433097,11517592,11529372,11541077,11026974,10517894,11351198,11351199,11529372,11713446,11857573,11865140,11819517.
U.S. Patent Applications :
16969362,17041305,17110179,17147080,17147096,17147412,17817207,17819910,17817217,17817226,17817232,17817239,17817247,17817273,17817276,17819209,17819214,17819219,17819909,17819910,17823419,17823445,17823448,17823454,17829087,17856793,17856806,17819909,17817232
Conclusion
Summary: No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN HARTNETT whose telephone number is (571)272-3077. The examiner can normally be reached Monday-Friday 8:00 AM - 5:00 PM EST.
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/BRIAN HARTNETT/ Examiner, Art Unit 1644
/JANET L ANDRES/ Supervisory Patent Examiner, Art Unit 1671