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 .
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 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.
Priority
The instant application, filed 12/13/2023, is a 371 filing of PCT/EP2022/066633, filed 06/17/2022, and claims foreign priority to EP21180126.1, filed 06/17/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 12/13/2023 is acknowledged. Claim 1 is amended, claims 2-17 are cancelled, and claims 18-32 are new. Claims 1 and 18-32 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/13/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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 22 and 32 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 22 recites the limitation “the antibody”. The claim depends on claim 21 which limits the substances of Group A, Group B and/or Group J as being “antibodies”, indicating that claim 21, and therefore claim 22, encompass embodiments with more than one antibody. Additionally, claim 1, on which the claim ultimately depends, recites “substances” in each group further indicating that the claims encompass embodiments with more than one antibody. It is unclear if the limitations in claim 22, which limit “the antibody” applies to any and all antibodies encompassed by the claim or, if not, what antibodies encompassed are limited by the structure recited in instant claim 22. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended. “
Additionally, claim 22 contains the trademark/trade name “Nanobody” in line 3. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the structure of the antibody and, accordingly, the identification/description is indefinite.
Claim 32 recites a population of TIL wherein the population of TIL has a “higher percentage of CD8 T cells expressing markers associated with tumour-specificity.” The term “higher percentage” is a relative term which renders the claim indefinite. The term “higher percentage” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For instance, the term “higher percentage” implies that the number of CD8 T cells expressing markers associated with tumour-specificity must be higher than some other population of TIL; however, the claim does not provide a reference for comparison that could be used to establish that the percentage of the claimed cells is higher.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 32 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Friese, C., et al (2020) CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer Scientific Reports 10(3914); 1-12 and supplemental materials (17 pages), published online 03 March 2020.
Friese studied TIL cultures supplemented with anti-CTLA-4 antibody and demonstrates cultures comprising, on average, 1x107 cells (Fig. 3). Friese further teaches fold expansions after rapid expansion with high dose IL-2 and aCTLA-4 and demonstrates expansions of 1,600 and 1,800-fold (page 3, paragraph 2). Friese further teaches that the proportion of CD8+ T cells was increased in TIL cultures when anti-CTLA-4 antibody was added to the tumor fragments during the initial TIL growth compared to TIL outgrowth when cultured with only IL-2 (page 3, paragraph 3).
Friese also studied whether the TIL cultures were able to recognize autologous tumor cell lines by co-culturing the TILs with autologous tumor cells for five hours in the presence of Golgi-Plug and measuring the expression of CD107a and the intracellular accumulation of TNF and IFN-γ. Tumor-reactive T cells were defined as cells expressing CD107a or secreting one of the cytokines (page 4, paragraph 3). Reactivity against autologous tumor cell lines was detected in three out of four patient TIL cultures before expansion, while all rapidly expanded TILs were able to recognize the autologous tumor cell line (page 4, paragraph 4). Friese then studied whether the tumor-reactivity was impacted by the addition of anti-CTLA-4 antibody during TIL culture. As shown in Fig. 5, the provision of CTLA-4 blockade to the tumor fragments yielded a higher number of tumor reactive T cells before and after rapid expansion. The majority of the reactive T cells were CD8+ T cells. Friese teaches that the experiments demonstrate that the addition of anti-CTLA-4 antibody in the tumor fragment cultures can improve the expansion of tumor-reactive TILs (page 5, paragraph 2).
Friese demonstrates populations of TILs comprising 1x107 cells and teaches that the culturing techniques result in a higher percentage of CD8+ T cells compared with IL-2 cultures alone with more tumor-reactive TILs based on markers such as CD107a, TNF, and IFN-γ.
Thus, Friese anticipates instant claim 32.
Claim 32 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2015/157636 A1 (Sarnaik, A. A., et al) 15 Oct 2015.
WO’636 teaches TIL expansion with tumor fragments and 4-1BB. WO’636 teaches that, although TILs were successfully expanded from the tumor fragments in 4/4 tumor samples, IL-2 alone yielded fewer cells than IL-2 together with 4-1BB co-stimulation provided early during the culture. Anti-4-1BB markedly increased the percentage and yield of CD8+CD3+ T cells at all times (6.34x106 vs 202x106). 41BB co-stimulation also increased the cytotoxic T cell activity of the expanded TIL. The expanded TIL could also be cryopreserved and later expanded using anti-CD3 and IL-2 (page 44, lines 16-22).
WO’636 also demonstrates that TILs expanded from tumor fragments with or without anti-41BB after secondary rapid expansion were analyzed for tumor-specific reactivity. The provision of agonist anti-4-1BB antibodies to initial tumor fragment cultures significantly increased the outgrowth of tumor-specific CD8+ T cells (page 38, lines 13-19). Reactivity as measured by co-culturing the TIL with autologous or HLA-A matched allogeneic tumor cell lines and tumor-specific IFN-gamma release was measured (page 37, lines 23-32). WO’636 also demonstrates increases in the percentage of Ki67+ cells in cultures with IL-2 and anti-4-1BB ab (Fig. 2B) and CD107a+ (Fig. 6C), compared to IL-2 alone.
WO’636 teaches a population of TIL expanded using 4-1BB agonist supplemented to cultures and teaches that the cultures provided a yield of CD8+CD3+ T cells of 2.02x108 cells, which was higher than cultures expanded in IL-2 alone. WO’636 also demonstrates that TIL expanded with anti-4-1BB results in higher tumor-specific reactivity as measured by markers including IFN-gamma, Ki67, and CD107a+.
Thus, WO’636 anticipates instant claim 32.
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 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 and 18-32 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/157636 A1 (Sarnaik, A. A., et al) 15 Oct 2015 in view of Friese, C., et al (2020) CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer Scientific Reports 10(3914); 1-12 and supplemental materials (17 pages), published online 03 March 2020 and Duraiswamy, J., et al (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T cell rejection function in tumors Cancer Res 73(12); 3591-3603 and supplemental materials (11 pages).
WO’636 teaches a method for ex vivo expanding tumor-infiltrating lymphocytes for use in adoptive cell therapy (ACT). The method involves culturing tumor fragments from the subject in a culture medium containing IL-2 and a 41BB agonist in any amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity and specificity. Also disclosed is a method for treating a tumor in a subject that involves treating the subject with nonmyeloablative lymphodepleting chemotherapy and administering tumor-infiltrating lymphocytes expanded with the disclosed methods (abstract).
WO’636 teaches that tumor-infiltrating lymphocyte (TIL) production is a 2-step process:
1) the pre-REP stage, where the cells are grown in standard lab media such as RPMI and treated with reagents such as irradiated feeder cells, and anti-CD3 antibodies to achieve the desired effect; and
2) the REP stage where the TIL are expanded in large enough culture amount for treating the patients.
The REP stage requires cGMP grade reagents and 30-40L of culture media. However, the pre-REP stage can utilize lab grade reagents, under the assumption that the lab grade reagents get diluted out during the REP stage, making it easier to incorporate alternative strategies into improving TIL production. Therefore, in some embodiments, the disclosed agonist and/or peptide or peptidomimetics can be included in the culture medium during the pre-REP stage (page 9, lines 6-16). The pre-REP and REP expansion stages disclosed by WO’636 meet the instant claim limitations of a first and second expansion.
WO’636 further teaches that the TIL are autologous and isolated from the mammal to be treated, i.e., autologous transfer (page 9, lines 17-20) and that the mammal is human (page 26, lines 2-4).
Fig. 11 provides a schematic of TIL expansion in which a tumor is removed by surgery, cut into fragments and put into culture plates with IL-2 for an initial TIL expansion or “pre-REP” phase. The expanded cells then undergo a rapid expansion (REP) phase in which anti-CD3, feeder cells, and IL-2 is added to the culture for expansion. Expanded TIL are then pooled into one infusion bag and infused into a patient with IL-2 following lymphodepletion therapy.
WO’636 teaches that the anti-CD3 antibody is OKT3 (page 10, lines 1-3), and that the feeder cells are irradiated PBMC (page 41, lines 9-11). The PBMC taught by WO’636 meet the instant claim limitation of antigen presenting cells (APCs) as evidenced by the instant disclosure which states that “In some embodiments, the antigen presenting feeder cells (APCs) are PBMCs” (page 22, line 30).
WO’636 teaches the inclusion of 4-1BB agonists in the pre-REP culture. WO’636 teaches that the disclosed results indicate that tumor fragments placed in culture to expand TIL for adoptive cell therapy are not statistic tissues, but small, dynamic tumor microenvironments that can be manipulated to alter the yield and phenotype of TILs being expanded for cell therapy as well as enrich for tumor reactivity and improved memory phenotype. 4-1BB co-stimulation enhancement in the system can manipulate these ex vivo tumor microenvironments to expand optimally active TIL for adoptive cell therapy (page 10, lines 26-32). Therefore, WO’636 teaches a method for ex vivo expansion of TIL for use in ACT in which the tumor fragments are cultured in a medium containing IL-2 and 4-1BB agonist in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity and specificity (page 11, lines 1-5).
WO’636 further teaches that the 4-1B agonist is an agonistic anti-4-1BB antibody capable of ligating 4-1BB on T cells to induce its co-stimulatory activity. WO’636 teaches that suitable antibodies include monoclonal, human, humanized, murine (mice), and chimeric antibodies (page 13, line 1 – page 15, line 24). WO’636 exemplifies the use of a fully human IgG4 monoclonal agonistic anti-4-1BB antibody, BMS 663513 (page 28, lines 11-12), which is urelumab.
WO’636 teaches that experiments were conducted to test how addition of anti-4-1BB affects total TIL yield and the rate of TIL outgrowth from the tumor fragments in a larger number of patient tumor samples. Addition of 4-1BB markedly accelerated the rate of TIL outgrowth over the first two weeks of culture in 1 representative patient tumor samples or 4 independent tumor fragments (Figure 2A). To further test the effects of anti-4-1BB, experiments were performed on an additional seven tumor samples (28 separate tumor fragments), which revealed this enhanced outgrowth of TIL after 3 weeks demonstrating a consistent phenomenon in a larger sampling of patient tumors (Fig. 2D) (page 34, lines 21-31). Fig. 2A demonstrates that the inclusion of anti-4-1BB in cultures with IL-2 significantly increased cell count and that, by days 11 and 13, cultures comprised over 1x107 cells. Fig. 2D demonstrates over 1 x 107 cells at the end of 3 weeks in cultures comprising IL-2 and 4-1BB ab.
Finally, TILs originally expanded from tumor fragments with or without added anti-4-1BB after secondary rapid expansion (REP) using anti-CD3 plus IL-2 were analyzed for tumor-specific reactivity. Here too, an enhanced anti-tumor reactivity of the post-REP product was found when 4-1BB co-stimulation was provided in the initial tumor fragment cultures (Fig. 6E), which is compared to IL-2 alone. Thus, provision of agonist anti-4-1BB antibodies to the initial tumor fragment cultures significantly increased the outgrowth of tumor specific CD8+ T cells for adoptive cell therapy (page 38, lines 13-19). WO’636 teaches that the anti-4-1BB antibody was shown not only to increase the rate of TIL expansion, but also significantly increases the rate yield of CD8+ T cells from the tumors while markedly enriching for tumor-specific CD8+ TIL. Moreover, these properties were also maintained after further secondary rapid expansion with anti-CD3, irradiated PBMC feeder cells, and IL-2 commonly used to generate the final TIL infusion products in clinical trials (page 41, lines 9-11).
WO’636 further teaches a method of treating a tumor/cancer in a subject comprising expanding TIL from a tumor fragment from the subject using the methods disclosed, treating the subject with nonmyeloablative lymphodepleting chemotherapy, and administering the TILs to the subject (page 46, claim 6; page 22, lines 4-9). WO’636 teaches that nonmyeloablative lymphodepleting chemotherapy is administered to the mammal prior to administering to the mammal the expanded tumor-infiltrating lymphocytes. The purpose of lymphodepletion is to make room for the infused lymphocytes, particularly by eliminating regulatory T cells and other non-specific T cells which compete for homeostatic cytokines (page 22, lines 17-21).
WO’636 teaches that the cancers treated by the disclosed compositions and methods include breast cancer, cervical cancer, Hodgkin lymphoma, liver cancer, lung cancer, melanoma, ovarian cancer, renal cancer, urinary bladder cancer, gastric cancer, pancreatic cancer, and colorectal cancer (page 25, lines 9-23).
WO’636 further teaches that the culture media can further contain a checkpoint inhibitor, such as an anti-PD-1 antibody, e.g., BMS 936558, which is nivolumab, anti-PD-L1 antibody, anti-CTLA-4 antibody, e.g., Ipilimumab, or any combination thereof (page 11, lines 1-7). WO’636 teaches that PD-1 blockade has been shown to facilitate anti-tumor T-cell priming, increase T-cell infiltration into tumors, and anti-tumor effector function. The effects of prior PD-1 blockade in vivo was determined on the expansion of tumor-specific TIL from B16 melanomas. Mice bearing B16 tumors were treated interperitoneally injection with normal IgG or blocking anti-PD-1 antibodies. Tumors were collected on day 21 and isolated TIL were cultured in vitro with NrIgG or anti-4-1BB antibodies for seven days. Addition of anti-4-1BB antibodies to the in vitro culture without prior anti-PD-1 in vivo led to enhanced anti-tumor activity of the cultured T cells. However, increased anti-tumor activity of the short-term cultured B16 TIL with anti-4-1BB was enhanced even more when mice were treated with anti-PD-1 in vivo prior to the isolation of the tumors and culture of the TILs ex vivo. Thus, PD-1 blockade in vivo prior to TIL expansion from resected tumors improves the effects of agonist anti-4-1BB antibody in enhancing anti-tumor reactivity of expanded TIL (page 38, line 26 – page 39, line 8).
WO’636, however, does not explicitly teach that the anti-PD-1 and/or anti-CTLA-4 antibody is added to a culture comprising the TILs before the first expansion as recited in the instant claims.
The teachings of Friese are as discussed above.
Friese further teaches that ACT with autologous TILs can induce durable complete tumor regression in patients with advanced melanoma. Effectors are currently underway to expand this treatment to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules, such as CTLA-4 can lead to inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8+ T cell output and TIL tumor reactivity. To exploit this, Friese used an anti-CTLA-4 blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8+ TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase (abstract).
Friese teaches that the activity of TILs can be impeded by antigen-presenting cells or tumor cells through immune checkpoints such as PD-1 or CTLA-4 expressed on the T cell surface which can be blocked by checkpoint inhibitors such as ipilimumab (anti-CTLA-4), nivolumab, and pembrolizumab (both anti-PD-1) (page 2, paragraph 2).
To test the effect of CTLA-4 blockade during the rapid expansion, each TIL culture was expanded with either IL-2 in a standard REP or by additionally adding anti-CTLA-4 antibody on day 0 and day 7 during the REP, thereby generating expanded TILs in four conditions. The median fold expansion in all conditions was higher than 1,300 fold (Fig. 3C). Adding CTLA-4 antibody during REP did not affect the fold expansion of TILs. However, TILs subjected to CTLA-4 blockade during tumor fragment cultures expanded to greater levels compared to TILs from tumor fragment cultures in IL-2 only (median 1,600 and 1,800-fold vs. 1,300 and 1,400-fold). Thus, CTLA-4 blockade of TILs during the early expansion phase improves the total number of TILs (page 3, paragraph 2).
Friese also teaches that suppression by Tregs seems to be mediated by the inhibition of the IL-2 receptor anti-chain induced by CTLA-4 and membrane bound TGF-B1. This interaction is blocked in the in vitro TIL cultures by anti-CTLA-4. Friese determined the frequency of Tregs in patients with a profound increase of CD8+ cells when the initial TIL culture was treated with anti-CTLA-4 antibody using flow cytometry. The proportion of Tregs within the CD3+ compartment was reduced in 3 out of 4 patients (page 7, paragraph 5).
Duraiswamy performed a study documenting parallel regulation of CD8+ T cells and Foxp3+ Tregs by PD-1. In addition, an additional role of CTLA-4 inhibitory receptor in further promoting dysfunction of CD8+ T effector cells in tumor models was identified. Duraiswamy teaches that two thirds of CD8+ TIL expressed PD-1, while one third to half of CD8+ TIL co-expressed PD-1 and CTLA-4. Double positive (PD-1+CTLA-4+) CD8+ TIL had characteristics of more severe dysfunction than single positive (PD-1+ or CTLA-4+) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T cell function (abstract).
Duraiswamy teaches that it is well established that tumors employ PD-1 and CTLA-4 inhibitory pathways to silence the immune system. Both pathways are critical for physiological homeostasis. While PD-1 is broadly expressed on activated T cells and other hematopoietic cells, CTLA-4 is expressed on activated T cells including regulatory T cells. Despite similarities as terminators of T-cell activation, the difference in regulatory roles of PD-1 and CTLA-4 pathways has been recognized. Tregs play critical roles in the control of anti-tumor immune responses and recent data has shown that blocking PD-1 and CTLA-4 can modulate Treg functions and enhance anti-tumor responses (page 2, paragraph 2). Duraiswamy provides evidence that reversal of T cell dysfunction can be achieved by simultaneously targeting effector T cells and Tregs. First, it is shown that CTLA-4 is preferentially expressed by PD-1+CD8+ T cells, and co-expression of both PD-1 and CTLA-4 is associated with marked dysfunction of antigen-specific T cells. Second, it is shown that blockade of PD-1 and CTLA-4 pathways reversed T cell dysfunction. Third, it is shown that adoptive transfer of CD8+CTLA-4+PD-1+ TILs that had been pre-treated in vitro with aPD-1 and aCTLA-4 antibodies eliminated tumors in vitro. Fourth, blockade of PD-1/PD-L1 pathway in Tregs attenuates their suppressive function (page 2, paragraph 4).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by WO’636 by adding anti-PD-1 and anti-CTLA-4 antibody to the culture of TILs prior to the first expansion as taught by Friese and further motivated by Duraiswamy. An ordinarily skilled artisan would have been motivated to add the anti-PD-1 and anti-CTLA-4 antibody to the culture of TILs prior to the first expansion because Friese teaches that adding the checkpoint blocking anti-CTLA-4 antibody in the initial phase of TIL culture results in more potent anti-tumor TILs in comparison to standard TIL cultures. An ordinarily skilled artisan would have been motivated to add both anti-PD-1 and anti-CTLA-4 as Duraiswamy teaches that blockade of both PD-1 and CTLA-4 in TIL cultures resulted in reversal of CD8+ TIL dysfunction, led to tumor rejection in two thirds of mice, and was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs and upregulation of key signaling molecules critical for T cell function. An ordinarily skilled artisan would have had a reasonable expectation of success as all of WO’636, Friese, and Duraiswamy studied the culturing and expansion of TIL and all three provide teachings concerning anti-PD-1 and anti-CTLA-4 antibodies in TIL culture. Additionally, WO’636 demonstrates that PD-1 blockade in vivo prior to TIL expansion from resected tumors improved the effects of agonist anti-4-1BB antibody in enhancing the anti-tumor reactivity of expanded TIL, which supports treating the TIL with checkpoint blockade prior to anti-4-1BB antibody.
Regarding claim 23, Duraiswamy further teaches that studies were performed in which CD8+CTLA-4+PD-1+ TILs from CT26 tumors were sorted and cultured in the presence of an a-PD-1 and a-CTLA-4 blocking antibodies for 7 days. It was found that in vitro treated cells showed profound increase in IFN-γ cytokine production and Ki-67 expression. These in vitro treated cells were adoptively transferred into CT26 tumor bearing mice and resulted in tumor regression in 75% of mice. In addition, the adoptively transferred TILs were still functional in the regressing tumors a week after treatment (page 5, paragraph 4).
Based on the teachings of Duraiswamy, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the culturing of the TIL with the antibodies up to 7 days before the first expansion. It would have been obvious to culture the with the antibodies up to 7 days before as Duraiswamy demonstrates that a 7 day culture with the antibodies is sufficient to alter cytokine production and increase the effectiveness of the TILs.
Additionally, it would have been obvious to use the teachings of Friese and Duraiswamy and optimization that was routine in the art to determine the optimal amount of time between culturing with the antibody and the first expansion. MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, Friese teaches benefits of culturing TILs with checkpoint blocking antibodies prior to expansion and Duraiswamy demonstrates that culturing TILs with aPD-1 and aCTLA-4 antibodies for 7 days provides effective changes to TILs. It would have been obvious to use these teachings as a starting point for routine optimization to determine the optimal amount of time between the antibody culturing step and the first expansion.
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.
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Claims 1 and 18-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 21-30, and 32-35 of copending Application No. 17/756,814 in view of WO 2015/157636 A1 (Sarnaik, A. A., et al) 15 Oct 2015 in view of Friese, C., et al (2020) CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer Scientific Reports 10(3914); 1-12 and supplemental materials (17 pages) and Duraiswamy, J., et al (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T cell rejection function in tumors Cancer Res 73(12); 3591-3603 and supplemental materials (11 pages).
App’814 claims a method for expanding TIL into a therapeutic population of TILs comprising culturing TILs obtained from a tumor resected from a mammal in cell culture medium comprising IL-2 and three or more tumor microenvironment (TME) stimulators to produce an expanded population of TILs, wherein the three or more TME stimulators are selected from the group consisting of pembrolizumab (a-PD1), ipilimumab (a-CTLA-4), urelumab, and/or utomilumab (both 4-1BB agonists), wherein the three or more TME stimulators are added to the cull culture medium simultaneously or between 1, 2, 3, 4, 5, 6, or 7 days apart; and supplementing the cell culture medium of the expanded population of TILs with additional IL-2, an OKT3 antibody, and antigen presenting cells (APCs) to produce a therapeutic population of cells. App’814 further claims a method of administering the therapeutic population of TILs to the mammal after a nonmyeloablative lymphodepletion chemotherapy is administered. App’814 further claims that the mammal has breast cancer, renal cell cancer, bladder cancer, melanoma, cervical cancer, gastric cancer, colorectal cancer, lung cancer, head and neck cancer, ovarian cancer, Hodgkin lymphoma, pancreatic cancer, liver cancer, or a sarcoma. App’814 claims that the second expanded population of cells produces 1x107 to 1x1012 cells. App’814 claims that the APCs are allogeneic feeder cells, PBMCs, or aAPCs and a step of processing the resected tumor fragments into multiple tumor fragments.
The claims of App’814 differ from the instantly claimed invention in the timing of the TME culture addition. Specifically, the instant claims require culturing the TIL with IL-2 and PD-1 and/or CTLA-4 followed by a first expansion with IL-2 and a substance that acts through the 4-1BB receptor. This modification, however, would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
The teachings of WO’636, Friese, and Duraiswamy are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the claims of App’814 with the methods disclosed by WO’636, in which a 4-1BB agonist is added to TIL during the first expansion, and adding anti-PD-1 and anti-CTLA-4 antibody to the culture of TILs prior to the first expansion as taught by Friese and further motivated by Duraiswamy. It would have been obvious to add the 4-1BB agonist to the first expansion as WO’636 demonstrates that addition of a 4-1BB agonist and IL-2 to the first expansion expands TIL with enriched tumor-reactivity and specificity. An ordinarily skilled artisan would have been motivated to add the anti-PD-1 and anti-CTLA-4 antibody to the culture of TILs prior to the first expansion because Friese teaches that adding a checkpoint blocking antibody, such as anti-CTLA-4 antibody, in the initial phase of TIL culture results in more potent anti-tumor TILs in comparison to standard TIL cultures. An ordinarily skilled artisan would have been motivated to add both anti-PD-1 and anti-CTLA-4 as Duraiswamy teaches that blockade of both PD-1 and CTLA-4 in TIL cultures resulted in reversal of CD8+ TIL dysfunction, led to tumor rejection in two thirds of mice, and was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs and upregulation of key signaling molecules critical for T cell function. An ordinarily skilled artisan would have had a reasonable expectation of success as all of App’814, WO’636, Friese, and Duraiswamy studied the culturing and expansion of TIL and all three provide teachings concerning anti-PD-1 and anti-CTLA-4 antibodies.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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