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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/06/2025 has been entered.
Applicant' s amendment and response filed on 10/06/2025 has been received and entered into the case.
Amendments
In the reply filed 10/06/2025, Applicant has amended claims 1, 22 and 45, and newly canceled claim 43.
Claim Status
Claims 1-2, 4, 6-7, 9, 12, 14, 19, 21-22, 29, 31, 33-34, 45, 47, 49-50 and 52 are pending.
Claims 21-22, 29, 31 and 33-34 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Election was made without traverse in the reply filed on 09/26/2024.
Claims 1-2, 4, 6-7, 9, 12, 14, 19, 45, 47, 49-50 and 52 are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 102 and 103
The prior rejections of claims 1-2, 4, 6-7, 9, 12, 14, 19, 45, 47, 49-50 and 52 under 35 U.S.C. 102 and 103 set forth in the prior Office action mailed on 06/06/2025 are withdrawn in light of Applicant’s amendment to claim 1 to recite new limitations that the CAR-T therapy and the IL-18BP are in two different compositions that are administered sequentially, which are not taught by prior art Busser et al.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 6-7, 12, 14, 45, 47, 49 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127) in view of Lichtenstein et al., (Factors predictive of CAR T cell associated hemophagocytic lymphohistiocytosis (HLH) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr4231, p. 1-7) and Canna et al., (J Allergy Clin Immunol. 2017; 139(5): 1698-1701. Prior art of record).
With respect to claim 1, Strati teaches a method of using anakinra, an IL-1 receptor antagonist, to avoid or minimize CAR T-cell therapy-associated toxicity (such as cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis (HLH), i.e., side effects) in a CAR-T therapy (the use of axicabtagene ciloleucel (axi-cel), i.e., an anti-CD19 CAR-T therapy) in a patient diagnosed with a disease (i.e., B-cell lymphoma) associated with expression of a tumor antigen (i.e., CD19 antigen) (see e.g., p. 3123, para 1). Strati teaches the method comprises treating the patients with standard axi-cel therapy (i.e., administration of the CAR-T therapy in a first composition, see p. 3123, para 2), and then “Anakinra was started at a median of 12 days (range, 6-41) after axi-cel infusion” (i.e., an IL-1 receptor antagonist in a second composition, see p. 3123, para 3) to mitigate CAR T-cell therapy-associated toxicity (see e.g., title), and teaches the first and second compositions are different compositions, which are administered sequentially, and the first composition (i.e., the CAR-T therapy) is administered before the second composition (i.e., the IL-1 receptor antagonist anakinra). Strati teaches 4 patients have clinical responses after initiation of anakinra and 4 are refractory (Figure 1A) (see p. 3123, the sentence before the last para).
However, Strati is silent on the second composition comprising an IL-18 binding molecule that is an IL-18 binding protein (IL-18BP) in claim 1.
Lichtenstein teaches in the context of CAR T cell therapy, hemophagocytic lymphohistiocytosis (HLH) occurs in a subset of those with cytokine release syndrome (CRS) (e.g., p. 3, “Introduction”). Lichtenstein teaches in patients with B-cell malignancies treated with anti-CD22 CAR T cells (p. 3, “Introduction”), higher IL-18 levels in the blood are associated with HLH occurrence (see p. 6, “Results” and see the table in the last page modified from Table 1 regarding IL-18 levels in the baseline blood (Day 0) and in the blood after CAR-T cell infusion (Day 5, 9, 13) which shows higher IL-18 levels in HLH at three of the timing points).
Canna teaches hemophagocytic disorders, such as macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), are life-threatening sepsis-like conditions (p. 1698, right col, para 1). Canna teaches extraordinary IL-18 levels are a feature of MAS, and IL-18 also enhances IL-12-driven IFN-g production that is the cytokine most implicated in driving familial forms of HLH (p. 1698, right col, para 2-3). Canna teaches a 6-week-old patient developed MAS-like syndrome with extraordinarily elevated free IL-18 (see Fig 2A) and was refractory to IL-1 blockade anakinra (p. 1698, last para). The patient was given recombinant human IL-18BP (rhIL-18BP), and her overall demeanor improved rapidly and the patient successfully restarted enteral feeding 11 days after rhIL-18BP initiation (e.g., p. 1699, left col, para 1 and Fig 1D). Canna teaches the patient’s improvement, coupled with ongoing studies in HLH and sepsis, help define relevant roles for IL-18, IL-1b, and IFN-g in sepsis-like systemic inflammation (p. 1701, left col, last para). Thus, Canna teaches IL-18BP administration can be used to treat MAS and HLH in patients with elevated IL-18.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of using an IL-1 receptor antagonist anakinra in treating CAR T-cell therapy-associated toxicity as taught by Strati, by combining IL-18BP administration as suggested by Lichtenstein and Canna with a reasonable expectation of success. Since Strati aims to mitigate CAR T-cell therapy-associated toxicity such as hemophagocytic lymphohistiocytosis (HLH) (see e.g., p. 3123, para 1), since Lichtenstein teaches higher IL-18 levels in the blood are associated with HLH occurrence after CAR-T therapy (see p. 6, “Results” and see the table in the last page), and since Canna suggests IL-18BP administration can be used to treat MAS and HLH in human patients with elevated free IL-18 level, one of ordinary skill in the art would have had a reason to combine IL-18BP with the IL-1 receptor antagonist in the second composition of Strati to minimize side effects related to the CAR-T therapy such as hemophagocytic lymphohistiocytosis (HLH).
With respect to claim 2 and claim 4, directed to the limitation wherein the IL-18BP modulates free IL-18 levels in the patient and inhibits IFN-gamma secretion, it must be noted that these wherein clauses do not recite an active step in the claimed method, but only the results of the administration step of the IL-18BP as suggested by Strati in view of Lichtenstein and Canna. MPEP 2111.04 I states a whereby clause (or a wherein clause) “in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, these wherein clauses do not provide any patentable weight in determining patentability of the claimed method. Nevertheless, Canna teaches IL-18BP reduces free IL-18 level (see Fig 2A, green line), and reduces CXCL9 level which is a chemokine induced by IFN-gamma (see Fig 2A, red line), thus teaches and suggests IL-18BP modulates free IL-18 levels in the patient and inhibits IFN-gamma secretion.
With respect to claim 6 and claim 7, directed to the disease being a cancer and further a hematological cancer being a malignant lymphoproliferative condition, as stated supra, Strati teaches the disease being a B-cell lymphoma (see e.g., p. 3123, para 1), and Lichtenstein teaches patients with B-cell malignancies (p. 3, “Introduction”).
With respect to claim 12, directed to the side effects being due to a cytokine release syndrome and wherein side effects include hemophagocytosis, as stated supra, Strati teaches CAR T-cell therapy-associated toxicity, such as cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis (HLH) (see e.g., p. 3123, para 1), and Lichtenstein teaches in the context of CAR T cell therapy, hemophagocytic lymphohistiocytosis (HLH) occurs in a subset of those with cytokine release syndrome (CRS) (e.g., p. 3, “Introduction”).
With respect to claim 14, directed to the IL-18BP decreasing IL-18 levels in the patient, this wherein clause does not recite an active step in the claimed method, but only the results of the administration step of the IL-18BP as suggested by Strati in view of Lichtenstein and Canna. Therefore, this wherein clause does not provide any patentable weight in determining patentability of the claimed method. See MPEP 2111.04 (I). Nevertheless, Canna teaches IL-18BP reduces free IL-18 level (see Fig 2A, green line), thus teaches IL-18BP decreases IL-18 levels in the patient.
With respect to claim 45, directed to the second composition comprising the IL-18BP being administered to the patient as an acute intervention during the CAR-T therapy, it is noted that the limitation “as an acute intervention” does not recite an active step in the claimed method, but only the intended purpose of the administration step of the IL-18BP as suggested by Strati in view of Lichtenstein and Canna, thus does not provide any patentable weight in determining patentability of the claimed method. Nevertheless, Strati teaches the second composition “was started at a median of 12 days (range, 6-41) after axi-cel infusion” (see p. 3123, para 3), and Lichtenstein teaches higher IL-18 levels are found in the blood starting at Day 5 after CAR-T cell infusion (see p. 6, “Results” and see the table in the last page modified from Table 1), thus both suggest the IL-18BP is administered to the patient as an acute intervention during the CAR-T therapy.
With respect to claims 47, 49 and 52, directed to the method further comprising determining an abnormal level of free IL-18 in a body fluid of the patient wherein the level of free IL-18 exceeds the level of free IL-18 in a body fluid of a heathy control subject, the body fluid being secretion fluids and the secretion fluids being serum, these claims are reasonably interpreted as the method further comprises determining the level of free IL-18 in a body fluid serum of the patient using an assay capable of detecting free IL-18 in serum and identifying the patient having the level of free IL-18 exceeding the level of free IL-18 in a body fluid of a heathy control subject. As stated supra, Lichtenstein teaches higher IL-18 levels are found in the blood starting at Day 5 after CAR-T cell infusion (see p. 6, “Results” and see the table in the last page modified from Table 1), and Canna “assessed serum for total IL-18, as well as free IL-18 using a novel assay, and found both to be extraordinarily elevated (Fig 2, A)” (see p. 1699, left col, para 1), thus teaches determining the level of free IL-18 in serum of the patient using an assay and identifying the patient having the level of free IL-18 exceeding the level of free IL-18 in a body fluid of a heathy control subject.
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of determining the level of free IL-18 in serum of the patient having had CAR-T therapy using an assay and identifying the patient having elevated level of free IL-18 in serum as suggested by Lichtenstein and Canna with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to identify patients with elevated free IL-18 that is associated with side effect HLH to administer the IL-18BP treatment.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s argument filed on 10/06/2025 is acknowledged.
Applicant argues that amendment to claim 1 to recite new limitations that the CAR-T therapy and the IL-18BP are in two different compositions that are administered sequentially, overcomes the prior rejection of, or over Busser et al. (Remarks, p. 7-11).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejections have been withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Strati in view of Lichtenstein and Canna as discussed above.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127) in view of Lichtenstein et al., (In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): Cancer Res 2020;80(16 Suppl):Abstract nr4231, p. 1-7) and Canna et al., (J Allergy Clin Immunol. 2017 May; 139(5): 1698-1701. Prior art of record), as applied to claim 1 above, and further in view of Chmielewski et al. (Cell Reports. 2017; 21: 3205-3219. Prior art of record).
With respect to claim 9, as stated supra, Strati teaches the use of axicabtagene ciloleucel (axi-cel), i.e., an anti-CD19 CAR-T therapy (see e.g., p. 3123, para 1), thus teaches a population of cells (i.e., CAR-T cells) is used in the CAR-T therapy which are engineered to express an anti-CD19 CAR. One of ordinary skill in the art would have immediately appreciated that the anti-CD19 CAR would comprise an antigen-binding domain, a transmembrane domain and an intracellular signaling domain.
However, Strati, Lichtenstein and Canna are silent on the CAR-T cells being further engineered to express IL-18.
Chmielewski teaches a population of CAR-T cells engineered to conditionally express IL-18 in the tumor environment to deliver the cytokine ‘‘on demand’’ and to selectively deposit it in the tumor tissue (abstract, p. 3205, last para – p. 3207, 1st para). Chmielewski teaches inducible IL-18 release polarizes CAR T cells toward T-bethigh FoxO1low early effectors in the tumor environment and the IL-18-CAR-T cells exhibit superior activity against cancers that were refractory to CAR T cells without cytokines (abstract, see e.g. p. 3209 and Fig 3).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of using IL-18BP in combination with a CAR-T therapy to treat cancer and to reduce side effects related to the CAR-T therapy suggested by Strati in view of Lichtenstein and Canna, by combining engineering an inducible IL-18 in the CAR-T cells as taught by Chmielewski with a reasonable expectation of success. Since Chmielewski teaches local IL-18 deposition in the tumor tissue by CAR T cells does not increase serum IL-18 levels, and systemic side effects through locally deposited IL-18 are not expected in a clinical situation, and inducible IL-18-CAR T cells are superior compared to CAR T cells without cytokines (p. 3215, left col, last para and abstract), one of ordinary skill in the art would have had a reason to combine engineering the CAR-T cells with an inducible IL-18 in order to improve therapeutic outcome of treating cancer with minimized side effects.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s argument filed on 10/06/2025 is acknowledged and have been discussed above.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127) in view of Lichtenstein et al., (In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr4231, p. 1-7) and Canna et al., (J Allergy Clin Immunol. 2017; 139(5): 1698-1701. Prior art of record), as applied to claim 1 above, and further in view of Uniprot (Uniprot #O95998, IL18BP_HUMAN. Downloaded from https://www.uniprot.org/uniprotkb/O95998/entry. Downloaded on 2/2/26. P. 1-10).
With respect to claim 19, as stated supra, Canna teaches recombinant human IL-18BP (e.g., p. 1699, left col, para 1), thus teaches the IL-18BP is human IL-18BP.
However, Strati, Lichtenstein and Canna are silent on the human IL-18BP being isoform a corresponding to SEQ ID NO: 2.
Uniprot teaches #O95998-2 represents human IL-18BP isoform A (IL-18BPA) and has been chosen as the canonical sequence (see p. 7, “Sequence & Isoforms”). The sequence of human IL-18BP isoform A comprises a sequence that is 100% identical to the sequence of instant SEQ ID NO:2 (see below).
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Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of using human IL-18BP in combination with a CAR-T therapy to reduce side effects related to the CAR-T therapy suggested by Strati in view of Lichtenstein and Canna, by choosing human IL-18BP isoform a corresponding to SEQ ID NO: 2 as taught by Uniprot with a reasonable expectation of success. Since Uniprot teaches human IL-18BP isoform A (IL-18BPA) has been chosen as the canonical sequence that is 100% identical to the sequence of instant SEQ ID NO:2 (see p. 7, “Sequence & Isoforms” and above), one of ordinary skill in the art would have had a reason to choose human IL-18BP isoform a in the method of Strati in view of Lichtenstein and Canna in order to obtain a functional human IL-18BP to reduce side effects.
Furthermore, the successful cloning and sequencing of the cDNA encoding a known protein (human IL-18BP) is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s argument filed on 10/06/2025 is acknowledged and have been discussed above.
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127) in view of Lichtenstein et al., (In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr4231, p. 1-7) and Canna et al., (J Allergy Clin Immunol. 2017; 139(5): 1698-1701. Prior art of record), as applied to claim 1 above, and further in view of Song et al., (Clinical Immunology. 2020 March; 214: 108382, p. 1-9).
Claim 50 is directed to the patient being further administered one check-point inhibitor that is a PD-1 inhibitor.
However, Strati, Lichtenstein and Canna are silent on the patient being further administered a PD-1 inhibitor.
Song summarizes the combination of CAR-T cell therapy with PD-1 blockade for the treatment of hematological malignancies (see e.g., title and abstract). Song teaches the combination of CAR-T cell therapy and programmed cell-death protein-1 (PD-1) blockade has been applied to enhance therapeutic efficacy in preclinical models and clinical trials (abstract and p. 5, section 4 “combined therapy”) and teaches some studies found it synergistic to combine the two novel immunotherapies, and incorporating PD-1 blockade and CAR-T together is proven effective in treating refractory and relapsed patients (p. 6, section 4.4. “Summary”, para 1).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of using IL-18BP in combination with a CAR-T therapy to treat hematological malignancies and to reduce side effects suggested by Strati in view of Lichtenstein and Canna, by combining a PD-1 inhibitor as suggested by Song with a reasonable expectation of success. Since Song teaches the combination of CAR-T cell therapy and PD-1 blockade has been applied to enhance therapeutic efficacy in preclinical models and clinical trials with synergistic effect (abstract and p. 5, section 4 “combined therapy” and p. 6, section 4.4. “Summary”, para 1), one of ordinary skill in the art would have had a reason to combine administering a PD-1 inhibitor with the CAR-T therapy as suggested by Song in order to enhance therapeutic efficacy in treating hematological malignancies.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s argument filed on 10/06/2025 is acknowledged and have been discussed above.
Withdrawn Double Patenting Rejections
The prior rejection of claims 1-2, 4, 6-7, 9, 12, 14, 19, 45, 47, 49-50 and 52 on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent No. 10,882,905 B2 (‘905) in view of Busser et al and Chmielewski et al. is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitations that the CAR-T therapy and the IL-18BP are in two different compositions that are administered sequentially, which are not taught by prior art Busser et al.
New Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 4, 6-7, 9, 12, 14, 19, 45, 47, 49-50 and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-12 and 22-29 of US Patent No. 10,882,905 B2 (‘905) in view of Lichtenstein et al., (In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr4231, p. 1-7), Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127), Chmielewski et al. (Cell Reports. 2017; 21: 3205-3219. Prior art of record) and Song et al., (Clin Immunol. 2020 March; 214: 108382, p. 1-9). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims 1-9, 11-12 and 22-29 of ‘905 recite a method of diagnosing and treating an IL-18 associated disease or disorder comprising quantifying the levels of free IL-18 in a body fluid sample from a subject using an assay capable of detecting free IL-18 in body fluids, diagnosing the subject with an IL-18 associated disease or disorder when the body fluids of said subject have been quantified to have abnormal levels of free IL-18, which exceed the levels of free IL-18 in body fluids of a healthy control subject by at least 5%; administering to the subject having an IL-18 associated disease or disorder a composition comprising IL-18BP or an active fragment thereof, or deletion variants of IL-18BP (claims 1-5), the IL-18 BP is a human IL-18BP isoform a having SEQ ID NO: 7 (claims 6-8, 100% identical to instant SEQ ID NO: 2), the disease is a macrophage activation syndrome (MAS) including primary, secondary and recurrent MAS (claims 9 and 11-12), accompanied by high levels of IL-18 (claims 22-29).
However, cited patented claims are silent on the IL-18 associated disease being side effects related to the CAR-T therapy.
Lichtenstein teaches in the context of CAR T cell therapy, hemophagocytic lymphohistiocytosis (HLH) occurs in a subset of those with cytokine release syndrome (CRS) (e.g., p. 3, “Introduction”). Lichtenstein teaches in patients with B-cell malignancies treated with anti-CD22 CAR T cells (p. 3, “Introduction”), higher IL-18 levels in the blood are associated with HLH occurrence (see p. 6, “Results” and see the table in the last page modified from Table 1 regarding IL-18 levels in the baseline blood (Day 0) and in the blood after CAR-T cell infusion (Day 5, 9, 13) which shows higher IL-18 levels in HLH at three of the timing points). Thus, Lichtenstein teaches an IL-18-associated disease being side effects related to the CAR-T therapy.
Strati teaches a method of using anakinra, an IL-1 receptor antagonist, to avoid or minimize CAR T-cell therapy-associated side effects (see e.g., p. 3123, para 1-3). Strati teaches the method comprises treating the patients with a CAR-T therapy in a first composition (see p. 3123, para 2), and then administering an IL-1 receptor antagonist in a second composition (see p. 3123, para 3), and teaches the first and second compositions are different compositions, which are administered sequentially, and the first composition (i.e., the CAR-T therapy) is administered before the second composition (i.e., the IL-1 receptor antagonist anakinra).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have cited the patented claims of ‘905, by choosing the IL-18 associated disease being side effects related to the CAR-T therapy as taught by Lichtenstein and by administering the CAR-T therapy and the IL-18BP sequentially as suggested by Strati with a reasonable expectation of success. Since Lichtenstein teaches higher IL-18 levels in the blood are associated with HLH occurrence in patients treated with anti-CD22 CAR T cells (p. 3, “Introduction” and p. 6, “Results”, and see the table in the last page modified from Table 1), and since Strati reduces to practice a method of minimizing side effects related to CAR-T therapy by administering the CAR-T therapy in the first composition followed by administering a cytokine antagonist in the second composition (see e.g., p. 3123, para 2-3), one of ordinary skill in the art would have had a reason to choose treating side effects related to CAR-T therapy by administering the IL-18BP after the CAR-T therapy in order to minimize the side effects related to CAR-T therapy.
However, cited patented claims are silent on the CAR-T cells further engineered to express IL-18.
Chmielewski teaches a population of CAR-T cells engineered to conditionally express IL-18 in the tumor environment to deliver the cytokine ‘‘on demand’’ and to selectively deposit it in the tumor tissue (abstract, p. 3205, last para – p. 3207, 1st para). Chmielewski teaches inducible IL-18 release polarizes CAR T cells toward T-bethigh FoxO1low early effectors in the tumor environment and the IL-18-CAR-T cells exhibit superior activity against cancers that were refractory to CAR T cells without cytokines (abstract, see e.g. p. 3209 and Fig 3).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have cited the patented claims of ‘905 in view of Lichtenstein and Strati, by combining engineering the CAR-T cells to express IL-18 as taught by Chmielewski with a reasonable expectation of success. Since Chmielewski teaches local IL-18 deposition in the tumor tissue by CAR T cells does not increase serum IL-18 levels, and systemic side effects through locally deposited IL-18 are not expected in a clinical situation, and inducible IL-18-CAR T cells are superior compared to CAR T cells without cytokines (p. 3215, left col, last para and abstract), one of ordinary skill in the art would have had a reason to combine engineering the CAR-T cells with an inducible IL-18 in order to improve therapeutic outcome of treating cancer with minimized side effects.
However, cited patented claims are silent on the patients being further administered a PD-1 inhibitor.
Song summarizes the combination of CAR-T cell therapy with PD-1 blockade for the treatment of hematological malignancies (see e.g., title and abstract). Song teaches the combination of CAR-T cell therapy and programmed cell-death protein-1 (PD-1) blockade has been applied to enhance therapeutic efficacy in preclinical models and clinical trials (abstract and p. 5, section 4 “combined therapy”) and teaches some studies found it synergistic to combine the two novel immunotherapies, and incorporating PD-1 blockade and CAR-T together is proven effective in treating refractory and relapsed patients (p. 6, section 4.4. “Summary”, para 1).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have cited the patented claims of ‘905 in view of Lichtenstein and Strati, by combining a PD-1 inhibitor as suggested by Song with a reasonable expectation of success. Since Song teaches the combination of CAR-T cell therapy and PD-1 blockade has been applied to enhance therapeutic efficacy in preclinical models and clinical trials with synergistic effect (abstract and p. 5, section 4 “combined therapy” and p. 6, section 4.4. “Summary”, para 1), one of ordinary skill in the art would have had a reason to combine administering a PD-1 inhibitor with the CAR-T therapy as suggested by Song in order to enhance therapeutic efficacy in treating hematological malignancies.
Since the instant application claims obvious over cited patent claims, in view of Lichtenstein, Strati, Chmielewski and Song, said claims are not patentably distinct.
Response to Traversal:
Applicant’s argument filed on 10/06/2025 is acknowledged and have been discussed above.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631