DETAILED ACTION
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 amendment and remarks, filed 8/26/26, are acknowledged.
Claims 68 and 76 have been amended.
Claim 159 has been added.
Claims 68, 73-74, 76-89, 159 are pending.
Claims 73-74, 77-89 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Claims 68, 76 and 159 are being acted upon.
The NSDP rejection over application 19/544,953 is withdrawn in view of the amendment to the claims in that application. The 102 rejection and 112a and 112b rejections are withdrawn in view of Applicant’s claim amendments.
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 68 and 76 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/157636, in view of US20030170238, Lee, 2004, and WO2016057841 (all of record).
WO2015/157636 teaches a method of adoptive cell therapy for treating a patient with cancer comprising culturing a TIL population in a culture medium containing IL-2 and a 4-1BB agonist (i.e. a TNFRSF agonist) to expand TIL, and proving a second rapid expansion in a culture medium comprising anti-CD3, PBMC, IL-2, harvesting the TIL and harvesting the expanded TIL (see page 2, 9-11, Figure 11, in particular). WO2015/157636 teaches using OKT3 as the anti-CD3 (see page 10, in particular). WO2015/157636 teaches that the first culture is performed for 3 weeks (i.e. 21 days, see page 28, in particular). WO2015/157636 teaches performing the second culture period for 2 weeks (see page 29, in particular). WO2015/157636 also teaches that generating optimal killer CD8 T cell responses requires co-stimulation, that can be provided via ligation of TNF family members, including OX40 and 4-1BB. WO2015/157636 teaches that OX40 is of particular interest as an agonist anti-OX40 monoclonal antibody augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity (see pages 23-24, in particular). WO2015/157636 also teaches that both OX40 and 4-1BB are expressed by freshly isolated TIL (see page 18, in particular).
The reference differs from the claimed invention in that it does not explicitly teach including an OX40 agonist antibody in the first culture.
Lee et al. teach that 4-1BB and OX40 dual co-stimulation synergistically stimulates CD8 T cell clonal expansion and robust effector function (see page 3002, in particular). Lee teach anti-OX40 antibody as an OX40 agonist.
The ‘272 publication teaches methods of culturing T cells for immunotherapy, including TILs, and teaches that T cells can be activated using a variety of monoclonal antibodies that activate costimulatory molecules, used singly or in combination, and particularly teaches using antibodies that interact with OX40 (see entire document, paragraph 98, in particular).
WO2016057841 teaches OX40 agonist antibodies include MED10562, which is a humanized monoclonal antibody (see paragraph 528, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include an anti-OX40 agonist antibody, as taught by Lee and the ‘272 publication, in the TIL cultures of WO2015/157636. The ordinary artisan at the time the invention was made would have been motivated to do so since the references teach that OX40L agonist antibody augments CD8 expansion and effector function, and that combined OX40 plus 4-1BB co-stimulation synergistically enhances CD8 T cell expansion, survival, and effector function. The ordinary artisan would have a reasonable expectation of success in including OX40L antibody, since WO2015/157636 specifically teaches that it is expressed by TIL, acts as a costimulatory molecule, and that anti-OX40 antibody can augment T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity. See also the ‘272 publication which teaches that T cells cultured for immunotherapy, including TILs can be activated using monoclonal antibodies that OX40. Additionally, WO2016057841 teaches OX40 agonist antibody MED10562 (i.e. tavolixizumab) is a known humanized OX40 agonist antibody. It would have been obvious to select from known available anti-OX40 antibodies, since doing so would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
Applicant’s arguments filed 8/26/26 have been fully considered, but they are not persuasive.
Applicant argues that there is no motivation or reasonable expectation of success to modify WO 2015/157636 as proposed in the rejection, because WO 2015/157636 measured expression of both 4-1BB and OX40 on the TIL, and that based on 4-1BB expression levels decided to question whether co-stimulation of 4-1BB in these early cultures could affect TIL outgrowth. Applicant argues that this shows that the reference found that OX40 was suboptimal for further investigation, and therefore there would not be a reason to include an OX40 agonist at all.
WO2015/157636 teaches that TIL samples, 4- IBB was mainly expressed on CD8+ TIL, whereas OX40 was also expressed but to a lesser extent. WO2015/157636 also teaches that generating optimal "killer" CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4- IBB (CD137). WO2015/157636 explains OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors.
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Applicant argues that the statement regarding OX40 on page 23 of WO2015/157636 is for treating patients rather than a cell culture medium. Applicant argues that the ‘238 publication is directed to an entirely different stage of manufacture involving reactivation just prior to T cell infusion, and does not relate to T cell expansion of TIL. Applicant argues that the ‘238 publication proposes screening the costimulatory combinations and does not provide any information regarding TIL expansion. Applicant argues Lee and WO2016/057841 do not provide a reasonable expectation of success since Lee is directed to using the agonist in vivo and WO2016/057841 is relied upon for a known humanized OX40 antibody.
WO2016/057841 teaches that the microenvironment within early tumor fragment cultures can be modulated to affect the outcome of TIL expansion. WO2016/057841 teaches that the tumor fragment culture system is an extension of the tumor microenvironment system, which can be further enhanced by addition of immunomodulators such as 4- IBB agonists to improve the output and phenotype of TIL for adoptive cell therapy (see paged 40-42). WO2015/157636 teaches that in addition to 4- IBB, OX40 was also expressed on TIL. WO2015/157636 also teaches that generating optimal "killer" CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4- IBB (CD137). WO2015/157636 explains OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors.
Furthermore, Lee et al. teach that 4-1BB and OX40 dual co-stimulation synergistically stimulates CD8 T cell clonal expansion and robust effector function in the context of a tumor microenvironment during rejection of established tumors (see page 3002, 3008, in particular). Lee teach anti-OX40 antibody as an OX40 agonist. The ‘238 publication also explains the role of stimulation, including trough OX40, to activate T cells, including TIL (see paragraph 98, in particular). Regarding Applicants arguments that in vivo teachings are not relevant, Lee teaches that dual co-stimulation via 4-1BB and OX40 is effective in the context of a tumor microenvironment during an in vivo tumor model. Since WO2016/057841 teaches that the tumor fragment culture system is an extension of the tumor microenvironment system, the ordinary artisan would have motivation and reasonable expectation of success to further enhance TIL expansion by including an OX40 agonist, along with 4-1BB agonist, in particular since WO2016/057841 teaches that TIL express both 4-1BB and OX40. Furthermore, it was recognized that OX40 agonists could be used in vitro to provide T cell costimulatory signals, as taught by the ‘238 publication. The teachings of the ‘238 publication are not limited to re-activation just prior to infusion as argued by Applicant. Rather, the ‘238 publication teaches proliferating T cells prior to reactivation, wherein the proliferation (i.e. expansion) is induced using a variety of mAb singly or in combination to provide costimulatory signals, and teaches antibodies that interact with OX40 provide costimulation (See paragraphs 97-99, in particular).
The references provide motivation and a reasonable expectation of success to include an OX40 agonist.
Applicant argues that the claimed invention provides unexpected results, citing Fig. 29-30, which are asserted to show that 4-1BB does not produce a statistically signal increase in CD8 TIL expression, while OX40 does.
This is not persuasive of unexpected results for several reasons. As an initial matter, unexpected results must compare the claimed invention with the closes prior art, and WO2015/157636 specifically teaches achieving increased CD8 TIL expansion. Furthermore, the size of the bars for OX40 and 4-1BB between Fig. 29 and 30 are not actually different, both appear to increase CD8 T cell expansion (the statistical difference could merely relate to the N for each experiment, wherein OX40 was repeated 5 times instead of 3 for 41BB). Furthermore, in Fig. 31, 4-1BB showed a much larger increase in CD8 expansion, and OX40 showed a minimal increase in CD8 TIL expansion. The discrepancies in these results are not explained.
Moreover, the asserted unexpected results appear to be generated with a single OX40 antibody under specific experimental conditions and are not commensurate in scope with the instant claims which encompass any OX40 agonist, and a range of different culture conditions (culture timeframes, concentration of reagents, etc.). Furthermore, increasing T cell expansion by including OX40 agonist would be expected, based on the prior art teachings above.
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.
Claim 68, 76, and 159 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65, 68-76, 82-98 of copending Application No. 17/050,552 (reference application, now issued as 12,642,268), in view of WO2015/157636, US20030170238, Lee, 2004, WO2016057841. Although the claims at issue are not identical, they are not patentably distinct from each other because the applications claim a method of treating a subject with cancer comprising expanding TIL with a first expansion with IL-2 for 3-14 days and a second rapid expansion with IL-2, OKT-3, and antigen presenting cells for 7-14 days, and administering the TIL. The applications claims PBMCs as APCs, including a 4-1BB agonist and/or OX40 agonist during the first expansion and the second expansion. Selecting 4-1BB and OX40 agonist antibodies would be obvious based on the teachings of WO2015/157636 US20030170238, Lee, 2004, and WO2016057841 for the same reasons set forth above. Regarding new claim 159, the claims is being included in the rejection since ‘442 application (now issued as the ‘268 patent) claims that OX40 agonist can be included in the first and second expansion.
Claims 68, 76, and 159 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11083752, 10517894, 11026974, 11058758, 10130659, 10166257, 10272113, 10363273, 10398734, 10420799, 10463697, 10639330, 10646517, 10695372, 10894063, 10925900, 11007225, 11026974, 11007226, 11013770, 11040070, 11052116, 11052115, 11357841, 11384337, 11401507, 11541077, 11865140, 11998568, 11529372, 11713446, 12104172, 12024748, 12226434, 12031157, 12188048, 11975028, 11969444, 11857573, 12495791, 12629356, 12194061, 12558375, 12642816, 12622927, 12611429, 12636318,12485145, 11517592,11369637, 11364266, 11351199, 11344581, 11266694, 11344580, 11351198, 11351197, 11311578, 11337998, 11344579, 11291687, 11273181, 11304980, 11304,979, 11273180, 11202804, 11241456, 11241456, 11202803, 11141438, 11123371, 11179419, 11058728 in view of WO2015/157636, US20030170238, Lee, 2004, WO2016057841, Ohshima, 1997 and Zhang, 2013.
The issue patents all claim TIL for treating cancer, or methods of making TIL for a subject with cancer, wherein the TIL are produced by a process comprising expanding TIL by obtaining TILs by a first expansion with IL-2 and a second rapid expansion with IL-2, OKT-3, and antigen presenting cells. The patents claim PBMCs as APCs. The issued patents either claim culture timeframes within the scope of the instant claims, or alternatively such timeframes would be obvious based on the teachings of WO2015/157636. Furthermore, including a 41BB and OX40 agonist would be obvious over WO2015/157636, US20030170238, Lee, 2004, and WO2016057841 for the same reasons set forth above. It is noted that claim 159 is being included since it would be obvious that PBMC added in the REP would express OX40L based on the teachings of Ohshima, 1997 and Zhang, 2013, for the same reason set forth below.
Applicant argues that it is not obvious to include an OX40L and 4-1BB agonist for the same reasons set forth above.
This is not persuasive for the same reasons set forth above.
Additionally, regarding the rejection over the ‘552 copending application, now issued as 12,642,268, as noted above, this application/patent specifically claims including a 4-1BB or OX40 agonist during the first expansion, the second expansion or both.
Claim 159 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/157636, US20030170238, Lee, 2004, and WO2016057841, as applied to claim 68, and further in view of Ohshima, 1997 and Zhang, 2013.
The teachings of WO2015/157636, US20030170238, Lee, 2004, and WO2016057841 are described above.
Ohshima and Zhang teach that OX40L (i.e. an OX40 agonist) is present on cells in peripheral blood mononuclear cells, such as monocytes and dendritic cells. Therefore, it would be obvious that when performing the second rapid expansion culture, that adding PBMC, as taught by WO2015/157636 would involve adding OX40L which is expressed on cells within the added PBMC, such as dendritic cells and monocytes, as taught by Ohshima and Zhang.
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 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
