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 .
Claim Status
Claims 86-103 are pending and under examination in the instant office action.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/127,050, 63/146,424, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 87 and 88-90 do not find support in the parent application because the claims are directed to 1) subtypes of mesothelioma such as peritoneal mesothelioma (all except pleural mesothelioma) and 2) wherein the subject has undergone a previous treatment for mesothelioma, which are not supported in the specification or the claims of the parent applications. Accordingly, claims 87 and 88-90 are given benefit to 63/248,944 filed 9/27/2021, where they are first supported.
If the Applicant disagrees with the determination of the examiner, Applicant is requested to provide the page and paragraph numbers where claims 87 and 88-90 find support in the earlier filed Applications.
Information Disclosure Statement
Applicants are kindly reminded of their duty to disclose pursuant to 37 C.F.R. 1.56 which encompasses the citation of references material to patentability of which Applicants are aware, such as references that may have been cited in the International Search Report of the parent applicant or in the specification, or Applicant’s own related issued U.S. Patents such as those cited in the NSDP rejections below.
Drawings
The drawings are objected to because Figs. 10, 11, 21, 26A-B, and 31 contain text that is too small with unclear lines such that the details are unreadable. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms Yervoy and Kymriah [0007] and Proleukin and CellGro GMP [00390], which are trade names or marks used in commerce, have been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See [00988], [001139].
Claim Interpretation
The examiner notes that in any claims that recite an optional limitation (claims 95, 101, and 103) any limitations recited after “optionally” or “further optionally” are interpreted as strictly optional and non-limiting of the claim.
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 86-103 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 86 is indefinite for the recitation of “culturing the first population of TILs for about 3-11 to obtain a second population of TILs” (emphasis is the examiner’s). The recitation of “about 3-11” is indefinite because there is no unit for the 3-11, so an artisan could not determine what the active step entails. For the purposes of expedited prosecution, the claims will be interpreted to read “about 3-11 days”.
Claim 86 is indefinite for the recitation of ““culturing the first population of TILs for about 3-11 to obtain a second population of TILs” and “culturing a second population of TILs for about 7-11 days”. The instant specification defines about as: “The terms "about" and "approximately" mean within a statistically meaningful range of a value. Such a range can be within an order of magnitude, preferably within 50% […]” [00419]. However, the term “statistically meaningful” does not have a definition in the specification and does not have a consistent definition in the art that could be used to assess what a statistically meaningful change would be. In addition, the specification does not give enough specific examples that an artisan would be able to determine what a statistically meaningful change in the length of time would be. For the purposes of expedited prosecution, the examiner will consider “about” to refer to an order of magnitude as suggested by the specification, and therefore “about 3-11” is interpreted as 0-22 days and “about 7-11” is interpreted as 0-22 days.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim 97 is indefinite for the recitation of “i. less than two years, from two years old to less than 21 years old” because it is unclear whether these are two separate limitations or whether both are required to meet i). Further, it is indefinite that a subject could be less than two and from two years old to less than 21 years old unless “less than two years” does not refer to age. Thus, the metes and bounds of the claim could not be determine by a person of ordinary skill in the art.
Claim 101 is indefinite for the recitation of “aldesleukin, or a biosimilar or variant thereof”. The claim is unclear because the metes and bounds of the biosimilar or variants thereof cannot be determined. The specification does not contain a definition of a “biosimilar or variant thereof” and it is unclear what the scope of variants of aldesleukin would include. Although the specification recites and incorporates numerous examples, these are non-limiting embodiments and it is unclear what would be included in the metes and bounds of biosimilars and variants thereof. The specification states, for example, that some embodiments include substitutions at positions K35, T37, R38, T41, F42, K43, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Yl07, wherein the numbering of the amino acid residues corresponds to SEQ ID NO: 5. In some embodiments, the amino acid position is selected from T37, R38, T41, F42, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Y107 [00391]. The specification also discloses embodiments comprising non-natural amino acids. An artisan would not be reasonably apprised of which sequences or what level of sequence identity would be required to be considered a variant of aldesleukin.
Claim 103 is indefinite for the recitation of “wherein the cancer is a cancer with a V600 mutation”. This is indefinite because the claim does not recite which protein the V600 mutation is found in, and therefore could refer to a V600 mutation in any protein. For the purposes of expedited prosecution, the claim will be interpreted as referring to a V600 mutation in BRAF.
Claim 103 is indefinite for the recitation of “a V600M4 mutation”. This term is not defined in the specification and although BRAF V600M4 are mentioned in the art, there was no definition found to define the metes and bounds of what mutations would be considered V600M4 mutations.
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.
Claims 86, 91-93, and 99-102 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312.
Fardis teaches a method of treating a melanoma refractory to other therapies using tumor infiltrating lymphocytes (Abstract). The method comprises obtaining a first population of TILs from a tumor resected from the patient by processing a tumor sample obtained by the patient into multiple fragments [0036]; performing a first expansion by culturing the first population of TILs in a cell culture medium for about 3-14 days [0036] and in particular for about 11 days ([0061], [0393], [0412], [0423-0424], [0426]) to obtain a second population of TILs; performing a second expansion for about 7-14 days [0036] and in particular for about 11 days ([0393], [0430], [0439], [0451]) to obtain a third population of TILs; and administering a therapeutically effective amount of the third population of TILs to the subject ([0036], [0078], [0638], [0651]). Fardis teaches a preferred embodiment wherein the cancer is metastatic double-refractory uveal melanoma [0351].
Regarding claims 91-92 Fardis teaches wherein the subject is also administered a therapy in combination with the therapy wherein the therapy is an immune checkpoint regulator including particular anti-PD-1 antibodies [0380].
Regarding claim 93, as evidenced by Chattopadhyay et. al., uveal melanoma is a collective term for choroid, ciliary body, or iris melanoma (Abstract) and therefore the uveal melanoma as taught by Fardis is inherently one of choroidal melanoma, ciliary body melanoma, or iris melanoma.
Regarding claims 99 and 100, Fardis teaches the method further comprising treating the patient with a non-myeloablative lymphodepletion regimen prior to administering the TILs to the patient [0068] wherein the lymphodepletion regimen comprises administering a cyclophosphamide at a dose of 60mg/m2 for two days followed by administration fludarabine at a dose of 25 60mg/m2 for five days [0069].
Regarding claim 101, Fardis teaches the method further comprising the step of treating the patient with an IL-2 regimen starting on the day after administration of the TILs to the patient [0070].
Regarding claim 102, Fardis teaches digesting the tumor fragments in enzymatic media, mechanically dissociating the tumor, and removing dead or red blood cells using density gradient separation (reads on purifying) [0400].
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.
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.
Claim 103 is rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190231820 to Fardis published 1 August 2019.
The teachings of Fardis in regards to claim 86 are in the 102 rejection above.
Regarding claim 103, Fardis teaches that patients with a BRAF mutation responded as well to TIL therapy as patients with wild-type BRAF [0168], Fig. 37. Fardis teaches that patients may or may not have mutations in the BRAF gene [0379], [0837] and that patients that are BRAF mutation-positive are treated after BRAF targeted therapy [0840]. Fardis teaches that patient who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor were excluded [0850].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of treating uveal melanoma comprising culturing and administering TILs as taught by Fardis as described in the 102 rejection above to patients with a BRAF V600 mutation as taught by Fardis in order to benefit from the response to TIL therapy in patients with mutated BRAF as taught by Fardis. This would have a reasonable expectation of success because Fardis teaches that some of the cancers that have mutations in BRAF are BRAF V600 mutation positive and that the TIL therapy was effective for BRAF mutation positive cancers.
Claims 87-90 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190231820 to Fardis published 1 August 2019 as applied to claim 86 above, and further in view of Anraku M, et. al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008 Apr;135(4):823-9. doi: 10.1016/j.jtcvs.2007.10.026. PMID: 18374762.
The teachings of Fardis in regards to claim 86 are in the 102 rejection above.
Regarding claims 87-90, Fardis teaches that “treatment of bulky, refractory cancers using adoptive autologous transfer of tumor infiltrating lymphocytes (TILs) represents a powerful approach to therapy for patients with poor prognoses” [0008]. Fardis teaches that the manufacturing process for TILs as described “indicates a surprising improvement in clinical efficacy of the TILs, as measured by DCR, ORR, and other clinical responses, with a similar time to response and safety profile compared to TILs manufactured using the Gen 1 process” [1208].
Fardis does not teach the method wherein the subject has mesothelioma, and wherein the mesothelioma is selected from a group including pleural mesothelioma.
This deficiency is resolved by Anraku et. al.
Anraku et. al. teaches that in patients with malignant pleural mesothelioma, the presence of CD8+ tumor-infiltrating lymphocytes was predictive of survival (Figure 4, p. 826 left column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining and expanding TILs as taught by Fardis using subjects that have malignant pleural mesothelioma of Anraku et. al. substituted for the malignant melanoma patients of Fardis in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs from the pleural mesothelioma patients would increase the number of TILs in the pleural mesothelioma patients and therefore improve survival as taught by Anraku et. al.
Regarding claims 88-90, Anraku et. al. teaches “Multimodality therapy with chemotherapy, surgery, and hemithoracic postoperative irradiation have demonstrated some benefit in survival for highly selected patients,2-4 but the majority of cases are noncurative. Therefore, some emerging modalities, such as immunotherapy5, intracavitary chemotherapy6,7, and photodynamic therapy8 have been tested to offer hope for improvement in both palliation and survival” (p. 823 ¶1). Anraku teaches that immune-based therapies have shown impact on tumor regression when combined with chemotherapy (p. 823 ¶2). Anraku further teaches that they observed a significant correlation between cisplatin/pemtrexed chemotherapy and high levels of CD8+ TILs and that cisplatin/pemtrexed is the only drug combination shown to have a significant impact on survival in a randomized clinical trial for MPM (p. 825 right column ¶ 3; p. 826 right column ¶2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the patients that had previous undergone treatment with cisplatin as taught by Anraku et. al. with the method of treating malignant melanoma by expanding and administering TILs as taught by Fardis in order to benefit from the increased immune response to the tumor cause by cisplatin/pemtrexed treatment as taught by Anraku et. al. This would have a reasonable expectation of success because an artisan would expect that a TIL therapy would be improved by using patients that have been previously treated with a therapy that increases tumor-reactive lymphocytes in the tumor. Additionally, Fardis et. al. teaches that cisplatin/pemtrexed in the only therapy that has been shown to extend survival; and therefore, it would have been obvious for a person of ordinary skill in the art to treat the patients with a standard chemotherapy regimen to ascertain any benefit prior to starting them on an experimental immunotherapy regimen.
Claims 94-95 and 97-98 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190231820 to Fardis published 1 August 2019 as applied to claim 86 above, and further in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701.
The teachings of Fardis in regards to claim 86 are in the 102 rejection above.
Regarding claims 94-95 and 97-98, Fardis teaches that “treatment of bulky, refractory cancers using adoptive autologous transfer of tumor infiltrating lymphocytes (TILs) represents a powerful approach to therapy for patients with poor prognoses” [0008]. Fardis teaches that the manufacturing process for TILs as described “indicates a surprising improvement in clinical efficacy of the TILs, as measured by DCR, ORR, and other clinical responses, with a similar time to response and safety profile compared to TILs manufactured using the Gen 1 process” [1208].
Fardis does not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a neuroblastoma, a sarcoma, or a central nervous system associated cancer.
This deficiency is resolved by Chowdhury et. al.
Chowdhury et. al. teaches that 115 pediatric tumors were assessed for the presence of CD8+ tumor-infiltrating lymphocytes (Abstract). Chowdhury teaches that the cancers assessed were Wing’s sarcoma, alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, osteosarcoma, and neuroblastoma (Table 1 p. 3). Chowdhury et. al. teaches that high CD8+ TIL in the tumor were associated with increased survival (Fig. 3B-D) and in particular CD8+ PD-1+ TIL (Fig. 3G); also see p. 2 right column. Chowdhury et. al. teaches that the age range at diagnosis was 1.4-16.5 for Ewing’s sarcoma; 1.3-16.2 for Alveolar rhabdomyosarcoma; 1.2-12.8 for embryonal rhabdomyosarcoma; 0.8-16.6 for osteosarcoma; and 0.1-16.9 for Neuroblastoma (Table 1 p. 3; reads on subject less than two or from 12 years old to less than 21 years old). Chowdhury et. al. teaches that all samples were taken at diagnosis (pre-therapy) (p. 6 right column ¶3 “Methods: Cases” section); therefore, the subjects read on claim 98 parts ii, iv, v, viii, xi, xiv because the patients have not undergone any treatment. Chowdhury et. al. teaches that the treatment burden and long-term deleterious effects from typically intensive multi-modal therapies in childhood cancers is high; and that additionally a number of tumor types such as high-risk neuroblastoma remain challenging to treat and still carry a poor prognosis with high treatment related mortality. Chowdhury et. al. teaches that immunotherapy is an attractive option that is potentially is more specific and less toxic (p. 1 left column “Introduction”).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining and expanding TILs as taught by Fardis using subjects that have pediatric cancers neuroblastoma or a sarcoma (reads on claims 86 and 94); wherein the pediatric cancer is osteosarcoma or Ewing sarcoma (reads on claim 95) as taught by Chowdhury substituted for the malignant melanoma patients of Fardis in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by Fardis from the pediatric neuroblastoma or Ewing sarcoma patients would increase the number of TILs in the pediatric cancer patients and therefore improve survival as taught by Chowdhury et. al.
Regarding claim 98, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the treatment naïve subject of Chowdhury et. al. without prior dinutuximab treatment for neuroblastoma, or dactinomycin treatment for Ewing sarcoma or rhabdomyosarcoma, or vincristine sulfate treatment for rhabdomyosarcoma in order to benefit from a potentially less toxic treatment for pediatric cancer as taught by Chowdhury et. al. with improved TILs as taught by Fardis. This would have a reasonable expectation of success because an artisan would expect the number of CD8+ PD-1+ TILs that would be expanded to correlate with those found in the tumor samples of Chowdhury et. al. if there is no intervening chemotherapy and therefore would expect them to be present with anti-tumor potential that can be improved by the expansion and adoptive transfer method of Fardis.
Claim 96 is rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20190231820 to Fardis published 1 August 2019 in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701 as applied to claims 86 and 94 above, and further in view of Grabovska Y, et. al. Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nat Commun. 2020 Aug 28;11(1):4324. doi: 10.1038/s41467-020-18070-y. PMID: 32859926; PMCID: PMC7455736.
The teachings of Fardis and Chowdhury in regards to claim 86 are in the 102 and 103 rejections above.
Fardis in view of Chowdhury does not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a central nervous system (CNS) cancer selected from the group of medulloblastoma, pineoblastoma, glioma, ependymoma, or glioblastoma.
This deficiency is resolved by Grabovska et. al.
Grabovska et. al. teaches profiling of the tumor immune microenvironment of pediatric CNS tumors of multiple subtypes including medulloblastomas and pediatric high grade gliomas (Abstract). Grabovska et. al. teaches “Post hoc testing (Dunn’s test) reveals the relative number of TILs and indeed the total amount of infiltrating cells was significantly less in high-grade tumor types such as embryonal tumors (i.e., MB, ATRT, and Embryonal tumours with multilayered rosettes) than in low-grade gliomas (LGGs) (p < 0.001)” (p. 4 left column ¶3). Grabovska et. al. teaches that the average infiltration eosinophils, CD4T, B-cell, Treg, NK, monocytes, and TILs decreased proportionally with increasing WHO Grade (p. 4 right column ¶1, Fig. 2c). Grabovska et. al. teach that medulloblastomas (MBs) had different immune signatures and different lymphocyte populations which correlated with survival (p. 6 left column, Fig. 3). Grabovska et. al. teaches that the tumor immune microenvironment is also associated with prognosis in pediatric high grade glioma (pHGG). Grabovska et. al. teaches that lower than median concentrations of B-cell and CD8T cells in a particular subgroup (WT-A) are associated with poor overall survival. Grabovska et. al. further teaches “It should be noted that prognostic associations with immune cell infiltration appear to be context dependent; increased CD8T infiltration, for instance, does not universally denote a poor outcome. The most directly comparable experience in pHGG was the HERBY Phase II Trial39. High CD8+ infiltration was significantly associated with increased survival in 34 cases (of various subtypes) who received Temezolomide/radiotherapy and Bevacizumab for which our results in pHGG WT-A are in accordance”(p. 11 left column ¶2). Grabovska et. al. teach “it seems to follow that an a priori paucity of infiltrating cytotoxic T-lymphocytes and the lack of a supportive TIME may be unconducive to immune checkpoint blockade as a therapeutic strategy, but instead may be amenable to approaches that alter the TIME or genetically redirect T-cell immunity” (p. 11 right column ¶3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding and administering TILs as taught by Fardis in view of Chowdhury using subjects that have pediatric cancers medulloblastoma or glioma as taught by Grabovska in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where administering expanded TILs may alter the tumor microenvironment or provide additional redirected T-cell immunity as taught by Grabovska. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by Fardis from medulloblastoma or glioma patients would increase the number of tumor-targeting TILs in the pediatric cancer patients and therefore an artisan would be able to modulate the tumor-immune microenvironment to improve survival as taught by Grabovska et. al.
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.
U.S. Patent No. 10130659
Claims 86, 91-93, and 99-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 9, 10, 16, 24 and 25 of U.S. Patent No. 10130659 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312.
Claim 1 and 16 teach a method of treating a subject with head and neck cancer and cervical cancer, respectively, the method comprising administering expanded TILs comprising obtaining a first population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments; performing a first expansion by culturing the TILs to produce a second population of TILs wherein the first expansion is performed for about 3-11 days; performing a second expansion to produce a third population of TILs for about 7-11 days; and administering a therapeutically effective dosage of the third population of TILs to the subject.
Claims 9 and 24 recite the method wherein there is a non-myeloablative lymphodepletion comprising administration of cyclophosphamide at a dose of 60 mg/m2/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days.
Claims 10 and 25 teach the method further comprising high dose IL-2 starting on the day after administering the T cells.
The difference between the claims of ‘659 and the instant claims is that the claims of ‘659 do not teach the cancer is uveal melanoma.
This deficiency is resolved by Fardis.
Fardis teaches a method of treating a melanoma refractory to other therapies using tumor infiltrating lymphocytes (Abstract). The method comprises obtaining a first population of TILs from a tumor resected from the patient by processing a tumor sample obtained by the patient into multiple fragments [0036]; performing a first expansion by culturing the first population of TILs in a cell culture medium for about 3-14 days [0036] and in particular for about 11 days ([0061], [0393], [0412], [0423-0424], [0426]) to obtain a second population of TILs; performing a second expansion for about 7-14 days [0036] and in particular for about 11 days ([0393], [0430], [0439], [0451]) to obtain a third population of TILs; and administering a therapeutically effective amount of the third population of TILs to the subject ([0036], [0078], [0638], [0651]). Fardis teaches a preferred embodiment wherein the cancer is metastatic double-refractory uveal melanoma [0351].
Regarding claims 91-92 Fardis teaches wherein the subject is also administered a therapy in combination with the therapy wherein the therapy is an immune checkpoint regulator including particular anti-PD-1 antibodies [0380].
Regarding claim 93, as evidenced by Chattopadhyay et. al., uveal melanoma is a collective term for choroid, ciliary body, or iris melanoma (Abstract) and therefore the uveal melanoma as taught by Fardis is inherently one of choroidal melanoma, ciliary body melanoma, or iris melanoma.
Regarding claim 102, Fardis teaches digesting the tumor fragments in enzymatic media, mechanically dissociating the tumor, and removing dead or red blood cells using density gradient separation (reads on purifying) [0400].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to combine the method of treating the uveal melanoma patients of Fardis comprising obtaining, expanding, and administering TILs and the method of obtaining, expanding, and administering TILs of ‘659 in order to benefit from a method of treating cancer by adoptive cell therapy on a new patient population. This would have a predictable effect because Fardis teaches a method of treating uveal melanoma using TILs, and therefore an artisan would expect a similar expansion and administration protocol for treating cancer of ‘659 to be similarly effective in uveal melanoma.
Regarding claim 103, Fardis teaches that patients with a BRAF mutation responded as well to TIL therapy as patients with wild-type BRAF [0168], Fig. 37. Fardis teaches that patients may or may not have mutations in the BRAF gene [0379], [0837] and that patients that are BRAF mutation-positive are treated after BRAF targeted therapy [0840]. Fardis teaches that patient who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor were excluded [0850].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of treating uveal melanoma comprising culturing and administering TILs as taught by ‘659 claims above to patients with a BRAF V600 mutation as taught by Fardis in order to benefit from the response to TIL therapy in patients with mutated BRAF as taught by Fardis. This would have a reasonable expectation of success because Fardis teaches that some of the cancers that have mutations in BRAF are BRAF V600 mutation positive and that the TIL therapy was effective for BRAF mutation positive cancers.
Claims 87-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 10, 16, 24 and 25 of U.S. Patent No. 10130659 in view of Anraku M, et. al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008 Apr;135(4):823-9. doi: 10.1016/j.jtcvs.2007.10.026. PMID: 18374762.
The teachings of claims 1, 9, 10, 16, 24 and 25 of U.S. Patent No. 10130659 are in the NSDP rejection above and are incorporated by reference herein.
The claims of ‘659 do not teach the method wherein the subject has mesothelioma, and wherein the mesothelioma is selected from a group including pleural mesothelioma.
This deficiency is resolved by Anraku et. al.
Anraku et. al. teaches that in patients with malignant pleural mesothelioma, the presence of CD8+ tumor-infiltrating lymphocytes was predictive of survival (Figure 4, p. 826 left column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining and expanding TILs as taught by ‘659 using subjects that have malignant pleural mesothelioma of Anraku et. al. substituted for the subjects with head and neck cancer or cervical cancer of ‘659 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs from the pleural mesothelioma patients would increase the number of TILs in the pleural mesothelioma patients and therefore improve survival as taught by Anraku et. al.
Regarding claims 88-90, Anraku et. al. teaches “Multimodality therapy with chemotherapy, surgery, and hemithoracic postoperative irradiation have demonstrated some benefit in survival for highly selected patients,2-4 but the majority of cases are noncurative. Therefore, some emerging modalities, such as immunotherapy5, intracavitary chemotherapy6,7, and photodynamic therapy8 have been tested to offer hope for improvement in both palliation and survival” (p. 823 ¶1). Anraku teaches that immune-based therapies have shown impact on tumor regression when combined with chemotherapy (p. 823 ¶2). Anraku further teaches that they observed a significant correlation between cisplatin/pemtrexed chemotherapy and high levels of CD8+ TILs and that cisplatin/pemtrexed is the only drug combination shown to have a significant impact on survival in a randomized clinical trial for MPM (p. 825 right column ¶ 3; p. 826 right column ¶2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the patients that had previous undergone treatment with cisplatin as taught by Anraku et. al. with the method of treating malignant melanoma by expanding and administering TILs as taught by ‘659 in order to benefit from the increased immune response to the tumor cause by cisplatin/pemtrexed treatment as taught by Anraku et. al. This would have a reasonable expectation of success because an artisan would expect that a TIL therapy would be improved by using patients that have been previously treated with a therapy that increases tumor-reactive lymphocytes in the tumor. Additionally, Anraku et. al. teaches that cisplatin/pemtrexed in the only therapy that has been shown to extend survival; and therefore, it would have been obvious for a person of ordinary skill in the art to treat the patients with a standard chemotherapy regimen to ascertain any benefit prior to starting them on an experimental immunotherapy regimen.
Claims 94-95 and 97-98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 10, 16, 24 and 25 of U.S. Patent No. 10130659 in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701.
The teachings of claims 1, 9, 10, 16, 24 and 25 of U.S. Patent No. 10130659 are in the NSDP rejection above and are incorporated by reference herein.
The claims of ‘659 do not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a neuroblastoma, a sarcoma, or a central nervous system associated cancer.
This deficiency is resolved by Chowdhury et. al.
Chowdhury et. al. teaches that 115 pediatric tumors were assessed for the presence of CD8+ tumor-infiltrating lymphocytes (Abstract). Chowdhury teaches that the cancers assessed were Wing’s sarcoma, alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, osteosarcoma, and neuroblastoma (Table 1 p. 3). Chowdhury et. al. teaches that high CD8+ TIL in the tumor were associated with increased survival (Fig. 3B-D) and in particular CD8+ PD-1+ TIL (Fig. 3G); also see p. 2 right column. Chowdhury et. al. teaches that the age range at diagnosis was 1.4-16.5 for Ewing’s sarcoma; 1.3-16.2 for Alveolar rhabdomyosarcoma; 1.2-12.8 for embryonal rhabdomyosarcoma; 0.8-16.6 for osteosarcoma; and 0.1-16.9 for Neuroblastoma (Table 1 p. 3; reads on subject less than two or from 12 years old to less than 21 years old). Chowdhury et. al. teaches that all samples were taken at diagnosis (pre-therapy) (p. 6 right column ¶3 “Methods: Cases” section); therefore, the subjects read on claim 98 parts ii, iv, v, viii, xi, xiv because the patients have not undergone any treatment. Chowdhury et. al. teaches that the treatment burden and long-term deleterious effects from typically intensive multi-modal therapies in childhood cancers is high; and that additionally a number of tumor types such as high-risk neuroblastoma remain challenging to treat and still carry a poor prognosis with high treatment related mortality. Chowdhury et. al. teaches that immunotherapy is an attractive option that is potentially is more specific and less toxic (p. 1 left column “Introduction”).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding, and administering TILs as taught by ‘659 using subjects that have pediatric cancers neuroblastoma or a sarcoma (reads on claims 86 and 94); wherein the pediatric cancer is osteosarcoma or Ewing sarcoma (reads on claim 95) as taught by Chowdhury substituted for the head and neck or cervical cancer patients of ‘659 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by ‘659 from the pediatric neuroblastoma or Ewing sarcoma patients would increase the number of TILs in the pediatric cancer patients and therefore improve survival as taught by Chowdhury et. al.
Regarding claim 98, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the treatment naïve subject of Chowdhury et. al. without prior dinutuximab treatment for neuroblastoma, or dactinomycin treatment for Ewing sarcoma or rhabdomyosarcoma, or vincristine sulfate treatment for rhabdomyosarcoma in order to benefit from a potentially less toxic treatment for pediatric cancer as taught by Chowdhury et. al. with improved TILs as taught by ‘659. This would have a reasonable expectation of success because an artisan would expect the number of CD8+ PD-1+ TILs that would be expanded to correlate with those found in the tumor samples of Chowdhury et. al. if there is no intervening chemotherapy and therefore would expect them to be present with anti-tumor potential that can be improved by the expansion and adoptive transfer method of Fardis.
Claims 96 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 10, 16, 24 and 25 of U.S. Patent No. 10130659 in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701 as applied to claims 86 and 94 above, and further in view of Grabovska Y, et. al. Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nat Commun. 2020 Aug 28;11(1):4324. doi: 10.1038/s41467-020-18070-y. PMID: 32859926; PMCID: PMC7455736
The teachings of ‘659 and Chowdhury regarding claims 86 and 94 are in the NSDP rejections above and are incorporated by reference herein.
‘659 claims in view of Chowdhury does not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a central nervous system (CNS) cancer selected from the group of medulloblastoma, pineoblastoma, glioma, ependymoma, or glioblastoma.
This deficiency is resolved by Grabovska et. al.
Grabovska et. al. teaches profiling of the tumor immune microenvironment of pediatric CNS tumors of multiple subtypes including medulloblastomas and pediatric high grade gliomas (Abstract). Grabovska et. al. teaches “Post hoc testing (Dunn’s test) reveals the relative number of TILs and indeed the total amount of infiltrating cells was significantly less in high-grade tumor types such as embryonal tumors (i.e., MB, ATRT, and Embryonal tumours with multilayered rosettes) than in low-grade gliomas (LGGs) (p < 0.001)” (p. 4 left column ¶3). Grabovska et. al. teaches that the average infiltration eosinophils, CD4T, B-cell, Treg, NK, monocytes, and TILs decreased proportionally with increasing WHO Grade (p. 4 right column ¶1, Fig. 2c). Grabovska et. al. teach that medulloblastomas (MBs) had different immune signatures and different lymphocyte populations which correlated with survival (p. 6 left column, Fig. 3). Grabovska et. al. teaches that the tumor immune microenvironment is also associated with prognosis in pediatric high grade glioma (pHGG). Grabovska et. al. teaches that lower than median concentrations of B-cell and CD8T cells in a particular subgroup (WT-A) are associated with poor overall survival. Grabovska et. al. further teaches “It should be noted that prognostic associations with immune cell infiltration appear to be context dependent; increased CD8T infiltration, for instance, does not universally denote a poor outcome. The most directly comparable experience in pHGG was the HERBY Phase II Trial39. High CD8+ infiltration was significantly associated with increased survival in 34 cases (of various subtypes) who received Temezolomide/radiotherapy and Bevacizumab for which our results in pHGG WT-A are in accordance”(p. 11 left column ¶2). Grabovska et. al. teach “it seems to follow that an a priori paucity of infiltrating cytotoxic T-lymphocytes and the lack of a supportive TIME may be unconducive to immune checkpoint blockade as a therapeutic strategy, but instead may be amenable to approaches that alter the TIME or genetically redirect T-cell immunity” (p. 11 right column ¶3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding and administering TILs as taught by ‘659 in view of Chowdhury using subjects that have pediatric cancers medulloblastoma or glioma as taught by Grabovska in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where administering expanded TILs may alter the tumor microenvironment or provide additional redirected T-cell immunity as taught by Grabovska. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by ‘659 from medulloblastoma or glioma patients would increase the number of tumor-targeting TILs in the pediatric cancer patients and therefore an artisan would be able to modulate the tumor-immune microenvironment to improve survival as taught by Grabovska et. al.
U.S. Patent No. 10272113
Claims 86, 91-93, and 99-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10, and 14-15 of U.S. Patent No. 10272113 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312.
Claim 1 teaches a method for treating a subject with cancer, the method comprising administering expanded TILs and an anti-PD-1 antibody comprising obtaining a first population of TILs from a tumor resected from a subject by processing a tumor sample obtained from the subject into multiple tumor fragments; performing a first expansion by culturing the TILs to produce a second population of TILs wherein the first expansion is performed for about 3-11 days; performing a second expansion to produce a third population of TILs for about 7-11 days; and administering a therapeutically effective dosage of the third population of TILs to the subject.
Claims 8 and 9 recite the method wherein a non-myeloablative lymphodepletion has been administered comprising administration of cyclophosphamide at a dose of 60 mg/m2/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days.
Claims 10 teaches the method further comprising high dose IL-2 starting on the day after administering the TIL cells.
Claim 14 teaches wherein the cancer is melanoma, HNSCC, cervical cancer, or NSLC. Claim 15 teaches wherein the cancer is melanoma or metastatic melanoma.
The difference between the claims of ‘113 and the instant claims is that the claims of ‘113 do not teach the cancer is uveal melanoma.
This deficiency is resolved by Fardis.
Fardis teaches a method of treating a melanoma refractory to other therapies using tumor infiltrating lymphocytes (Abstract). The method comprises obtaining a first population of TILs from a tumor resected from the patient by processing a tumor sample obtained by the patient into multiple fragments [0036]; performing a first expansion by culturing the first population of TILs in a cell culture medium for about 3-14 days [0036] and in particular for about 11 days ([0061], [0393], [0412], [0423-0424], [0426]) to obtain a second population of TILs; performing a second expansion for about 7-14 days [0036] and in particular for about 11 days ([0393], [0430], [0439], [0451]) to obtain a third population of TILs; and administering a therapeutically effective amount of the third population of TILs to the subject ([0036], [0078], [0638], [0651]). Fardis teaches a preferred embodiment wherein the cancer is metastatic double-refractory uveal melanoma [0351].
Regarding claims 91-92 Fardis teaches wherein the subject is also administered a therapy in combination with the therapy wherein the therapy is an immune checkpoint regulator including particular anti-PD-1 antibodies [0380].
Regarding claim 93, as evidenced by Chattopadhyay et. al., uveal melanoma is a collective term for choroid, ciliary body, or iris melanoma (Abstract) and therefore the uveal melanoma as taught by Fardis is inherently one of choroidal melanoma, ciliary body melanoma, or iris melanoma.
Regarding claim 102, Fardis teaches digesting the tumor fragments in enzymatic media, mechanically dissociating the tumor, and removing dead or red blood cells using density gradient separation (reads on purifying) [0400].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to combine the method of treating the uveal melanoma patients of Fardis comprising obtaining, expanding, and administering TILs and the method of obtaining, expanding, and administering TILs of ‘113 in order to benefit from a method of treating cancer by adoptive cell therapy on a new patient population. This would have a predictable effect because Fardis teaches a method of treating uveal melanoma using TILs, and therefore an artisan would expect a similar expansion and administration protocol for treating cancer of ‘113 to be similarly effective in uveal melanoma.
Regarding claim 103, Fardis teaches that patients with a BRAF mutation responded as well to TIL therapy as patients with wild-type BRAF [0168], Fig. 37. Fardis teaches that patients may or may not have mutations in the BRAF gene [0379], [0837] and that patients that are BRAF mutation-positive are treated after BRAF targeted therapy [0840]. Fardis teaches that patient who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor were excluded [0850].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of treating uveal melanoma comprising culturing and administering TILs as taught by ‘113 claims above to patients with a BRAF V600 mutation as taught by Fardis in order to benefit from the response to TIL therapy in patients with mutated BRAF as taught by Fardis. This would have a reasonable expectation of success because Fardis teaches that some of the cancers that have mutations in BRAF are BRAF V600 mutation positive and that the TIL therapy was effective for BRAF mutation positive cancers.
Claims 87-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over 1, 8-10, and 14-15 of U.S. Patent No. 10272113 in view of Anraku M, et. al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008 Apr;135(4):823-9. doi: 10.1016/j.jtcvs.2007.10.026. PMID: 18374762.
The teachings of claims 1, 8-10, and 14-15 of U.S. Patent No. 10272113 are in the NSDP rejection above and are incorporated by reference herein.
The claims of ‘113 do not teach the method wherein the subject has mesothelioma, and wherein the mesothelioma is selected from a group including pleural mesothelioma.
This deficiency is resolved by Anraku et. al.
Anraku et. al. teaches that in patients with malignant pleural mesothelioma, the presence of CD8+ tumor-infiltrating lymphocytes was predictive of survival (Figure 4, p. 826 left column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining and expanding TILs as taught by ‘113 using subjects that have malignant pleural mesothelioma of Anraku et. al. substituted for the subjects with generic cancer or generic melanoma of ‘113 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs from the pleural mesothelioma patients would increase the number of TILs in the pleural mesothelioma patients and therefore improve survival as taught by Anraku et. al.
Regarding claims 88-90, Anraku et. al. teaches “Multimodality therapy with chemotherapy, surgery, and hemithoracic postoperative irradiation have demonstrated some benefit in survival for highly selected patients,2-4 but the majority of cases are noncurative. Therefore, some emerging modalities, such as immunotherapy5, intracavitary chemotherapy6,7, and photodynamic therapy8 have been tested to offer hope for improvement in both palliation and survival” (p. 823 ¶1). Anraku teaches that immune-based therapies have shown impact on tumor regression when combined with chemotherapy (p. 823 ¶2). Anraku further teaches that they observed a significant correlation between cisplatin/pemtrexed chemotherapy and high levels of CD8+ TILs and that cisplatin/pemtrexed is the only drug combination shown to have a significant impact on survival in a randomized clinical trial for MPM (p. 825 right column ¶ 3; p. 826 right column ¶2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the patients that had previous undergone treatment with cisplatin as taught by Anraku et. al. with the method of treating malignant melanoma by expanding and administering TILs as taught by ‘113 in order to benefit from the increased immune response to the tumor cause by cisplatin/pemtrexed treatment as taught by Anraku et. al. This would have a reasonable expectation of success because an artisan would expect that a TIL therapy would be improved by using patients that have been previously treated with a therapy that increases tumor-reactive lymphocytes in the tumor. Additionally, Anraku et. al. teaches that cisplatin/pemtrexed in the only therapy that has been shown to extend survival; and therefore, it would have been obvious for a person of ordinary skill in the art to treat the patients with a standard chemotherapy regimen to ascertain any benefit prior to starting them on an experimental immunotherapy regimen.
Claims 94-95 and 97-98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10, and 14-15 of U.S. Patent No. 10272113 in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701.
The teachings of claims 1, 8-10, and 14-15 of U.S. Patent No. 10272113 are in the NSDP rejection above and are incorporated by reference herein.
The claims of ‘659 do not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a neuroblastoma, a sarcoma, or a central nervous system associated cancer.
This deficiency is resolved by Chowdhury et. al.
Chowdhury et. al. teaches that 115 pediatric tumors were assessed for the presence of CD8+ tumor-infiltrating lymphocytes (Abstract). Chowdhury teaches that the cancers assessed were Wing’s sarcoma, alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, osteosarcoma, and neuroblastoma (Table 1 p. 3). Chowdhury et. al. teaches that high CD8+ TIL in the tumor were associated with increased survival (Fig. 3B-D) and in particular CD8+ PD-1+ TIL (Fig. 3G); also see p. 2 right column. Chowdhury et. al. teaches that the age range at diagnosis was 1.4-16.5 for Ewing’s sarcoma; 1.3-16.2 for Alveolar rhabdomyosarcoma; 1.2-12.8 for embryonal rhabdomyosarcoma; 0.8-16.6 for osteosarcoma; and 0.1-16.9 for Neuroblastoma (Table 1 p. 3; reads on subject less than two or from 12 years old to less than 21 years old). Chowdhury et. al. teaches that all samples were taken at diagnosis (pre-therapy) (p. 6 right column ¶3 “Methods: Cases” section); therefore, the subjects read on claim 98 parts ii, iv, v, viii, xi, xiv because the patients have not undergone any treatment. Chowdhury et. al. teaches that the treatment burden and long-term deleterious effects from typically intensive multi-modal therapies in childhood cancers is high; and that additionally a number of tumor types such as high-risk neuroblastoma remain challenging to treat and still carry a poor prognosis with high treatment related mortality. Chowdhury et. al. teaches that immunotherapy is an attractive option that is potentially is more specific and less toxic (p. 1 left column “Introduction”).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding, and administering TILs as taught by ‘113 using subjects that have pediatric cancers neuroblastoma or a sarcoma (reads on claims 86 and 94); wherein the pediatric cancer is osteosarcoma or Ewing sarcoma (reads on claim 95) as taught by Chowdhury substituted for the generic cancer patients of ‘113 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by ‘113 from the pediatric neuroblastoma or Ewing sarcoma patients would increase the number of TILs in the pediatric cancer patients and therefore improve survival as taught by Chowdhury et. al.
Regarding claim 98, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the treatment naïve subject of Chowdhury et. al. without prior dinutuximab treatment for neuroblastoma, or dactinomycin treatment for Ewing sarcoma or rhabdomyosarcoma, or vincristine sulfate treatment for rhabdomyosarcoma in order to benefit from a potentially less toxic treatment for pediatric cancer as taught by Chowdhury et. al. with improved TILs as taught by ‘113. This would have a reasonable expectation of success because an artisan would expect the number of CD8+ PD-1+ TILs that would be expanded to correlate with those found in the tumor samples of Chowdhury et. al. if there is no intervening chemotherapy and therefore would expect them to be present with anti-tumor potential that can be improved by the expansion and adoptive transfer method of Fardis.
Claims 96 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10, and 14-15 of U.S. Patent No. 10272113 in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701 as applied to claims 86 and 94 above, and further in view of Grabovska Y, et. al. Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nat Commun. 2020 Aug 28;11(1):4324. doi: 10.1038/s41467-020-18070-y. PMID: 32859926; PMCID: PMC7455736
The teachings of ‘113 and Chowdhury regarding claims 86 and 94 are in the NSDP rejections above and are incorporated by reference herein.
‘113 claims in view of Chowdhury does not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a central nervous system (CNS) cancer selected from the group of medulloblastoma, pineoblastoma, glioma, ependymoma, or glioblastoma.
This deficiency is resolved by Grabovska et. al.
Grabovska et. al. teaches profiling of the tumor immune microenvironment of pediatric CNS tumors of multiple subtypes including medulloblastomas and pediatric high grade gliomas (Abstract). Grabovska et. al. teaches “Post hoc testing (Dunn’s test) reveals the relative number of TILs and indeed the total amount of infiltrating cells was significantly less in high-grade tumor types such as embryonal tumors (i.e., MB, ATRT, and Embryonal tumours with multilayered rosettes) than in low-grade gliomas (LGGs) (p < 0.001)” (p. 4 left column ¶3). Grabovska et. al. teaches that the average infiltration eosinophils, CD4T, B-cell, Treg, NK, monocytes, and TILs decreased proportionally with increasing WHO Grade (p. 4 right column ¶1, Fig. 2c). Grabovska et. al. teach that medulloblastomas (MBs) had different immune signatures and different lymphocyte populations which correlated with survival (p. 6 left column, Fig. 3). Grabovska et. al. teaches that the tumor immune microenvironment is also associated with prognosis in pediatric high grade glioma (pHGG). Grabovska et. al. teaches that lower than median concentrations of B-cell and CD8T cells in a particular subgroup (WT-A) are associated with poor overall survival. Grabovska et. al. further teaches “It should be noted that prognostic associations with immune cell infiltration appear to be context dependent; increased CD8T infiltration, for instance, does not universally denote a poor outcome. The most directly comparable experience in pHGG was the HERBY Phase II Trial39. High CD8+ infiltration was significantly associated with increased survival in 34 cases (of various subtypes) who received Temezolomide/radiotherapy and Bevacizumab for which our results in pHGG WT-A are in accordance”(p. 11 left column ¶2). Grabovska et. al. teach “it seems to follow that an a priori paucity of infiltrating cytotoxic T-lymphocytes and the lack of a supportive TIME may be unconducive to immune checkpoint blockade as a therapeutic strategy, but instead may be amenable to approaches that alter the TIME or genetically redirect T-cell immunity” (p. 11 right column ¶3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding and administering TILs as taught by ‘113 in view of Chowdhury using subjects that have pediatric cancers medulloblastoma or glioma as taught by Grabovska in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where administering expanded TILs may alter the tumor microenvironment or provide additional redirected T-cell immunity as taught by Grabovska. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by ‘113 from medulloblastoma or glioma patients would increase the number of tumor-targeting TILs in the pediatric cancer patients and therefore an artisan would be able to modulate the tumor-immune microenvironment to improve survival as taught by Grabovska et. al.
U.S. Patent No. 10398734
Claims 86, 91-93, and 99-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10398734 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312.
Claim 1 teaches a cryopreserved tumor infiltrating lymphocytes (TIL) composition comprising a therapeutic population of TILs wherein the product is produced by obtaining a first population of TILs from a tumor resected from a subject into multiple tumor fragments and culturing the first population of TILs for about 3-11 days to obtain a second population of TILs; performing a second expansion by culturing the second population of TILs to produce a third population of TILs, wherein the third population of TILs is a therapeutic population.
The difference between the claims of ‘734 and the instant claims is that the claims of ‘734 teach a product produced by a method and not a method of treating cancer; and they do not teach that the tumor is from a subject with uveal melanoma, pediatric cancer, or mesothelioma.
This deficiency is resolved by Fardis.
Fardis teaches a method of treating a melanoma refractory to other therapies using tumor infiltrating lymphocytes (Abstract). The method comprises obtaining a first population of TILs from a tumor resected from the patient by processing a tumor sample obtained by the patient into multiple fragments [0036]; performing a first expansion by culturing the first population of TILs in a cell culture medium for about 3-14 days [0036] and in particular for about 11 days ([0061], [0393], [0412], [0423-0424], [0426]) to obtain a second population of TILs; performing a second expansion for about 7-14 days [0036] and in particular for about 11 days ([0393], [0430], [0439], [0451]) to obtain a third population of TILs; and administering a therapeutically effective amount of the third population of TILs to the subject ([0036], [0078], [0638], [0651]). Fardis teaches a preferred embodiment wherein the cancer is metastatic double-refractory uveal melanoma [0351].
Regarding claims 91-92 Fardis teaches wherein the subject is also administered a therapy in combination with the therapy wherein the therapy is an immune checkpoint regulator including particular anti-PD-1 antibodies [0380].
Regarding claim 93, as evidenced by Chattopadhyay et. al., uveal melanoma is a collective term for choroid, ciliary body, or iris melanoma (Abstract) and therefore the uveal melanoma as taught by Fardis is inherently one of choroidal melanoma, ciliary body melanoma, or iris melanoma.
Regarding claim 102, Fardis teaches digesting the tumor fragments in enzymatic media, mechanically dissociating the tumor, and removing dead or red blood cells using density gradient separation (reads on purifying) [0400].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to combine the method of treating the uveal melanoma patients of Fardis comprising obtaining, expanding, and administering TILs and by substituting the product of ‘734 produced by a method of obtaining and expanding TILs in order to benefit from a method of treating cancer by adoptive cell therapy on a new patient population and to benefit from a known use of a cryopreserved TIL product. This would have a predictable effect because Fardis teaches a method of treating uveal melanoma using TILs, and therefore an artisan would expect a similar expansion and administration protocol for producing the TIL product of ‘734 to be similarly effective when the product is used in a method of treating uveal melanoma.
Regarding claim 103, Fardis teaches that patients with a BRAF mutation responded as well to TIL therapy as patients with wild-type BRAF [0168], Fig. 37. Fardis teaches that patients may or may not have mutations in the BRAF gene [0379], [0837] and that patients that are BRAF mutation-positive are treated after BRAF targeted therapy [0840]. Fardis teaches that patient who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor were excluded [0850].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of treating uveal melanoma comprising expanding and administering the TILs as taught by modified ‘734 claims above to patients with a BRAF V600 mutation as taught by Fardis in order to benefit from the response to TIL therapy in patients with mutated BRAF as taught by Fardis. This would have a reasonable expectation of success because Fardis teaches that some of the cancers that have mutations in BRAF are BRAF V600 mutation positive and that the TIL therapy was effective for BRAF mutation positive cancers.
Claims 87-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10398734 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 as applied to claim 86 above, and further in view of Anraku M, et. al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008 Apr;135(4):823-9. doi: 10.1016/j.jtcvs.2007.10.026. PMID: 18374762.
The teachings of claim 1 of U.S. Patent No. 10398734 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 as applied to claim 86 are in the NSDP rejection above and are incorporated by reference herein.
Modified ‘734 in view of Fardis does not teach the method wherein the subject has mesothelioma, and wherein the mesothelioma is selected from a group including pleural mesothelioma.
This deficiency is resolved by Anraku et. al.
Anraku et. al. teaches that in patients with malignant pleural mesothelioma, the presence of CD8+ tumor-infiltrating lymphocytes was predictive of survival (Figure 4, p. 826 left column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining and expanding TILs as taught by ‘113 using subjects that have malignant pleural mesothelioma of Anraku et. al. substituted for the subjects with generic cancer or generic melanoma of ‘113 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs from the pleural mesothelioma patients would increase the number of TILs in the pleural mesothelioma patients and therefore improve survival as taught by Anraku et. al.
Regarding claims 88-90, Anraku et. al. teaches “Multimodality therapy with chemotherapy, surgery, and hemithoracic postoperative irradiation have demonstrated some benefit in survival for highly selected patients,2-4 but the majority of cases are noncurative. Therefore, some emerging modalities, such as immunotherapy5, intracavitary chemotherapy6,7, and photodynamic therapy8 have been tested to offer hope for improvement in both palliation and survival” (p. 823 ¶1). Anraku teaches that immune-based therapies have shown impact on tumor regression when combined with chemotherapy (p. 823 ¶2). Anraku further teaches that they observed a significant correlation between cisplatin/pemtrexed chemotherapy and high levels of CD8+ TILs and that cisplatin/pemtrexed is the only drug combination shown to have a significant impact on survival in a randomized clinical trial for MPM (p. 825 right column ¶ 3; p. 826 right column ¶2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the patients that had previous undergone treatment with cisplatin as taught by Anraku et. al. with the method of treating malignant melanoma by expanding and administering TILs as taught by modified ‘734 in view of Fardis in order to benefit from the increased immune response to the tumor cause by cisplatin/pemtrexed treatment as taught by Anraku et. al. This would have a reasonable expectation of success because an artisan would expect that a TIL therapy would be improved by using patients that have been previously treated with a therapy that increases tumor-reactive lymphocytes in the tumor. Additionally, Anraku et. al. teaches that cisplatin/pemtrexed in the only therapy that has been shown to extend survival; and therefore, it would have been obvious for a person of ordinary skill in the art to treat the patients with a standard chemotherapy regimen to ascertain any benefit prior to starting them on an experimental immunotherapy regimen.
Claims 94-95 and 97-98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10398734 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 as applied to claim 86 above in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701.
The teachings of claim 1 of U.S. Patent No. 10398734 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 (‘modified ‘734’) as applied to claim 86 are in the NSDP rejection above and are incorporated by reference herein.
The claims of modified ‘734 do not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a neuroblastoma, a sarcoma, or a central nervous system associated cancer.
This deficiency is resolved by Chowdhury et. al.
Chowdhury et. al. teaches that 115 pediatric tumors were assessed for the presence of CD8+ tumor-infiltrating lymphocytes (Abstract). Chowdhury teaches that the cancers assessed were Wing’s sarcoma, alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, osteosarcoma, and neuroblastoma (Table 1 p. 3). Chowdhury et. al. teaches that high CD8+ TIL in the tumor were associated with increased survival (Fig. 3B-D) and in particular CD8+ PD-1+ TIL (Fig. 3G); also see p. 2 right column. Chowdhury et. al. teaches that the age range at diagnosis was 1.4-16.5 for Ewing’s sarcoma; 1.3-16.2 for Alveolar rhabdomyosarcoma; 1.2-12.8 for embryonal rhabdomyosarcoma; 0.8-16.6 for osteosarcoma; and 0.1-16.9 for Neuroblastoma (Table 1 p. 3; reads on subject less than two or from 12 years old to less than 21 years old). Chowdhury et. al. teaches that all samples were taken at diagnosis (pre-therapy) (p. 6 right column ¶3 “Methods: Cases” section); therefore, the subjects read on claim 98 parts ii, iv, v, viii, xi, xiv because the patients have not undergone any treatment. Chowdhury et. al. teaches that the treatment burden and long-term deleterious effects from typically intensive multi-modal therapies in childhood cancers is high; and that additionally a number of tumor types such as high-risk neuroblastoma remain challenging to treat and still carry a poor prognosis with high treatment related mortality. Chowdhury et. al. teaches that immunotherapy is an attractive option that is potentially is more specific and less toxic (p. 1 left column “Introduction”).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding, and administering TILs as taught by modified ‘734 using subjects that have pediatric cancers neuroblastoma or a sarcoma (reads on claims 86 and 94); wherein the pediatric cancer is osteosarcoma or Ewing sarcoma (reads on claim 95) as taught by Chowdhury substituted for the generic cancer patients of modified ‘734 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by modified ‘734 from the pediatric neuroblastoma or Ewing sarcoma patients would increase the number of TILs in the pediatric cancer patients and therefore improve survival as taught by Chowdhury et. al.
Regarding claim 98, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the treatment naïve subject of Chowdhury et. al. without prior dinutuximab treatment for neuroblastoma, or dactinomycin treatment for Ewing sarcoma or rhabdomyosarcoma, or vincristine sulfate treatment for rhabdomyosarcoma in order to benefit from a potentially less toxic treatment for pediatric cancer as taught by Chowdhury et. al. with improved TILs as taught by modified ‘734. This would have a reasonable expectation of success because an artisan would expect the number of CD8+ PD-1+ TILs that would be expanded to correlate with those found in the tumor samples of Chowdhury et. al. if there is no intervening chemotherapy and therefore would expect them to be present with anti-tumor potential that can be improved by the expansion and adoptive transfer method of Fardis.
Claims 96 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10398734 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 and Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701 as applied to claims 86 and 94 above, and further in view of Grabovska Y, et. al. Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nat Commun. 2020 Aug 28;11(1):4324. doi: 10.1038/s41467-020-18070-y. PMID: 32859926; PMCID: PMC7455736
The teachings of modified ‘734 in view of Fardis and Chowdhury regarding claims 86 and 94 are in the NSDP rejections above and are incorporated by reference herein.
‘734 claims in view of Fardis and Chowdhury does not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a central nervous system (CNS) cancer selected from the group of medulloblastoma, pineoblastoma, glioma, ependymoma, or glioblastoma.
This deficiency is resolved by Grabovska et. al.
Grabovska et. al. teaches profiling of the tumor immune microenvironment of pediatric CNS tumors of multiple subtypes including medulloblastomas and pediatric high grade gliomas (Abstract). Grabovska et. al. teaches “Post hoc testing (Dunn’s test) reveals the relative number of TILs and indeed the total amount of infiltrating cells was significantly less in high-grade tumor types such as embryonal tumors (i.e., MB, ATRT, and Embryonal tumours with multilayered rosettes) than in low-grade gliomas (LGGs) (p < 0.001)” (p. 4 left column ¶3). Grabovska et. al. teaches that the average infiltration eosinophils, CD4T, B-cell, Treg, NK, monocytes, and TILs decreased proportionally with increasing WHO Grade (p. 4 right column ¶1, Fig. 2c). Grabovska et. al. teach that medulloblastomas (MBs) had different immune signatures and different lymphocyte populations which correlated with survival (p. 6 left column, Fig. 3). Grabovska et. al. teaches that the tumor immune microenvironment is also associated with prognosis in pediatric high grade glioma (pHGG). Grabovska et. al. teaches that lower than median concentrations of B-cell and CD8T cells in a particular subgroup (WT-A) are associated with poor overall survival. Grabovska et. al. further teaches “It should be noted that prognostic associations with immune cell infiltration appear to be context dependent; increased CD8T infiltration, for instance, does not universally denote a poor outcome. The most directly comparable experience in pHGG was the HERBY Phase II Trial39. High CD8+ infiltration was significantly associated with increased survival in 34 cases (of various subtypes) who received Temezolomide/radiotherapy and Bevacizumab for which our results in pHGG WT-A are in accordance”(p. 11 left column ¶2). Grabovska et. al. teach “it seems to follow that an a priori paucity of infiltrating cytotoxic T-lymphocytes and the lack of a supportive TIME may be unconducive to immune checkpoint blockade as a therapeutic strategy, but instead may be amenable to approaches that alter the TIME or genetically redirect T-cell immunity” (p. 11 right column ¶3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding and administering TILs as taught by modified ‘734 in view of Chowdhury using subjects that have pediatric cancers medulloblastoma or glioma as taught by Grabovska in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where administering expanded TILs may alter the tumor microenvironment or provide additional redirected T-cell immunity as taught by Grabovska. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by modified ‘734 in view of Chowdhury from medulloblastoma or glioma patients would increase the number of tumor-targeting TILs in the pediatric cancer patients and therefore an artisan would be able to modulate the tumor-immune microenvironment to improve survival as taught by Grabovska et. al.
U.S. Patent No. 10905718
Claims 86, 91-93, and 99-103 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-16, and 18 of U.S. Patent No. 10905718 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312.
Claim 1 teaches a method for treating a subject with cancer, the method comprising administering to the subject a TIL pharmaceutical composition comprising an expanded population of TILs and a cryopreservant, wherein the expanded population of TILs exhibit IFN-γ secretion of at least five-fold in vitro as compared to a non-expanded population of TILs. In order to construe the scope of the expanded population of TILs of claim 1, the specification was consulted (MPEP §804.II.B.1). The specification teaches that the TILs that secret at least five-fold IFN-γ in vitro as compared to non-expanded population of TILs (Col. 4 lines 15-17) are the same as populations made by a method that involves performing a first expansion from about 3-14 days to obtain a second population of TILs, performing a second expansion from about 7-14 days to obtain the third population of TILs, wherein the third population is a therapeutic population (Col. 2 lines 20-56; Col. 98 lines 53-Col. 99 line 24). In particular the first period and the second period are performed within 11 days (Col. 3 lines 39-41)
The difference between the claims of ‘718 and the instant claims is that the claims of ‘718 teach a method of treating comprising administering a TIL population with a particular function as described, but do not teach that the subject has uveal melanoma, pediatric cancer, or mesothelioma.
This deficiency is resolved by Fardis.
Fardis teaches a method of treating a melanoma refractory to other therapies using tumor infiltrating lymphocytes (Abstract). The method comprises obtaining a first population of TILs from a tumor resected from the patient by processing a tumor sample obtained by the patient into multiple fragments [0036]; performing a first expansion by culturing the first population of TILs in a cell culture medium for about 3-14 days [0036] and in particular for about 11 days ([0061], [0393], [0412], [0423-0424], [0426]) to obtain a second population of TILs; performing a second expansion for about 7-14 days [0036] and in particular for about 11 days ([0393], [0430], [0439], [0451]) to obtain a third population of TILs; and administering a therapeutically effective amount of the third population of TILs to the subject ([0036], [0078], [0638], [0651]). Fardis teaches a preferred embodiment wherein the cancer is metastatic double-refractory uveal melanoma [0351].
Regarding claims 91-92 Fardis teaches wherein the subject is also administered a therapy in combination with the therapy wherein the therapy is an immune checkpoint regulator including particular anti-PD-1 antibodies [0380].
Regarding claim 93, as evidenced by Chattopadhyay et. al., uveal melanoma is a collective term for choroid, ciliary body, or iris melanoma (Abstract) and therefore the uveal melanoma as taught by Fardis is inherently one of choroidal melanoma, ciliary body melanoma, or iris melanoma.
Regarding claim 102, Fardis teaches digesting the tumor fragments in enzymatic media, mechanically dissociating the tumor, and removing dead or red blood cells using density gradient separation (reads on purifying) [0400].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to combine the method of treating the uveal melanoma patients of Fardis comprising obtaining, expanding, and administering TILs and the method of treating a generic cancer by administering TILs with the functional property as claimed by ‘718 wherein the TILs with the functional property (five-fold increased IFNγ) are the same as cells produced by the same method as taught in Fardis in order to benefit from a method of treating cancer by adoptive cell therapy on a new patient population and to benefit from a method of treating with a population of TILs with a desirable IFNγ level as taught by ‘718. This would have a predictable effect because Fardis teaches a method of treating uveal melanoma using TILs, and therefore an artisan would expect to be able to combine the method of treating of Fardis and the method of treating of ‘718 to be similarly effective when used for a particular subtype of melanoma (uveal melanoma) as taught for melanoma in general in ‘718.
Regarding claim 103, Fardis teaches that patients with a BRAF mutation responded as well to TIL therapy as patients with wild-type BRAF [0168], Fig. 37. Fardis teaches that patients may or may not have mutations in the BRAF gene [0379], [0837] and that patients that are BRAF mutation-positive are treated after BRAF targeted therapy [0840]. Fardis teaches that patient who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor were excluded [0850].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of treating uveal melanoma comprising expanding and administering the TILs as taught by modified ‘718 above to patients with a BRAF V600 mutation as taught by Fardis in order to benefit from the response to TIL therapy in patients with mutated BRAF as taught by Fardis. This would have a reasonable expectation of success because Fardis teaches that some of the cancers that have mutations in BRAF are BRAF V600 mutation positive and that the TIL therapy was effective for BRAF mutation positive cancers.
Claims 87-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over 1, 14-16, and 18 of U.S. Patent No. 10905718 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 as applied to claim 86 above, and further in view of Anraku M, et. al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008 Apr;135(4):823-9. doi: 10.1016/j.jtcvs.2007.10.026. PMID: 18374762.
The teachings of claims 1, 14-16, and 18 of U.S. Patent No. 10905718 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 as applied to claim 86 are in the NSDP rejection above and are incorporated by reference herein.
Modified ‘718 in view of Fardis does not teach the method wherein the subject has mesothelioma, and wherein the mesothelioma is selected from a group including pleural mesothelioma.
This deficiency is resolved by Anraku et. al.
Anraku et. al. teaches that in patients with malignant pleural mesothelioma, the presence of CD8+ tumor-infiltrating lymphocytes was predictive of survival (Figure 4, p. 826 left column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining and expanding TILs as taught by ‘113 using subjects that have malignant pleural mesothelioma of Anraku et. al. substituted for the subjects with generic cancer or generic melanoma of ‘113 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs from the pleural mesothelioma patients would increase the number of TILs in the pleural mesothelioma patients and therefore improve survival as taught by Anraku et. al.
Regarding claims 88-90, Anraku et. al. teaches “Multimodality therapy with chemotherapy, surgery, and hemithoracic postoperative irradiation have demonstrated some benefit in survival for highly selected patients,2-4 but the majority of cases are noncurative. Therefore, some emerging modalities, such as immunotherapy5, intracavitary chemotherapy6,7, and photodynamic therapy8 have been tested to offer hope for improvement in both palliation and survival” (p. 823 ¶1). Anraku teaches that immune-based therapies have shown impact on tumor regression when combined with chemotherapy (p. 823 ¶2). Anraku further teaches that they observed a significant correlation between cisplatin/pemtrexed chemotherapy and high levels of CD8+ TILs and that cisplatin/pemtrexed is the only drug combination shown to have a significant impact on survival in a randomized clinical trial for MPM (p. 825 right column ¶ 3; p. 826 right column ¶2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the patients that had previous undergone treatment with cisplatin as taught by Anraku et. al. with the method of treating malignant melanoma by expanding and administering TILs as taught by modified ‘718 in view of Fardis in order to benefit from the increased immune response to the tumor cause by cisplatin/pemtrexed treatment as taught by Anraku et. al. This would have a reasonable expectation of success because an artisan would expect that a TIL therapy would be improved by using patients that have been previously treated with a therapy that increases tumor-reactive lymphocytes in the tumor. Additionally, Anraku et. al. teaches that cisplatin/pemtrexed in the only therapy that has been shown to extend survival; and therefore, it would have been obvious for a person of ordinary skill in the art to treat the patients with a standard chemotherapy regimen to ascertain any benefit prior to starting them on an experimental immunotherapy regimen.
Claims 94-95 and 97-98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-16, and 18 of U.S. Patent No. 10905718 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 as applied to claim 86 above in view of Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701.
The teachings of claims 1, 14-16, and 18 of U.S. Patent No. 10905718 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 (‘modified ‘718’) as applied to claim 86 are in the NSDP rejection above and are incorporated by reference herein.
The claims of modified ‘718 do not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a neuroblastoma, a sarcoma, or a central nervous system associated cancer.
This deficiency is resolved by Chowdhury et. al.
Chowdhury et. al. teaches that 115 pediatric tumors were assessed for the presence of CD8+ tumor-infiltrating lymphocytes (Abstract). Chowdhury teaches that the cancers assessed were Wing’s sarcoma, alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, osteosarcoma, and neuroblastoma (Table 1 p. 3). Chowdhury et. al. teaches that high CD8+ TIL in the tumor were associated with increased survival (Fig. 3B-D) and in particular CD8+ PD-1+ TIL (Fig. 3G); also see p. 2 right column. Chowdhury et. al. teaches that the age range at diagnosis was 1.4-16.5 for Ewing’s sarcoma; 1.3-16.2 for Alveolar rhabdomyosarcoma; 1.2-12.8 for embryonal rhabdomyosarcoma; 0.8-16.6 for osteosarcoma; and 0.1-16.9 for Neuroblastoma (Table 1 p. 3; reads on subject less than two or from 12 years old to less than 21 years old). Chowdhury et. al. teaches that all samples were taken at diagnosis (pre-therapy) (p. 6 right column ¶3 “Methods: Cases” section); therefore, the subjects read on claim 98 parts ii, iv, v, viii, xi, xiv because the patients have not undergone any treatment. Chowdhury et. al. teaches that the treatment burden and long-term deleterious effects from typically intensive multi-modal therapies in childhood cancers is high; and that additionally a number of tumor types such as high-risk neuroblastoma remain challenging to treat and still carry a poor prognosis with high treatment related mortality. Chowdhury et. al. teaches that immunotherapy is an attractive option that is potentially is more specific and less toxic (p. 1 left column “Introduction”).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding, and administering TILs as taught by modified ‘718 using subjects that have pediatric cancers neuroblastoma or a sarcoma (reads on claims 86 and 94); wherein the pediatric cancer is osteosarcoma or Ewing sarcoma (reads on claim 95) as taught by Chowdhury substituted for the generic cancer patients of modified ‘718 in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where CD8+ TILs are correlated with survival. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by modified ‘718 from the pediatric neuroblastoma or Ewing sarcoma patients would increase the number of TILs in the pediatric cancer patients and therefore improve survival as taught by Chowdhury et. al.
Regarding claim 98, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat the treatment naïve subject of Chowdhury et. al. without prior dinutuximab treatment for neuroblastoma, or dactinomycin treatment for Ewing sarcoma or rhabdomyosarcoma, or vincristine sulfate treatment for rhabdomyosarcoma in order to benefit from a potentially less toxic treatment for pediatric cancer as taught by Chowdhury et. al. with improved TILs as taught by modified ‘718 This would have a reasonable expectation of success because an artisan would expect the number of CD8+ PD-1+ TILs that would be expanded to correlate with those found in the tumor samples of Chowdhury et. al. if there is no intervening chemotherapy and therefore would expect them to be present with anti-tumor potential that can be improved by the expansion and adoptive transfer method of Fardis.
Claims 96 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-16, and 18 of U.S. Patent No. 10905718 in view of U.S. 20190231820 to Fardis published 1 August 2019 as evidenced by Chattopadhyay, Chandrani, et al. "Uveal melanoma: From diagnosis to treatment and the science in between." Cancer 122.15 (2016): 2299-2312 and Chowdhury, Ferdousi, et al. "PD-L1 and CD8+ PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy." OncoImmunology 4.10 (2015): e1029701 as applied to claims 86 and 94 above, and further in view of Grabovska Y, et. al. Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nat Commun. 2020 Aug 28;11(1):4324. doi: 10.1038/s41467-020-18070-y. PMID: 32859926; PMCID: PMC7455736
The teachings of modified ‘718 in view of Fardis and Chowdhury regarding claims 86 and 94 are in the NSDP rejections above and are incorporated by reference herein.
‘718 claims in view of Fardis and Chowdhury does not teach the method wherein the subject has a pediatric cancer, and wherein the pediatric cancer is a central nervous system (CNS) cancer selected from the group of medulloblastoma, pineoblastoma, glioma, ependymoma, or glioblastoma.
This deficiency is resolved by Grabovska et. al.
Grabovska et. al. teaches profiling of the tumor immune microenvironment of pediatric CNS tumors of multiple subtypes including medulloblastomas and pediatric high grade gliomas (Abstract). Grabovska et. al. teaches “Post hoc testing (Dunn’s test) reveals the relative number of TILs and indeed the total amount of infiltrating cells was significantly less in high-grade tumor types such as embryonal tumors (i.e., MB, ATRT, and Embryonal tumours with multilayered rosettes) than in low-grade gliomas (LGGs) (p < 0.001)” (p. 4 left column ¶3). Grabovska et. al. teaches that the average infiltration eosinophils, CD4T, B-cell, Treg, NK, monocytes, and TILs decreased proportionally with increasing WHO Grade (p. 4 right column ¶1, Fig. 2c). Grabovska et. al. teach that medulloblastomas (MBs) had different immune signatures and different lymphocyte populations which correlated with survival (p. 6 left column, Fig. 3). Grabovska et. al. teaches that the tumor immune microenvironment is also associated with prognosis in pediatric high grade glioma (pHGG). Grabovska et. al. teaches that lower than median concentrations of B-cell and CD8T cells in a particular subgroup (WT-A) are associated with poor overall survival. Grabovska et. al. further teaches “It should be noted that prognostic associations with immune cell infiltration appear to be context dependent; increased CD8T infiltration, for instance, does not universally denote a poor outcome. The most directly comparable experience in pHGG was the HERBY Phase II Trial39. High CD8+ infiltration was significantly associated with increased survival in 34 cases (of various subtypes) who received Temezolomide/radiotherapy and Bevacizumab for which our results in pHGG WT-A are in accordance”(p. 11 left column ¶2). Grabovska et. al. teach “it seems to follow that an a priori paucity of infiltrating cytotoxic T-lymphocytes and the lack of a supportive TIME may be unconducive to immune checkpoint blockade as a therapeutic strategy, but instead may be amenable to approaches that alter the TIME or genetically redirect T-cell immunity” (p. 11 right column ¶3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating cancer comprises obtaining, expanding and administering TILs as taught by modified ‘718 in view of Chowdhury using subjects that have pediatric cancers medulloblastoma or glioma as taught by Grabovska in order to treat a different cancer subtype and to benefit from an improved method of expanding TILs on a patient population where administering expanded TILs may alter the tumor microenvironment or provide additional redirected T-cell immunity as taught by Grabovska. This would have a reasonable expectation of success because an artisan would predict that adoptive transfer of TILs as taught by modified ‘718 in view of Chowdhury from medulloblastoma or glioma patients would increase the number of tumor-targeting TILs in the pediatric cancer patients and therefore an artisan would be able to modulate the tumor-immune microenvironment to improve survival as taught by Grabovska et. al.
Additional Non-Statutory Double Patenting Rejections:
Patent No:
Rejected over Application Claims:
Difference between reference patent claims and instant claims
Application/Patent with similar (prov.) NSDP rejections:
10166257
1, 8-10, 14-15
Recites generic cancer and melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
10363273
1, 8-10, 16, 23-25
Recites treating a subject with head and neck cancer or cervical cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
10420799
1
Recites a method for obtaining and expanding TILs but does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10463697
1, 8-10, 13, 15
Recites a method for treating a subject with generic cancer, and melanoma, metastatic melanoma in particular but does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
10639330
1
Recites a method for obtaining and expanding TILs but does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10646571
1, 8-10, 14-15
Recites a method for treating a generic cancer comprising administering TILs but does not recite uveal melanoma, pediatric cancer, or mesothelioma; recites a first expansion of 7-11 days rather than 3-11 days
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
10894063
1
Recites a product-by-process claiming a population of expanded TILs produced by the method; does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10918666
1
Recites a method for obtaining and expanding TILs but does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10925900
1, 8-10, 13
Recites a method for treating a subject with melanoma, does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
10933094
1
Recites a method of treating a subject with generic cancer comprising administering a pharmaceutical composition comprising TILs wherein the TILs exhibit IFNγ secretion of at least 1000 pg/mL, does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘718 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10946044
1, 7-9, 12
Recites a method of treating a subject with generic cancer, or melanoma in particular, comprising administering a pharmaceutical composition comprising TILs wherein the TILs exhibit IFNγ secretion of at least 1000 pg/mL, does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘718 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10946045
1, 7-9, 12
Recites a method of treating a subject with generic cancer, or melanoma in particular, comprising administering TILs wherein the TILs exhibit five-fold increased IFNγ secretion, does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘718 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10953046
1, 15-17, 19
Recites a method of treating a subject with generic cancer, or melanoma in particular, comprising administering a pharmaceutical composition comprising TILs wherein the TILs exhibit five-fold increased IFNγ secretion, does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘718 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10953046
1, 15-17, 20
Recites a method of treating a subject with generic cancer, or melanoma in particular, comprising administering a pharmaceutical composition comprising TILs exhibit IFNγ secretion of at least 1000 pg/mL, does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘718 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11007225
1, 2, 15-17, 20, 22
Recites a method for treating a subject with generic cancer, and melanoma, metastatic melanoma in particular but does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11007226
1, 16-19
Recites a method for obtaining and expanding TILs from a subject; does not recited a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11013770
1, 8-10, 14
Recites a method for treating a subject with generic cancer, and melanoma, comprising obtaining, expanding, and administering TILs and an anti-PD-L1 antibody but does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11026974
1
Recites a method for obtaining and expanding TILs but does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11040070
1
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11052116
1
Recites a cryopreserved TIL composition created by a method of expanding identical to instant expansion steps; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11168304
1
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11058728
1, 2, 12-14, 17, 18
Recites a method for treating a subject with generic cancer, and melanoma, comprising obtaining, expanding, and administering TILs and an anti-PD-L1 antibody but does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11083752
1-4, 13-15, 18
Recites a method for treating a subject with generic cancer, and melanoma, comprising obtaining, expanding, and administering TILs and an anti-PD-L1 antibody but does not recite uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11123371
1-4, 13
Recites a cryopreserved TIL composition created by a method of expanding identical to instant expansion steps; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11141438
1-6, 15
Recites a cryopreserved TIL composition created by a method of expanding identical to instant expansion steps; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11179419
1-4, 14
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11202803
1-3, 13-15, 17
Recites treating a subject with melanoma and metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11202804
1-4, 12-14, 16-17
Recites treating a subject with generic cancer, melanoma, and metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11220670
1-2, 11, 13
Recites treating a subject with generic cancer, melanoma, and metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma; does not recite the length of time for the first and second cell culture (reads on expansion); deficiency resolved by Fardis
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11241456
1-3, 12-14, 16-17
Recites treating a subject with generic cancer, melanoma, and metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11254913
1-4, 11-14
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11266694
1-4, 12-14, 17-18
Recites treating a subject with generic cancer, melanoma, and metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11273180
1-4, 15
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma; does not recite non-myeloablative depletion regimen or further treating the subject with an IL-2 regimen (deficiency resolved by Fardis)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11273181
1-4, 12-13, 15-17
Recites treating a subject with generic cancer, melanoma, and metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11291687
1-5, 8
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11293009
1-2, 17-19
Recites a method for treating generic cancer comprising expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma; does not recite the length of the first and the second culture steps (deficiency resolved by Fardis)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11304979
1-4
Recites a method for treating generic cancer comprising expanding TILs from a subject; does not recite the length of time for the first and second cell culture (reads on expansion); deficiency resolved by Fardis
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11304980
1, 13
Recites a product-by-process of TILs made by a first and second expansion; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11311578
1-4, 9-11, 16-17
Recites a method for treating generic cancer comprising expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11337998
1, 4-6
Recites a method for treating generic cancer comprising expanding TILs from a subject; does not recite a method of treating uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11344579
1
Recites a cryopreserved TIL composition created by a method of expanding identical to instant expansion steps; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11344580
1, 4-6
Recites a product-by-process claiming a population of expanded TILs produced by the method; does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11344581
1-4, 14, 17
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11351197
1-5
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11351198
1-5, 10
Recites a product-by-process composition of cryopreserved TILs produced by a method
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11351199
1
Recites a method for obtaining and expanding TILs but does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11529372
1, 5-8, 22-23
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11364266
1-5, 9-11, 16, 17-23
Recites a method for treating generic cancer comprising expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma; length of first expansion
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11369637
1, 9-11
Recites a method for treating generic cancer comprising expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11384337
1
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11401507
1, 22-23
Recites a method of treating uveal melanoma comprising two TIL expansion steps, does not recite the length of the first and second expansion step (resolved by Faris)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11433097
1
Recites a method of treating double-refractory metastatic melanoma; does not recite uveal melanoma, mesothelioma, or pediatric cancer
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11517592
1-3, 15-17, 19
Recites a method for treating melanoma comprising expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma; length of first expansion
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11541077
1-7, 16-18, 21-22
Recites a method for obtaining and expanding TILs from a subject and administering the TILs to the subject, wherein the subject has melanoma; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11026974
1
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10517894
1, 12
Recites a method of treating double refractory metastatic melanoma comprising administering a therapeutically effective population of TILs; does not recite identical expansion protocol (resolved by Fardis)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11857573
1, 14-15
Recites a product-by-process claiming a population of expanded TILs produced by the method; does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11713446
1
Recites a method for obtaining and expanding TILs from a subject; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11865140
1, 13, 14, 20
Recites a product-by-process claiming a population of expanded TILs produced by the method; does not recite a method of treating or administering
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11819517
1
Recites a method of treating double refractory metastatic melanoma comprising administering a therapeutically effective population of TILs; does not recite obtaining and expanding the TILs (resolved by Fardis)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11357841
1, 4-5, 9-11
Recites treating a subject with generic cancer, rather than uveal melanoma, pediatric cancer, or mesothelioma
‘659 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
11981921
1, 14-20, 29
Recites a method of making a population of TILs; does not recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12104172
1-3
Recites a method for expanding TILs from a subject and administering the TILs to the subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12226522
1, 8-12
Recites a method of administering TILs to a subject with endometrial cancer; does not explicitly recite treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
12280140
1
Recites a method for expanding TILs from a subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12453697
1
Recites a method for expanding TILs from a subject and administering the TILs to the subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12343380
18, 21, 24
Recites treating a subject with generic cancer, rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
12473532
1, 26-27
Recites a method for expanding TILs from a subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
10695372
1
Recites a product-by-process made by the method; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11168303
1
Recites a method for expanding TILs from a subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
11998568
1-5, 13-15, 17-18
Recites treating a subject with generic cancer and in particular melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
12121541
1, 8-10, 13
Recites treating a subject with generic cancer and in particular melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
12194061
1
Recites a cryopreserved composition of TILs product-by-process; does not recite method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12226434
1
Recites a method for expanding TILs from a subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12188048
1, 15-17
Recites composition of TILs product-by-process; does not recite method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12024718
1, 19, 22
Recites a method for expanding TILs from a subject; does not explicitly recite a method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12031157
1
Recites composition of TILs product-by-process; does not recite method of treating or treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
12495791
1, 21, 26
Recites treating a subject with generic cancer and in particular melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
Additional Provisional Non-Statutory Double Patenting Rejections
These rejections are provisional because the claims of the reference applications have not been patented.
Application No:
Rejected over Application Claims:
Difference between reference patent claims and instant claims
Application/Patent with similar (prov.) NSDP rejections:
16969362
1, 37, 38, 43
Recites a method of treating with generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17050552
65, 70-72
Recites a method of treating with generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17110179
1, 8-11, 13,
Recites a method of treating with generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17147080
1, 22
Recites method for expanding TILs; does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17290705
1
Recites method for expanding TILs; does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17290710
1, 29, 37, 39
Recites a method of treating NSCLC; does not recite length of first and second expansion (resolved by Fardis) or uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17415175
1
Recites method for expanding TILs; does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17610671
367
Recites method for expanding TILs; does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17771723
159
Recites method for expanding TILs; does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17817217
1-4, 13-15
Recites a method of treating with melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17817239
1, 14, 15
Recites a method of treating melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17817273
1
Recites product-by-process TILs; does not recite treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17817276
1, 13-15
Recites a method of treating melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17823419
1, 29
Recites product-by-process TILs; does not recite treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17823448
1
Recites product-by-process TILs; does not recite treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17823454
1-5, 26-30
Recites a method of treating with generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17829087
1, 14, 17
Recites method for expanding TILs; does not recite the particular expansion timing (resolved by Fardis); does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17838127
35
Recites method for expanding TILs; does not recite the particular expansion timing (resolved by Fardis); does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17856793
1-3, 14-16
Recites a method of treating with generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
17856806
1
Recites product-by-process TILs; does not recite treating uveal melanoma, pediatric cancer, or mesothelioma
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17997648
228
Recites method for expanding TILs; does not recite the particular expansion timing (resolved by Fardis); does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
17997731
30
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18247877
2, 4
Recites a method of treating with NSCLC rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18247878
2, 4
Recites a method of treating with NSCLC rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18256421
162
Recites a method of treating a generic cancer with a BRAF and/or MEK inhibitor rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18256798
20, 61-62, 67
Recites a method of treating a generic cancer with TILs and a PD-1 or PD-L1 inhibitor rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18262365
10
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18262843
10
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18291536
2
Recites a method of treating a generic cancer with TILs and a KRAS inhibitor rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18429006
68
Recites method for expanding TILs; does not recite the particular expansion timing (resolved by Fardis); does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18551138
136
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18555513
2
Recites a method of treating a generic cancer with TILs rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18560898
19
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18609772
12
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18619119
1
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18661510
1
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18673083
149
Recites a method of treating NSCLC with TILs rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18674562
107
Recites a method of treating melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18707719
1
Recites a method of treating generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18745958
71
Recites a method of treating generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18832901
9
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18849440
3, 4, 5, 7, 98-102
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18858710
38, 46
Recites a method of treating generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18886988
14, 24-26
Recites a method of treating NSCLC rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
18984595
1
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
18996872
2
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
19011427
1
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
19040480
31-50
Recites method of treating generic melanoma including uveal melanoma including digest and expand steps; does not recite particular length of expansion steps (resolved by Fardis)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska and ‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19050082
11, 21-22
Recites a method of treating double-refractory metastatic melanoma rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19128904
1
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
19146518
1-73
Recites a method of treating NSCLC rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19219845
21
Recites a method of treating generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19326908
1, 146
Recites a method of treating generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19340364
1
Recites method for expanding TILs does not recite method of treating or cancer subtypes
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska
19354447
1
Recites a method of treating endometrial cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19460207
1
Recites a method of treating NSCLC rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19544953
1-45
Recites method of treating NSCLC including uveal melanoma including digest and expand steps; does not recite particular length of expansion steps (resolved by Fardis)
‘734 in view of: Fardis, evidenced by Chattopadhyay; further in view of Chowdhury and Grabovska and ‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
19544953
1, 65
Recites a method of treating generic cancer rather than uveal melanoma, pediatric cancer, or mesothelioma
‘113 in view of: Fardis, evidenced by Chattopadhyay; Chowdhury; and Grabovska
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678