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 .
Claims 136-138, 140, 142, 146-148 and 151-162 are pending.
Applicant's election with traverse of (A) modifying is carried out on the second population of TILs from the first expansion and before the second expansion as in claim 147(b), (B) a TALE method as in now claim 152), (C) CD69 as the specific genetic medication that reduce expression, (D) IL-15 as the specific genetic modification that enhance expression as in claim 148(b), and (E) melanoma as the species of cancer in the reply filed on July 1, 2026 is acknowledged. The traversal is on the ground(s) that first, the instant invention as claimed is not limited to a single species. For example, the pending claims recite selecting CD39LO/CD69LO and/or CD39/CD69 double negative TILs for expansion. For similar reasons, when electing specific genetic modification(s) that reduce expression, as in claim 148(a), Applicant respectfully requests electing at least both CD39 and CD69, rather than a single gene product, as the target(s) for reducing expression. In addition, most species in the pending claims have close relationship which can be recognized by a skilled artisan, based on the instant disclosures and common knowledge. Thus, there is no extra burden for a skilled artisan to search and identify prior art related to the claimed species. Therefore, Applicant respectfully requests reconsideration and/or withdrawal of the instant Requirement. A rejoinder of non-elected species is also respectfully requested, upon identifying allowable subject matter in the pending claims.
Upon reconsideration, CD39 as the species of target for reducing expression has been withdrawn so that both CD39 and CD69 genes are genetically modified in TILs for reduction.
Contrary to applicant’s assertion that that there is no extra burden for a skilled artisan to search and identify prior art for all species, there is a serious burden to search genetically TILs comprising genetically modification that reduces expression of any and all CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFI3, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, BTLA, CD160, TIGIT, TET2, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP 10, CASP3, CASP6, CASP7, FADD, FAS,SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCYlA2, GUCYlA3, GUCYlB2, GUCYlB3, and TOX and/or genetic modification that enhances expression of any and all CCR2, CCR4,CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL-4, IL-7, IL-10, IL-21, the NOTCH 1/2 intracellular domain (ICD), and the NOTCH ligand mDLL1 because these species are not obvious variants of each other based on the current record. The methods are distinct because they require different reagents, method steps and endpoints. Thus, they are patently distinct.
The request for rejoinder of addition species upon the allowance of a generic claim is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 136-138, 140, 142, 146-148 and 151-162, drawn to a method of expanding tumor infiltrating lymphocytes (TILs) that read on (A) modifying is carried out on the second population of TILs from the first expansion and before the second expansion as in claim 147(b), (B) a TALE method for genetically modifying method, (C) CD39 and CD69 as the specific genetic medication that reduce expression, (D) IL-15 as the specific genetic modification that enhance expression as in claim 148(b), and (E) melanoma as the species of cancer and a method of treating a patient or subject having cancer that read on , are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/163,730, filed March 19, 2021, 63/255,657, filed Oct 14, 2021 and 63/280,536 filed November 17, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on July 1, 2026 and July 8, 2024 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
The listing of references in the specification at page 688 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings filed on September 18,2023 are acceptable.
Specification
The amendment to the specification filed on July 1, 2026 has been entered.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 136 is objected to because of the following informalities: “3-11” and “7-11” should have been “3 to 11” and “7 to 11”.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 151-152 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 applicant regards as the invention.
Claim 151 recites the limitation "the genetically modifying" in claim 136. There is insufficient antecedent basis for this limitation in the claim. Claim 151 should depend from claim 146.
Claim 151 recites the limitation “said one or more immune checkpoint genes” in claim 136. There is insufficient antecedent basis for this limitation in the claim.
Claim 152 recites the limitation "the genetically modifying" in claim 136. There is insufficient antecedent basis for this limitation in the claim. Claim 152 should depend from claim 146.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 136-138, 140, 142, 146-148 and 151-162 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 136 encompasses a method of expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs, the method comprising the steps of:
(a) obtaining and/or receiving a first population of TILs from a tumor sample that contains a mixture of tumor and the TILs, wherein the tumor sample is obtained from a surgical resection, needle biopsy, core biopsy, or small biopsy from a cancer in a patient or subject having cancer;
(b) selecting CD39LO/CD69LO and/or CD39/CD69 double negative TILs from the first population of TILs in (a) to obtain a population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs;
(c) performing a first expansion by culturing the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed for about 3-11 days to obtain the second population of TILs;
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-11 days to obtain the third population of TILs;
(e) harvesting the third population of TILs obtained from step (d); and
(f) transferring the harvested third TIL population from step (e) to an infusion bag.
Claim 137 encompasses the method of claim 136, wherein the third population of TILs comprises a therapeutic population of TILs.
Claim 138 encompasses the method of claim 136, wherein i) the first expansion is performed in a closed container providing a first gas-permeable surface area; and/or ii) the second expansion is performed in a closed container providing a second gas- permeable surface area.
Claim 140 encompasses the method of claim 136, wherein the method further comprises adding the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs selected in step (b) into a closed system.
Claim 142 encompasses the method of claim 140, wherein the transition i) from step (b) to step (c);ii) from step (c) to step (d);iii) from step (d) to step (e); and/or iv) from step (e) to step (f) occurs without opening the system.
Claim 146 encompasses the method of claim 136, wherein the method further comprises genetically modifying the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs and/or the second population of TILs and/or the third population of TILs at any time prior to the harvesting such that the third population of TILs comprise genetically modified TILs.
Claim 147 encompasses the method of claim 146, wherein
(a) the modifying is carried out on the second population of TILs from the first expansion, or the third population of TILs from the second expansion, or both;
(b) the modifying is carried out on the second population of TILs from the first expansion and before the second expansion;
(c) the modifying is carried out on the third population of TILs from the second expansion; and/or
(d) the modifying is carried out after the harvesting.
Claim 148 encompasses the method of claim 146, wherein:
(a) the genetically modified TILs further comprises an additional a genetic modification that reduces expression of one or more of CD39 (elected species), CD69 (elected species), CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFI3, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1,BTLA, CD160, TIGIT, TET2, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP 10, CASP3, CASP6, CASP7, FADD, FAS,SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCYlA2, GUCYlA3, GUCYlB2, GUCYlB3, and TOX, and/or
(b) the genetically modified TILs comprises a genetic modification that enhances expression of CCR2, CCR4,CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL-4, IL-7, IL-10, IL-15 (elected species), IL-21, the NOTCH 1/2 intracellular domain (ICD), and the NOTCH ligand mDLLI.
Claim 151 encompasses the method of claim 136, wherein the genetically modifying step is performed using a programmable nuclease that mediates the generation of a double-strand or single-strand break at said one or more immune checkpoint genes.
Claim 137 encompasses the method of claim 136, wherein the genetically modifying is performed using one or more methods selected from a CRISPR method, a TALE method, a zinc finger method, and a combination thereof.
Claim 153 encompasses the method of claim 136, wherein the tumor sample obtained from the subject is processed into tumor fragments or a tumor digest, prior to obtaining the first population of TILs.
Claim 154 encompasses the method of claim 136, wherein the third population of TILs harvested in step (e) exhibits an increased subpopulation of CD8+ cells relative to the first and/or second population of TILs.
Claim 155 encompasses the method of claim 136, wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, non-small-cell lung cancer (NSCLC), lung cancer, bladder cancer, breast cancer, triple negative breast cancer, cancer caused by human papilloma virus, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), renal cancer, and renal cell carcinoma.
Claim 156 encompasses the method of claim 136, wherein the third population of TILs harvested in step (e) is cryopreserved using a cryopreservation process.
Claim 157 encompasses the method of claim 136, wherein the cell culture medium for the first expansion and/or the cell culture medium for the second expansion further comprise a protein kinase B (AKT) inhibitor.
Claim 158 encompasses the method of claim 157, wherein the protein kinase B (AKT) inhibitor is selected from the group consisting of ipatasertib, GSK690693, GSK2141795, GSK2110183, AZD5363, GDC-0068, AT7867, CCT128930, MK-2206, BAY 1125976, Perifosine, Oridonin, Herbacetin, Tehranolide, Isoliquiritigenin, Scutellarin, Honokiol, SB-203580, SC79, Miltefosine, PF- 04691502, A-674563, Archexin, oleandrin, AKT inhibitor VIII, AT13148, TIC 10, afuresertib, uprosertib, triciribine, SR13668, A-443654, Deguelin, PHT-427, Miransertib, TAS-117, MSC2363318A, Triciribine phosphate, XL418, SC66, Vevorisertib, PX-316, API-1, ALM301, COTI-2, DC 120, TD52, Artemisinin, Guggulsterone, Cenisertib, 3CAI, Borussertib, PF- AKT400, Hu7691, and pharmaceutically acceptable salts thereof.
Claim 159 encompasses a method of treating a patient or subject having cancer, comprising:
(a) obtaining and/or receiving a first population of TILs from a tumor sample that contains a mixture of tumor and the TILs, wherein the tumor sample is obtained from a surgical resection, needle biopsy, core biopsy, or small biopsy from the patient or subject;
(b) selecting CD39LO/CD69LO and/or CD39/CD69 double negative TILs from the first population of TILs in (a) to obtain a population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs;
(c) performing a first expansion by culturing the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed for about 3-11 days to obtain the second population of TILs;
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-11 days to obtain the third population of TILs;
(e) harvesting the third population of TILs obtained from step (d);
(f) transferring the harvested third TIL population from step (e) to an infusion bag; and
(g) administering to the patient or subject a therapeutically effective dosage of the harvested third TIL population.
Claim 160 encompasses the method of claim 159, wherein the patient or subject is further administered a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs, and/or an IL-2 regimen starting on the same day as or on the day after administering the third population of TILs.
Claim 162 encompasses the method of claim 160, wherein (a) the non-myeloablative lymphodepletion regimen comprises cyclophosphamide at a dose of 60 mg/kg/day for two days followed by fludarabine at a dose of 25 mg/m2/day for five days; and/or (b) the IL-2 regimen is a high-dose IL-2 regimen comprising 600,000 or 720,000 IU/kg of aldesleukin, or a biosimilar or variant thereof.
Claim 162 encompasses the method of claim 159, wherein the therapeutically effective dosage of the harvested third population of TIL comprises from about 1 x109 to about 100 x109 TILs.
The specification discloses a closed process for expanding CD39lo/CD69lo and/or CD39-/CD69- double negative tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs and a method of treating a patient or subject having cancer by administering the patient or subject in vitro expanded CD39lo/CD69lo and/or CD39-/CD69- double negative autologous tumor infiltrating lymphocytes (TILs).
Regarding genetically modified TILs (claims 146-147, 151-152) such as any genetic modification
that reduces expression of any one or more CD39 and CD69 (elected species), CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFI3, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1,BTLA, CD160, TIGIT, TET2, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP 10, CASP3, CASP6, CASP7, FADD, FAS,SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCYlA2, GUCYlA3, GUCYlB2, GUCYlB3, and TOX, and/or
(b) the genetically modified TILs comprises a genetic modification that enhances expression of CCR2, CCR4,CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL-4, IL-7, IL-10, IL-15 (species), IL-21, the NOTCH 1/2 intracellular domain (ICD), and the NOTCH ligand mDLLI (claim 148), there is no engineered TILs defective in CD39 and CD69 while enhance IL-15 using CRISPR/Cas9, TALE, zinc finger mediated gene editing or in combination thereof.
There is no direction or guidance on how to make genetically modified TILs having reduced expression of any and all CD39 and CD69 (elected species), CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFI3, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1,BTLA, CD160, TIGIT, TET2, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP 10, CASP3, CASP6, CASP7, FADD, FAS,SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCYlA2, GUCYlA3, GUCYlB2, GUCYlB3, and TOX, and/or increased expression of any and all CCR2, CCR4,CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL-4, IL-7, IL-10, IL-15 (species), IL-21, the NOTCH 1/2 intracellular domain (ICD), and the NOTCH ligand mDLLI.
There is no objective evidence of any TILs comprising genetically modified gene to reduce any one or more CD39, and CD69, much less inactivate all CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFI3, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1,BTLA, CD160, TIGIT, TET2, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP 10, CASP3, CASP6, CASP7, FADD, FAS,SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCYlA2, GUCYlA3, GUCYlB2, GUCYlB3, and TOX and/or enhances expression of IL-15 (elected species), let alone all CCR2, CCR4,CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL-4, IL-7, IL-10, IL-15, IL-21, the NOTCH 1/2 intracellular domain (ICD), and the NOTCH ligand mDLLI using any programmable nuclease that mediates double-strand or single-strand brake at one or more immune checkpoint genes, or using CRISPR, TALE, zinc finger method alone or in combination (claims 151-152) in the specification as filed.
There are no working examples of TILs population having the loss of all genes encoding proteins above and enhanced T cell-mediated specific lysis of cancer cells, improve progression free survival (PFS) in any cancer patients.
There is no objective evidence of any genetically modified TILs using TALENs to disrupt any and all genes above and retain their cytotoxic capacity in vitro or in vivo.
Regarding treating cancer patient by administering any third TIL population (claim 159), the specification discloses administering ex-vivo expanded autologous, which is human leukocyte antigen (HLA) matched, CD39lo/CD69lo and/or CD39-/CD69- double negative tumor specific CD8+ infiltrating lymphocytes (TILs) for adoptive cell immunotherapy (ACT). TILs are isolated from patient and expanded in vitro, before re-infusion into lymphodepleted patients, from which they were initially isolated. TIL preparations containing elevated numbers of tumor-specific CD8+ T cells with stem-cell-like properties (Stem) mediate clinical responses and persist long term.
However, the specification does not teach treating patient using ex vivo-expanding any heterologous (HLA non-matched donor) CD8+ tumor-infiltrating lymphocytes (TILs) for treating solid tumor.
There is no objective evidence in the specification as filed administering melanoma tumor antigen specific TILs can treat other tumor such as ovarian cancer, cervical cancer, non-small-cell lung cancer (NSCLC), lung cancer, bladder cancer, breast cancer, triple negative breast cancer, cancer caused by human papilloma virus, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), renal cancer, and renal cell carcinoma.
Regarding aldesleukin variant thereof (claim 161), the term “variant” encompasses any substitution, deletion, addition or a combination thereof, the specification discloses aldesleukin comprises the amino acid sequence of SEQ ID NO: 4.
However, the specification does not teach any variant of SEQ ID NO: 4 comprising any substitution, deletion, addition or a combination thereof, such that the variant maintains structure and function.
Chang (Journal Biol Chem 23(7): 13349-13355, 1996; PTO 892) teaches interleukin 2 having a point mutation at position 51 Proline for threonine (T51P) altered tertiary structure as revealed in the near-UV CD spectrum, reduced internalization of high affinity receptors. Consequently, although it possesses ~10-fold lower binding affinity. The dissociation rate constant for this analog was only slightly faster than that for IL-2. Deletions in the cytoplasmic domain of the IL-2R β-subunit resulted in the loss of signaling in response to IL-2 without influencing internalization.
It is unpredictable which amino acid substitution, deletion, addition or a combination thereof such that the variant or mutant maintains 3-D structure, receptor binding and biological activity.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
A “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967) (“If n-propylamine had been used in making the compound instead of n-butylamine, the compound of claim 13 would have resulted.
A “patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”), see MPEP 2163.IIAii
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
As such, it is submitted that a skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus of IL-2 variants, and genetically modified TILs encompassed by the claimed methods at the time of filing.
Therefore, only (1) a method of expanding CD39lo/CD69lo and/or CD39-/CD69- double negative, tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs and (b) a method of treating a patient or subject having cancer by administering the patient or subject in vitro expanded CD39lo/CD69lo and/or CD39-/CD69- double negative, CD8+ autologous tumor infiltrating lymphocytes (TILs), but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 136, 137, 138, 142, 149, 148, 151-153, 155-156 and 159-162 are rejected under 35 U.S.C. 103 as being unpatentable over Simpson-Abelson et al (WO2019100023, published May 23, 2019; PTO 892) in view of Krishna et al (Science 370: 1328-1334, December 11, 2020; PTO 892).
Claim 136 encompasses a method of expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs, the method comprising the steps of:
(a) obtaining and/or receiving a first population of TILs from a tumor sample that contains a mixture of tumor and the TILs, wherein the tumor sample is obtained from a surgical resection, needle biopsy, core biopsy, or small biopsy from a cancer in a patient or subject having cancer;
(b) selecting CD39LO/CD69LO and/or CD39/CD69 double negative TILs from the first population of TILs in (a) to obtain a population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs;
(c) performing a first expansion by culturing the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed for about 3-11 days to obtain the second population of TILs;
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-11 days to obtain the third population of TILs;
(e) harvesting the third population of TILs obtained from step (d); and
(f) transferring the harvested third TIL population from step (e) to an infusion bag.
Claim 137 encompasses the method of claim 136, wherein the third population of TILs comprises a therapeutic population of TILs.
Claim 138 encompasses the method of claim 136, wherein i) the first expansion is performed in a closed container providing a first gas-permeable surface area; and/or ii) the second expansion is performed in a closed container providing a second gas- permeable surface area.
Claim 140 encompasses the method of claim 136, wherein the method further comprises adding the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs selected in step (b) into a closed system.
Claim 142 encompasses the method of claim 140, wherein the transition i) from step (b) to step (c);ii) from step (c) to step (d);iii) from step (d) to step (e); and/or iv) from step (e) to step (f) occurs without opening the system.
Claim 146 encompasses the method of claim 136, wherein the method further comprises genetically modifying the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs and/or the second population of TILs and/or the third population of TILs at any time prior to the harvesting such that the third population of TILs comprise genetically modified TILs.
Claim 147 encompasses the method of claim 146, wherein
(a) the modifying is carried out on the second population of TILs from the first expansion, or the third population of TILs from the second expansion, or both;
(b) the modifying is carried out on the second population of TILs from the first expansion and before the second expansion;
(c) the modifying is carried out on the third population of TILs from the second expansion; and/or
(d) the modifying is carried out after the harvesting.
Claim 148 encompasses the method of claim 146, wherein:
(a) the genetically modified TILs further comprises an additional a genetic modification that reduces expression of one or more of CD39 (elected species), CD69 (elected species), CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFI3, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1,BTLA, CD160, TIGIT, TET2, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP 10, CASP3, CASP6, CASP7, FADD, FAS,SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCYlA2, GUCYlA3, GUCYlB2, GUCYlB3, and TOX, and/or
(b) the genetically modified TILs comprises a genetic modification that enhances expression of CCR2, CCR4,CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL-4, IL-7, IL-10, IL-15 (elected species), IL-21, the NOTCH 1/2 intracellular domain (ICD), and the NOTCH ligand mDLLI.
Claim 151 encompasses the method of claim 136, wherein the genetically modifying step is performed using a programmable nuclease that mediates the generation of a double-strand or single-strand break at said one or more immune checkpoint genes.
Claim 152 encompasses the method of claim 136, wherein the genetically modifying is performed using one or more methods selected from a CRISPR method, a TALE method, a zinc finger method, and a combination thereof.
Claim 153 encompasses the method of claim 136, wherein the tumor sample obtained from the subject is processed into tumor fragments or a tumor digest, prior to obtaining the first population of TILs.
Claim 154 encompasses the method of claim 136, wherein the third population of TILs harvested in step (e) exhibits an increased subpopulation of CD8+ cells relative to the first and/or second population of TILs.
Claim 155 encompasses the method of claim 136, wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, non-small-cell lung cancer (NSCLC), lung cancer, bladder cancer, breast cancer, triple negative breast cancer, cancer caused by human papilloma virus, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), renal cancer, and renal cell carcinoma.
Claim 156 encompasses the method of claim 136, wherein the third population of TILs harvested in step (e) is cryopreserved using a cryopreservation process.
Claim 159 encompasses a method of treating a patient or subject having cancer, comprising:
(a) obtaining and/or receiving a first population of TILs from a tumor sample that contains a mixture of tumor and the TILs, wherein the tumor sample is obtained from a surgical resection, needle biopsy, core biopsy, or small biopsy from the patient or subject;
(b) selecting CD39LO/CD69LO and/or CD39/CD69 double negative TILs from the first population of TILs in (a) to obtain a population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs;
(c) performing a first expansion by culturing the population of CD39LO/CD69LO and/or CD39/CD69 double negative enriched TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the first expansion is performed for about 3-11 days to obtain the second population of TILs;
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-11 days to obtain the third population of TILs;
(e) harvesting the third population of TILs obtained from step (d);
(f) transferring the harvested third TIL population from step (e) to an infusion bag; and
(g) administering to the patient or subject a therapeutically effective dosage of the harvested third TIL population.
Claim 160 encompasses the method of claim 159, wherein the patient or subject is further administered a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs, and/or an IL-2 regimen starting on the same day as or on the day after administering the third population of TILs.
Claim 162 encompasses the method of claim 160, wherein (a) the non-myeloablative lymphodepletion regimen comprises cyclophosphamide at a dose of 60 mg/kg/day for two days followed by fludarabine at a dose of 25 mg/m2/day for five days; and/or (b) the IL-2 regimen is a high-dose IL-2 regimen comprising 600,000 or 720,000 IU/kg of aldesleukin, or a biosimilar or variant thereof.
Claim 162 encompasses the method of claim 159, wherein the therapeutically effective dosage of the harvested third population of TIL comprises from about 1 x109 to about 100 x109 TILs.
Regarding claims 136, 137, 138, 142, Simpson-Abelson teaches a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising:
(a) obtaining a first population of TILs from a fine needle aspirate (FNA) or a small biopsy obtained from a tumor in a patient;
(b) adding the first population into a closed system;
(c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the cell culture medium is supplemented with OKT-3 at any one of days 1-3, wherein the first expansion is performed for about 3 days to about 12 days in order to obtain the second population of TILs, wherein the second population of TILs comprises at least 5 c 107 TILs by about 3 days to about 12 days when the first population of TILs is from a small biopsy, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area as per claim 138, wherein the first expansion is performed for about 3 days to about 12 days to obtain the second population of TILs, wherein the second population of TILs is at least 25-fold greater in number than the first population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system as per claim 142;
(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 3 days to about 12 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system;
(e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and
(f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system, see entire document, para. [0095], in particular.
Regarding claim 146, Simpson-Abelson teaches that the first TIL population (sometimes referred to as the bulk TIL population) or the second TIL population (which can in some embodiments include populations referred to as the REP TIL populations) can be subjected to genetic modifications for suitable treatments prior to expansion or after the first expansion and prior to the second expansion, see para. [00533].
Regarding claim 148, Simpson-Abelson teaches that Simpson-Abelson teaches that non-limiting examples of genes that may be silenced or inhibited by permanently gene-editing TILs via a CRISPR method include PD-l, CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGF , PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, BTLA, CD160, TIGIT, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP10, CASP3, CASP6, CASP7, FADD, FAS, SMAD2, SMAD3, SMAD4, SMAD 10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCY1A2, GUCY1A3, GUCY1B2, and GUCY1B3, see para. [001084]. The term “or” does not require “CD39”, “CD69”.
Non-limiting examples of genes that may be enhanced by permanently gene-editing TILs via a CRISPR method include CCR2, CCR4, CCR5, CXCR2, CXCR3, CX3CR1, IL-2, IL12, IL-15 (elected species), and IL-21, see para. [001085].
Regarding claim 151, Simpson-Abelson teaches the gene-editing process may comprise the use of a programmable nuclease that mediates the generation of a double-strand or single-strand break at one or more immune checkpoint genes, see para. [001077].
Regarding claim 152, Simpson-Abelson teaches that genetically modification is performing using CRISPR method, see para. [001086] to [001087] or a TALE method, see para. [001088] to [001090], [001093] to [001094] or a zinc finger method, see para. [001095] to [001096].
Regarding claim 153, Simpson-Abelson teaches that the TILs are obtained from tumor digests, prior to obtaining the first population of TILs, see para. [00507] to [00509]. In some embodiments, tumor digests were generated by incubation in enzyme media, for example but not limited to RPMI 1640, 2mM GlutaMAX, 10 mg/mL gentamicin, 30 U/mL DNase, and 1.0 mg/mL collagenase, followed by mechanical dissociation (GentleMACS, Miltenyi Biotec, Auburn, CA). After placing the tumor in enzyme media, the tumor can be mechanically dissociated for approximately 1 minute. The solution can then be incubated for 30 minutes at 37 °C in 5% CO2 and it then mechanically disrupted again for approximately 1 minute. After being incubated again for 30 minutes at 37 °C in 5% CO2, the tumor can be mechanically disrupted a third time for approximately 1 minute. In some embodiments, after the third mechanical disruption if large pieces of tissue were present, 1 or 2 additional mechanical dissociations were applied to the sample, with or without 30 additional minutes of incubation at 37 °C in 5% CO2. In some embodiments, at the end of the final incubation if the cell suspension contained a large number of red blood cells or dead cells, a density gradient separation using Ficoll can be performed to remove these cells, see para. [00507] to [00509].
Regarding claim 155, Simpson-Abelson teaches that the cancer or tumor is selected from the group consisting of lung, melanoma, head and neck, cervical, ovarian, pancreatic, glioblastoma, colorectal, and sarcoma, see para. [0085], non-small cell lung carcinoma (NSCLC), see para. [0086].
Regarding claim 156, Simpson-Abelson teaches that the TIL population obtained from the first expansion, referred to as the second TIL population, can be subjected to a second expansion (which can include expansions sometimes referred to as REP) and then cryopreserved in manufacturing process, see para. [00172].
Regarding claim 159, Simpson-Abelson teaches a method for treating a subject with cancer, the method comprising administering expanded tumor infiltrating lymphocytes (TILs) comprising:
(a) obtaining a first population of TILs from a fine needle aspirate (FNA) or a small biopsy from a tumor resected from a subject;
(b) adding the first population into a closed system;
(c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs, wherein the cell culture medium is supplemented with OKT-3 at any one of days 1-3, wherein the first expansion is performed for about 3 days to about 12 days in order to obtain the second population of TILs, wherein the second population of TILs comprises at least 5 c 107 TILs by about 3 days to about 12 days when the first population of TILs is from a small biopsy, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs, wherein the second population of TILs is at least 25-fold greater in number than the first population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system;
(d) performing a second expansion by supplementing the cell culture medium of the
second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 3 days to about 12 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system;
(e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and
(f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system;
(g) optionally cryopreserving the infusion bag comprising the harvested TIL population from step (f) using a cryopreservation process; and
(h) administering a therapeutically effective dosage of the third population of TILs from the infusion bag in step (g) to the patient, see para. [00130].
Regarding claim 160, Simpson-Abelson teaches that prior to administering a therapeutically effective dosage of TIL cells in step (h), a non-myeloablative lymphodepletion regimen has been administered to the patient, see para. [00148]. In some embodiments, the method further comprises the step of treating the patient with a high-dose IL-2 regimen starting on the day after administration of the TIL cells to the patient in step (h), see para. [00150].
Regarding claim 161, Simpson-Abelson teaches that the non-myeloablative lymphodepletion regimen comprises the steps of 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, see para. [00149].
In some embodiments, the high-dose IL-2 regimen comprises 600,000 or 720,000 IU/kg administered as a 15-minute bolus intravenous infusion every eight hours until tolerance, see para. [00151]. Suitable recombinant forms of IL-2 such as aldesleukin (PROLEUKIN, available commercially from multiple suppliers in 22 million IU per single use vials), as well as the form of recombinant IL-2 commercially supplied by CellGenix, Inc., Portsmouth, NH, USA (CELLGRO GMP) or ProSpec-Tany TechnoGene Ltd., East Brunswick, NJ, USA (Cat. No. CYT-209-b) and other commercial equivalents from other vendors. Aldesleukin (des-alanyl-l, serine-l25 human IL-2) is a nonglycosylated human recombinant form of IL-2 with a molecular weight of approximately 15 kDa. The amino acid sequence of aldesleukin suitable for use in the invention is given in Table 2 (SEQ ID NO:4), see para. [00453].
Regarding claim 162, Simpson-Abelson teaches that the therapeutic effective dosage of TIL is about 2.3x1010 to about 13.7 x1010. In some embodiments, the therapeutically effective dosage is about 7.8xl010 TILs, particularly of the cancer is melanoma. The reference about 2.3x1010 to about 13.7 x1010 is within the claimed range of from about 1 x 109 to about 100 x 109, para. [00575]. Example of the number of TILs is in the range of 1xl09, 2x109, 3x109, 4x109, 5x109, 6x109, 7x109, 8x109, 9xl09, lx1010, 2xl010, 3xl010, 4xl010, 5xl010, 6xl010, 7xl010, 8xl010, 9xl010, lx1011, see para. [00458].
Simpson-Abelson does not teach selecting CD39 and CD69 double negative TILs from tumor sample (first population of TILs in (a) to obtain a population of CD39 and CD69 double negative enriched TILs and performs a first expansion of said CD39 and CD69 double negative as per claim 136 and wherein the TILs harvested in step € exhibits an increased subpopulation of CD8+ cells relative to the first and/or second population of TILs as per claim 154.
However, Krishna et al has identified memory-progenitor CD39-negatgive stem-like phenotype (CD39-CD69-) and CD8+ associated with complete cancer regression and TIL persistence whereas a terminally differentiated CD39-positve state (CD39+CD69+) and CD8+ associated with poor TIL persistence, see entire document, abstract, p. 1, right col, p. 6, Fig. 4, p. 7, left col. in particular. The 3733 complete response (CR) infusion product shows CD39, CD69 phenotype of bulk CD8+ TILs, consistent with the idea of TIL expansion from the progenitor stem-like state, see Fig. 33A 32.7, p. 7, left col.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Simpson-Abelson and Krishna by preselecting TILs that express CD39lo/CD69lo and/or CD39-/CD69- double negative from resected tumor tissue as taught by Krishana for in vitro culture using the rapid expansion procedure of Simpson-Abelson having increased CD8+ phenotype as taught by Krishna to arrive at the claimed invention with a reasonable expectation success, i.e., CD39-, CD69-phenotype of bulk CD8+ TILs having progenitor stem-like state to prevent T-cell exhaustion.
One of ordinary skill in the art would have been motivated to do so because Krishna teaches that memory-progenitor CD39-negatgive stem-like phenotype (CD39-CD69-) and CD8+ associated with complete cancer regression and TIL persistence.
One of ordinary skill in the art would have had a reasonable expectation of success in selecting CD39/CD69 double negative phenotype TILs for expansion because Krishna teaches that persistence of memory-progenitor CD39-negatgive stem-like phenotype (CD39-CD69-) and CD8+ TILs is associated with complete cancer regression in adoptive cell transfer therapy, see abstract, in particular.
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 157 and 158 are rejected under 35 U.S.C. 103 as being unpatentable over Simpson-Abelson et al (WO2019100023, published May 23, 2019; PTO 892) in view of Krishna et al (Science 370: 1328-1334, December 11, 2020; PTO 892) as applied to claims 136, 137, 138, 142, 149, 148, 151-153, 155-156 and 159-162 mentioned above and further in view of Chartier-Courtaud et al (US20220033775, claimed earliest priority to 62/756,031, filed November 5, 2018; PTO 892) or Forman et al (US20180320133, published November 8, 2018; PTO 892) or Crompton et al (Cancer Res 75(2): 296-305, 2015; PTO 1449).
The teachings of Simpson-Abelson et al and Krishna et al have been discussed supra.
The references do not teach the method of expanding tumor infiltrating lymphocytes (TILs) by including a protein kinase B (AKT) inhibitor such as ipatasertib as per claim 158 in the cell culture medium of the first expansion and/or second expansion as per claim 157.
However, Chartier-Courtaud teaches a method of treating a cancer in a patient suffering therefrom with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
(a) resecting a tumor from the patient;
(b) obtaining a first population of TILs from the tumor;
(c) performing an initial expansion of the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the second population of TILs is at least 5-fold greater in number than the first population of TILs, wherein the first cell culture medium comprises IL-2, a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and at least one AKT pathway inhibitor (AKTi), and wherein the initial expansion is performed over a period of 21 days or less;
(d) performing a rapid expansion of the second population of TILs in a second cell culture medium to obtain a third population of TILs, wherein the third population of TILs is at least 50-fold greater in number than the second population of TILs after 7 days from the start of the rapid expansion; wherein the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist and at least one AKT pathway inhibitor (AKTi), and wherein the rapid expansion is performed over a period of 14 days or less;
(e) harvesting the third population of TILs; and (f) administering a therapeutically effective portion of the third population of TILs to the patient.
Examples of AKT inhibitor include afuresertib, uprosertib, ipatasertib (see para. [0348]), AT7867 (see para. [0350]), AT13148, MK-2206, LY294002, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof, see para. [0043], [0048], [0053], [0365].
Regarding claim 157, Chartier-Courtaud teaches the use of Akt inhibitors during the initial expansion of TILs and during the second expansion of TILs. In other embodiments, the invention provides methods using a priming initial expansion comprising exposing TILs to Akt inhibitor, OKT-3 and IL-2 in culture to achieve an initial activation of TILs and a second rapid expansion comprising exposing TILs to additional OKT-3, IL-2 and APCs in culture to boost the initial activation of TILs, see para. [0366]. In other embodiments, the invention provides methods using a priming initial expansion comprising exposing TILs to Akt inhibitor, OKT-3, IL-2 and APCs in culture to achieve an initial activation of TILs and a second rapid expansion comprising exposing TILs to additional OKT-3, IL-2 and APCs in culture to boost the initial activation of TILs, see para. [0366] to [0367].
Likewise, Forman et al teaches methods entail culturing and/or expanding T cells, e.g., CAR-expressing T cells, in the presence of an Akt inhibitor, e.g., Akt Inhibitor VIII (CAS No. 612847-09-3). T cell types that can be cultured and/or expanded in the presence of an Akt inhibitor include: CAR T cells, tumor Infiltrating lymphocytes (“TIL”), TCR-engineered T cells, or T cell clones, see entire document, Summary, in particular.
Akt inhibitors include: the Akt inhibitor is selected from the group consisting of: Akt Inhibitor VIII (1,3-dihydro-1-[1-[[4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl]methyl]-4-piperidinyl]-2H-benzimidazol-2-one), Akt Inhibitor X (2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine, monohydrochloride), MK-2206 (8-(4-(1-aminocyclobutyl)phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one), uprosertib (N-((S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide), ipatasertib ((S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one), AZD 5363 (4-Piperidinecarboxamide, 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)), perifosine, GSK690693, GDC-0068, tricirbine, CCT128930, A-674563, PF-04691502, AT7867, miltefosine, PHT-427, honokiol, triciribine phosphate, and KP372-1A (10H-indeno[2,1-e]tetrazolo[1,5-b][1,2,4]triazin-10-one), Akt Inhibitor IX (CAS 98510-80-6), see para. [0005].
Additional Akt inhibitors include: ATP-competitive inhibitors, e.g. isoquinoline-5-sulfonamides (e.g., H-8, H-89, NL-71-101), azepane derivatives (e.g., (−)-balanol derivatives), aminofurazans (e.g., GSK690693), heterocyclic rings (e.g., 7-azaindole, 6-phenylpurine derivatives, pyrrolo[2,3-d]pyrimidine derivatives, CCT128930, 3-aminopyrrolidine, anilinotriazole derivatives, spiroindoline derivatives, AZD5363, A-674563, A-443654), phenylpyrazole derivatives (e.g., AT7867, AT13148), thiophenecarboxamide derivatives (e.g., Afuresertib (GSK2110183), 2-pyrimidyl-5-amidothiophene derivative (DC120), uprosertib (GSK2141795); Allosteric inhibitors, e.g., 2,3-diphenylquinoxaline analogues (e.g., 2,3-diphenylquinoxaline derivatives, triazolo[3,4-f][1,6]naphthyridin-3(2H)-one derivative (MK-2206)), alkylphospholipids (e.g., Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-18-OCH3) ilmofosine (BM 41.440), miltefosine (hexadecylphosphocholine, HePC), perifosine (D-21266), erucylphosphocholine (ErPC), erufosine (ErPC3, erucylphosphohomocholine), indole-3-carbinol analogues (e.g., indole-3-carbinol, 3-chloroacetylindole, diindolylmethane, diethyl 6-methoxy-5,7-dihydroindolo [2,3-b]carbazole-2,10-dicarboxylate (SR13668), OSU-A9), Sulfonamide derivatives (e.g., PH-316, PHT-427), thiourea derivatives (e.g., PIT-1, PIT-2, DM-PIT-1, N-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-N′-(3-bromophenyl)-thiourea), purine derivatives (e.g., Triciribine (TCN, NSC 154020), triciribine mono-phosphate active analogue (TCN-P),4-amino-pyrido[2,3-d]pyrimidine derivative API-1, 3-phenyl-3H-imidazo[4,5-b]pyridine derivatives, ARQ 092), BAY 1125976, 3-methyl-xanthine, quinoline-4-carboxamide, 2-[4-(cyclohexa-1,3-dien-1-yl)-1H-pyrazol-3-yl]phenol, 3-oxo-tirucallic acid, 3α- and 3β-acetoxy-tirucallic acids, acetoxy-tirucallic acid; and irreversible inhibitors, e.g., natural products, antibiotics, Lactoquinomycin, Frenolicin B, kalafungin, medermycin, Boc-Phe-vinyl ketone, 4-hydroxynonenal (4-HNE), 1,6-naphthyridinone derivatives, and imidazo-1,2-pyridine derivatives, see para. [0006].
Crompton teaches that Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics, see entire document, title, in particular. Akti-treated TIL have enhanced expression of naïve-associated genes and decreased expression of effector memory-associated genes, see Figure 2D and enhances persistence of human TIL and improves survival of transferred anti-tumor cells in mouse model of ACT, see p. 8, in particular.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Simpson-Abelson and Krishna with teachings of Chartier-Courtaud, Forman and Crompton by including any one of the protein kinase B (AKTi) inhibitor such as ipatasertib in the culture medium of the first and second expansion to arrive at the claimed invention with a reasonable expectation success, e.g., enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.
One of ordinary skill in the art would have been motivated to have made and used any one of the AKT inhibitor for TILs expansion as taught by Chartier-Courtaud or Forman because it would be desirable to expand potent tumor-specific lymphocytes with memory cell characteristics as taught by Crompton.
One of ordinary skill in the art would have had a reasonable expectation of success in using AKT inhibitor for TILs expansion because AKT inhibitor for TILs expansion was known in the art, as taught by Chartier-Courtaud, Forman and Crompton.
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
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 claims at issue 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); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
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Claims 136-138, 140, 142, 153, 154, 155, 159-162 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-3 of copending Application No. 19/011,427 in view of Krishna et al (Cancer Immunotherapy 370: 1328-1334, December 11, 2020; PTO 892).
Copending claim 1 recites a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs using a two-step expansion process comprising:
(i) performing a first expansion step of a first population of TILs by culturing a fine needle aspirate (FNA) tumor biopsy or a small biopsy comprising the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the first culture medium comprises IL-2, and wherein the first expansion is performed for 3-11 days; and
(ii) performing a second expansion step by culturing the second population of TILs in a second culture medium comprising IL-2, OKT-3, and APCs, to produce a third population of TILs, wherein the second expansion is performed for 3-11 days,
wherein the third population of TILs is the therapeutic population of TILs comprising from about 1 x 109 to about 10 x 1010 TILs sufficient for a therapeutically effective dosage, wherein said FNA is obtained with a 25-18 gauge needle or small biopsy is obtained with a 16-11 gauge needle, this corresponds to instant claims 136, and 162.
2. (Previously Presented) The method according to claim 1, wherein step (ii) is a rapid expansion process (REP), which corresponds to instant claim 136.
3. (Previously Presented) The method according to claim 2, wherein step (i) is a pre-REP step, which corresponds to instant claim 136.
4. (Previously Presented) The method according to claim 1, wherein after step (ii), the third population of TILs are removed from the second culture medium and cryopreserved in a storage medium, which corresponds to instant claim 136.
9. (Previously Presented) The method according to claim 1, wherein the third population of TILs express CD4, CD8, and TCR aP at levels similar to freshly harvested cells, which corresponds to instant claim 154.
10. (Previously Presented) The method according to claim 1, wherein the APCs are peripheral blood mononuclear cells (PBMCs).
13. (Previously Presented) The method according to claim 1, wherein the APCs are artificial APCs (aAPCs) or autologous APCs.
14. (Previously Presented) The method according to claim 1, wherein the therapeutic population of TILs are infused into a patient, which corresponds to instant claim 161.
18. (Previously Presented) The method according to claim 1, wherein the FNA tumor biopsy or small biopsy is obtained from a tumor selected from the group consisting of lung, melanoma, breast, head and neck, cervical, ovarian, pancreatic, glioblastoma, colorectal, and sarcoma, which corresponds to instant claim 155.
19. (Previously Presented) The method according to claim 18, wherein the lung tumor is a non-small cell lung carcinoma (NSCLC), and wherein the patient has previously undergone surgical treatment.
20. (Previously Presented) The method according to claim 1, wherein the first population of TILs in step (i) are obtained from a FNA tumor biopsy.
22. (Previously Presented) The method according to claim 1, wherein the first population of TILs in step (i) are obtained from a small biopsy.
24. (Previously Presented) The method according to claim 1, wherein step (ii) is repeated one to four times in order to obtain sufficient TILs in the therapeutic population of TILs for a therapeutically effective dosage of the TILs, which is an obvious variation.
The ‘427 application does not teach selecting CD39lo/CD69Lo and/or CD39/CD69 double negative ILGs from the first population of TILs as per claim 136.
However, Krishna et al identified memory-progenitor CD39-negatgive stem-like phenotype (CD39-CD69-) and CD8+ associated with complete cancer regression and TIL persistence whereas a terminally differentiated CD39-positve state (CD39+CD69+) and CD8+ associated with poor TIL persistence, see entire document, abstract, p. 1, right col, p. 6, Fig. 4, p. 7, left col. in particular. The 3733 complete response (CR) infusion product shows CD39, CD69 phenotype of bulk CD8+ TILs, consistent with the idea of TIL expansion from the progenitor stem-like state, see Fig. 33A 32.7, p. 7, left col.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of the ‘427 application and Krishna by preselecting TILs that express CD39lo/CD69lo and/or CD39/CD69 double negative from resected tumor tissue as taught by Krishana for in vitro culture using the rapid expansion procedure of the ‘427 application having increased CD8+ phenotype as taught by Krishna to arrive at the claimed invention with a reasonable expectation success, i.e., CD39-, CD69-phenotype of bulk CD8+ TILs having progenitor stem-like state to prevent T-cell exhaustion.
One of ordinary skill in the art would have been motivated to do so because Krishna teaches that memory-progenitor CD39-negatgive stem-like phenotype (CD39-CD69-) and CD8+ associated with complete cancer regression and TIL persistence.
One of ordinary skill in the art would have had a reasonable expectation of success in selecting CD39/CD69 double negative phenotype TILs for expansion because Krishna teaches persistence of memory-progenitor CD39-negatgive stem-like phenotype (CD39-CD69-) and CD8+ TILs is associated with complete cancer regression in adoptive cell transfer therapy, see abstract, in particular.
This is a provisional double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 157 and 158 are provisionally rejected on the ground of nonstatutory double patenting over claims 1-3 of copending Application No. 19/011,427 in view of Krishna et al (Cancer Immunotherapy 370: 1328-1334, December 11, 2020; PTO 892) as applied to claims 136-138, 140, 142, 153, 154, 155. 159-162 mentioned above and further in view of Chartier-Courtaud et al (US20220033775, claimed earliest priority to 62/756,031, filed November 5, 2018; PTO 892) or Forman et al (US2018320133, published November 8, 2018; PTO 892) or Crompton et al (Cancer Res 75(2): 296-305, 2015; PTO 1449).
The teachings of the ‘427 application and Krishna et al have been discussed supra.
The references do not teach the method of expanding tumor infiltrating lymphocytes (TILs) by including a protein kinase B (AKT) inhibitor such as ipatasertib as per claim 158 in the cell culture medium of the first expansion and/or second expansion as per claim 157.
Chartier-Courtaud teaches a method of treating a cancer in a patient suffering therefrom with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
(a) resecting a tumor from the patient;
(b) obtaining a first population of TILs from the tumor;
(c) performing an initial expansion of the first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein the second population of TILs is at least 5-fold greater in number than the first population of TILs, wherein the first cell culture medium comprises IL-2, a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and at least one AKT pathway inhibitor (AKTi), and wherein the initial expansion is performed over a period of 21 days or less;
(d) performing a rapid expansion of the second population of TILs in a second cell culture medium to obtain a third population of TILs, wherein the third population of TILs is at least 50-fold greater in number than the second population of TILs after 7 days from the start of the rapid expansion; wherein the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist and at least one AKT pathway inhibitor (AKTi), and wherein the rapid expansion is performed over a period of 14 days or less;
(e) harvesting the third population of TILs; and (f) administering a therapeutically effective portion of the third population of TILs to the patient.
Examples of AKT inhibitor include afuresertib, uprosertib, ipatasertib (see para. [0348]), AT7867 (see para. [0350]), AT13148, MK-2206, LY294002, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof, see para. [0043], [0048], [0053], [0365].
Regarding claim 157,. Chartier-Courtaud teaches that the invention provides methods using Akt inhibitors during the initial expansion of TILs and during the second expansion of TILs.
In other embodiments, the invention provides methods using a priming initial expansion comprising exposing TILs to Akt inhibitor, OKT-3 and IL-2 in culture to achieve an initial activation of TILs and a second rapid expansion comprising exposing TILs to additional OKT-3, IL-2 and APCs in culture to boost the initial activation of TILs, see para. [0366]. In other embodiments, the invention provides methods using a priming initial expansion comprising exposing TILs to Akt inhibitor, OKT-3, IL-2 and APCs in culture to achieve an initial activation of TILs and a second rapid expansion comprising exposing TILs to additional OKT-3, IL-2 and APCs in culture to boost the initial activation of TILs, see para. [0367].
Likewise, Forman et al teaches methods entail culturing and/or expanding T cells, e.g., CAR-expressing T cells, in the presence of an Akt inhibitor, e.g., Akt Inhibitor VIII (CAS No. 612847-09-3). T cell types that can be cultured and/or expanded in the presence of an Akt inhibitor include: CAR T cells, Tumor Infiltrating lymphocytes (“TIL”), TCR-engineered T cells, or T cell clones, see entire document, Summary, in particular.
Akt inhibitors include: the Akt inhibitor is selected from the group consisting of: Akt Inhibitor VIII (1,3-dihydro-1-[1-[[4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl]methyl]-4-piperidinyl]-2H-benzimidazol-2-one), Akt Inhibitor X (2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine, monohydrochloride), MK-2206 (8-(4-(1-aminocyclobutyl)phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one), uprosertib (N-((S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)furan-2-carboxamide), ipatasertib ((S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one), AZD 5363 (4-Piperidinecarboxamide, 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)), perifosine, GSK690693, GDC-0068, tricirbine, CCT128930, A-674563, PF-04691502, AT7867, miltefosine, PHT-427, honokiol, triciribine phosphate, and KP372-1A (10H-indeno[2,1-e]tetrazolo[1,5-b][1,2,4]triazin-10-one), Akt Inhibitor IX (CAS 98510-80-6), see para. [0005].
Additional Akt inhibitors include: ATP-competitive inhibitors, e.g. isoquinoline-5-sulfonamides (e.g., H-8, H-89, NL-71-101), azepane derivatives (e.g., (−)-balanol derivatives), aminofurazans (e.g., GSK690693), heterocyclic rings (e.g., 7-azaindole, 6-phenylpurine derivatives, pyrrolo[2,3-d]pyrimidine derivatives, CCT128930, 3-aminopyrrolidine, anilinotriazole derivatives, spiroindoline derivatives, AZD5363, A-674563, A-443654), phenylpyrazole derivatives (e.g., AT7867, AT13148), thiophenecarboxamide derivatives (e.g., Afuresertib (GSK2110183), 2-pyrimidyl-5-amidothiophene derivative (DC120), uprosertib (GSK2141795); Allosteric inhibitors, e.g., 2,3-diphenylquinoxaline analogues (e.g., 2,3-diphenylquinoxaline derivatives, triazolo[3,4-f][1,6]naphthyridin-3(2H)-one derivative (MK-2206)), alkylphospholipids (e.g., Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-18-OCH3) ilmofosine (BM 41.440), miltefosine (hexadecylphosphocholine, HePC), perifosine (D-21266), erucylphosphocholine (ErPC), erufosine (ErPC3, erucylphosphohomocholine), indole-3-carbinol analogues (e.g., indole-3-carbinol, 3-chloroacetylindole, diindolylmethane, diethyl 6-methoxy-5,7-dihydroindolo [2,3-b]carbazole-2,10-dicarboxylate (SR13668), OSU-A9), Sulfonamide derivatives (e.g., PH-316, PHT-427), thiourea derivatives (e.g., PIT-1, PIT-2, DM-PIT-1, N-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-N′-(3-bromophenyl)-thiourea), purine derivatives (e.g., Triciribine (TCN, NSC 154020), triciribine mono-phosphate active analogue (TCN-P),4-amino-pyrido[2,3-d]pyrimidine derivative API-1, 3-phenyl-3H-imidazo[4,5-b]pyridine derivatives, ARQ 092), BAY 1125976, 3-methyl-xanthine, quinoline-4-carboxamide, 2-[4-(cyclohexa-1,3-dien-1-yl)-1H-pyrazol-3-yl]phenol, 3-oxo-tirucallic acid, 3α- and 3β-acetoxy-tirucallic acids, acetoxy-tirucallic acid; and irreversible inhibitors, e.g., natural products, antibiotics, Lactoquinomycin, Frenolicin B, kalafungin, medermycin, Boc-Phe-vinyl ketone, 4-hydroxynonenal (4-HNE), 1,6-naphthyridinone derivatives, and imidazo-1,2-pyridine derivatives, see para. [0006].
Crompton teaches that Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics, see entire document, title, in particular. Akti-treated TIL have enhanced expression of naïve-associated genes and decreased expression of effector memory-associated genes, see Figure 2D and enhances persistence of human TIL and improves survival of transferred anti-tumor cells in mouse model of ACT, see p. 8, in particular.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of the ‘427 application and Krishna with teachings of Chartier-Courtaud, Forman and Crompton by including any one of the protein kinase B (AKT) inhibitor such as ipatasertib in the culture medium of the first and second expansion to arrive at the claimed invention with a reasonable expectation success, e.g., enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.
One of ordinary skill in the art would have been motivated to have made and used any one of the AKT inhibitor for TILs expansion as taught by Chartier-Courtaud or Forman because it would be desirable to expand potent tumor-specific lymphocytes with memory cell characteristics as taught by Crompton.
One of ordinary skill in the art would have had a reasonable expectation of success in using AKT inhibitor for TILs expansion because AKT inhibitor for TILs expansion was known in the art, as taught by Chartier-Courtaud, Forman and Crompton.
This is a provisional double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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