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
Amendments
In the reply filed on 05/19/2026, Applicant has amended claims 9 and 47.
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Claims 21-22, 29, 31 and 33-34 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.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.
Maintained 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 stand rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127. Prior art of record) 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. Prior art of record) 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 the 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 05/19/2026 is acknowledged.
Applicant first argues that Strati teaches the two HLH subjects after CAR-T therapy did not respond to anakinra treatment (Strati, at page 3126, 2nd column). Lichtenstein discloses an association between HLH and elevated levels of IL-18 expression in subjects that have developed HLH based on CAR-T cell therapy, but none of the subjects are actually treated. Canna’s subject had a MAS-like syndrome but was not classified to have HLH or MAS. Thus, one of ordinary skill in the art would not have had a reason to replace the IL-1 receptor antagonist of Strati with IL-18BP to minimize side effects related to the CAR-T therapy such as HLH, and further would not have an expectation of success in arriving at the instantly claimed methods, at least based on the Examiner's reasoning for using HLH as the connecting indication through each of the cited references, since HLH was not treated in any of the cited references (Remarks, p. 7-8).
Applicant’s argument has been fully considered but it is not persuasive.
As stated supra, Strati aims to minimize CAR T-cell therapy-associated toxicity (such as cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis (HLH)) in a CAR-T therapy, by using an IL-1 receptor antagonist anakinra (see e.g., p. 3123, para 1). As Applicant has correctly pointed out that Strati teaches the two HLH subjects after CAR-T therapy did NOT respond to anakinra treatment (Strati, at page 3126, 2nd column, and Remarks, p. 8), one of ordinary skill in the art would therefore have had a reason to search for other approaches to minimize HLH associated with CAR-T cell therapy. As Applicant has pointed out that Lichtenstein discloses an association between HLH and elevated levels of IL-18 expression in subjects that have developed HLH based on CAR-T cell therapy (Remarks, p. 8), one of ordinary skill in the art would have had a reason to target high level of IL-18 for minimizing HLH. In regard to approaches targeting high level of IL-18, Canna teaches an approach to administer recombinant human IL-18BP (rhIL-18BP) to a subject having MAS-like syndrome with high level of IL-18 (it is noted that Strati teaches “In both patients treated for HLH, the latter was characterized by pancytopenia, elevated serum ferritin and triglyceride levels, decreased fibrinogen levels, and bone marrow evidence of hemophagocytosis” (p. 3125, Fig 1 legend, emphasis added), and Canna teaches the treated subject has acute rise in inflammatory markers, relative thrombocytopenia, and rising ferritin, consistent with an MAS-like syndrome, (see p. 1698, right col, last full para, emphasis added), thus the treated subject of Canna has similar symptoms as that of HLH in Strati. It is further noted that Canna teaches the patient was treated with IL-1 blockade (anakinra) with minimal response (see p. 1698, last para), thus this patient did NOT respond to anakinra treatment as well). Thus, one of ordinary skill in the art would have had a reason to administer IL-18BP as an approach to target high level of IL-18 to minimize HLH associated with CAR-T cell therapy.
In regard to a reasonable expectation of success, since Lichtenstein discloses an association between HLH and elevated levels of IL-18 expression in subjects that have developed HLH based on CAR-T cell therapy (Remarks, p. 8), and since Canna demonstrates administering IL-18BP successfully treats the patient with similar symptoms as that of HLH and further having high level of IL-18 and not responding to anakinra treatment, one of ordinary skill in the art would have had a reasonable expectation of success in administering IL-18BP to Strati’s HLH subjects that would have high level of IL-18 (as suggested by Lichtenstein) and do not respond to anakinra treatment (as taught by Strati) to obtain successful treatment as suggested by Canna.
Applicant additionally argues that there are differences in the mechanisms of action between CAR-T HLH-like reactions of Strati versus the NLRC4 gain-of-function (GOF) mutation of Canna, with potential implications for clinical management, particularly regarding acute (in Strati’s CAR-T HLH-like reactions) versus chronic inflammatory disease of Canna. Given the differences in mechanistic action, a person skilled in the art would not have adapted the treatments described in Strati by substituting IL-18BP of Canna for the IL-1 receptor antagonist of Strati and had an expectation of success in treatment of the subject (Remarks, p. 9 and post filing art Hines and prior art Canna 2014).
Applicant’s argument and the cited art have been fully considered but they are not persuasive.
As stated supra, Canna teaches MAS and HLH are life-threatening sepsis-like conditions notable for hyperferritinemia, acute cytopenias, and hepatitis, (see p. 1698, right col, para 1, emphasis added), and the treated subject, having NLRC4 gain-of-function (GOF) mutation, has acute rise in inflammatory markers, relative thrombocytopenia, and rising ferritin, consistent with an MAS-like syndrome, (see p. 1698, right col, last full para, emphasis added). Consistently, Strati teaches “In both patients treated for HLH, the latter was characterized by pancytopenia, elevated serum ferritin and triglyceride levels, decreased fibrinogen levels, and bone marrow evidence of hemophagocytosis” (p. 3125, Fig 1 legend, emphasis added). Thus, Canna’s subject has similar symptoms as that of HLH associated with CAR-T cell therapy of Strati. Furthermore, Canna’s subject has the same response to anakinra treatment as that of Strati (i.e., both do not respond to anakinra). Lastly, since Lichtenstein discloses an association between HLH and elevated levels of IL-18 expression in subjects that have developed HLH based on CAR-T cell therapy (Remarks, p. 8), suggesting that Strati’s subjects would likely have elevated level of IL-18, Canna’s subject would have had the same therapeutic target, i.e., elevated level of IL-18 as that of Strati. In summary, although there are apparent differences in the mechanisms of action between CAR-T HLH-like reactions of Strati versus the NLRC4 gain-of-function (GOF) mutation of Canna as argued by Applicant and supported by cited art Hines and Canna 2014, one of ordinary skill in the art would have acknowledged that Strati’s CAR-T HLH-like reactions would share similar symptoms, the same elevated level of IL-18 that can be used as a therapeutic target, and react similarly to anakinra as that of NLRC4 gain-of-function (GOF) mutation of Canna. Thus, one of ordinary skill in the art would have had a reason to substitute IL-18BP of Canna for the IL-1 receptor antagonist of Strati in the method of Strati, and would have had a reasonable expectation of success in obtaining minimized side effect.
Applicant further argues that Lichtenstein teaches several variables associated with increased HLH risk, including reduced NK-cell numbers, increased CD3+ T-cell counts, an elevated CD3+/NK ratio, and higher IL-18 levels. Importantly, elevated IL-18 levels were not retained among the independent predictive variables in the final model. Thus, it would not be obvious that blocking IL-18 would be the main therapeutic path to prevent/treat HLH-like toxicities following CAR-T cell infusion and a person skilled in the art would not have an expectation of success in arriving at the instant claims (Remarks, p. 10).
Applicant’s argument has been fully considered but it is not persuasive.
As stated supra, Lichtenstein clearly teaches in the context of CAR T cell therapy, 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, one of ordinary skill in the art would have had a reason to target these high levels of IL-18 for minimizing HLH after CAR-T cell infusion, and would have had a reason to use IL-18BP as suggested by Canna since Canna has reduced to practice an approach for targeting high levels of IL-18 to treat diseases with similar symptoms as HLH (see discussion above). One of ordinary skill in the art would have had a reasonable expectation of success in obtaining minimization of HLH symptoms since Canna has demonstrated successful treatment of MAS-like syndrome that has similar symptoms as HLH. The other variables and independent predictive variables associated with HLH taught by Lichtenstein do not negate the fact that there are higher IL-18 levels in HLH after CAR-T cell therapy, and would not dissuade an ordinary skill in the art from targeting the high levels of IL-18 for minimizing HLH symptoms.
Applicant finally argues the Examiner has selectively culled different elements from each of the prior art references using impermissible hindsight to arrive at the instantly claimed methods (Remarks, p. 10-11).
Applicant’s argument has been fully considered but it is not persuasive.
In response to applicant's argument, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, as stated supra, Strati aims to minimize CAR T-cell therapy-associated toxicity such as CRS or HLH, by using an IL-1 receptor antagonist anakinra (see e.g., p. 3123, para 1). Lichtenstein discloses an association between HLH and elevated levels of IL-18 expression in subjects that have developed HLH based on CAR-T cell therapy (Remarks, p. 8). Therefore, one of ordinary skill in the art would have had a reason to target the high level of IL-18 for minimizing HLH. Canna teaches an approach to administer recombinant human IL-18BP (rhIL-18BP) to a subject having MAS-like syndrome (that has similar symptoms as HLH) and having high level of IL-18. Thus, one of ordinary skill in the art would have had a reason to administer IL-18BP as an approach to target the high level of IL-18 to minimize HLH associated with CAR-T cell therapy. As discussed above, the other factors associated with HLH taught by Lichtenstein do not negate the fact that there are higher IL-18 levels in HLH after CAR-T cell therapy, and would not dissuade an ordinary skill in the art from targeting the high levels of IL-18 for minimizing HLH symptoms.
Claim 9 stands rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127. Prior art of record) 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. Prior art of record) 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 05/19/2026 is acknowledged and have been discussed above.
Claim 19 stands rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127. Prior art of record) 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. Prior art of record) 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. Prior art of record).
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 05/19/2026 is acknowledged and have been discussed above.
Claim 50 stands rejected under 35 U.S.C. 103 as being unpatentable over Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127. Prior art of record) 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. Prior art of record) 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. Prior art of record).
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 05/19/2026 is acknowledged and have been discussed above.
Maintained 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).
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Claims 1-2, 4, 6-7, 9, 12, 14, 19, 45, 47, 49-50 and 52 stand 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. Prior art of record), Strati et al., (Blood Adv. 2020 July 14; 4(13): 3123-3127. Prior art of record), 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. Prior art of record). 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 05/19/2026 is acknowledged and have been discussed above.
Conclusion
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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