DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 9-17, 19-23 filed October 06, 2025 are currently pending.
Status of Claims
As indicated in the Office Action of 04/07/2025, claims 10-11 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of Formula (I) there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/18/2025.
Response to Amendment
Applicant’s amendments, filed 10/06/2025 are acknowledged. Claims 1-8 and 18 have been canceled in their entirety. Claim 9 is directed to a method for treating and/or preventing cytokine release syndrome (CRS), the method consisting essentially of administering to a subject experiencing, or at risk of developing, CRS an effective amount of a compound, wherein the compound is
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or a salt and/or solvate thereof. Claim 17 is directed to the similar method of claim 9 further comprising a secondary therapeutic agent, including a steroid. Claims 22-23 have been added, directed to either the methodology of claim 9 or 17, wherein the subject has graft-vs-host disease.
Applicant's arguments, filed 10/06/2025 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 112-Paragraph D
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 is directed to a method for treating and/or preventing cytokine release syndrome (CRS), the method consisting essentially of administering to a subject experiencing, or at risk of developing, CRS an effective amount of a compound, wherein the compound is
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or a salt and/or solvate thereof. Claims 14-16 are directed to the method of claim 9, wherein administering comprises: administering to a subject that has previously be administered a first therapy for which CRS is a known, suspected, or potential side effect; or administering to a subject who will be, or is concurrently being, administered a first therapy for which CRS is a known, suspected, or potential side effect. Claim 14 fails to further limit the scope of claim 9 as claim 14 embraces the transitional phrase “comprising”, while the claim from which it depends embraces the transitional phrase “consisting essentially thereof”. As shown in MPEP 2111.03, the transitional phrase is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). As such, given the broadest reasonable interpretation of claim 14, said claim broadens the methodology of claim 9 as it does not exclude additional, unrecited elements or method steps. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. This situation is also present in claims 15 and 16.
Claim Rejections - 35 USC § 103-Rejection(s) Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 9, 12-17, 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Novik (WO2016/132366 published 08/25/2016) and Jensen (WO2017/165571 published 09/28/2017).
Claim interpretation is as follows: Claim 9 is directed to method for treating and/or preventing cytokine release syndrome (CRS), the method consisting essentially of administering to a subject experiencing, or at risk of developing, CRS an effective amount of a compound, wherein the compound is
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or a salt and/or solvate thereof.
Applicant is reminded of MPEP 2111.03 wherein for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). In the present case, Applicant has not defined the scope of the transitional phrase “consisting essentially thereof” in the specification. Nor is there any disclosure in the specification about what constitutes a material change in the basic and novel characteristic of the invention. As such, for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103 "consisting essentially of" will be construed as equivalent to "comprising” which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In the present case, the claim embraces additional, unrecited elements such as apoptotic cell supernants.
Novik teaches the method of treating cytokine release syndrome in a neoplastic subject in need who is receiving CAR-T therapy. Novik teaches that said cytokine release syndrome produces a systemic inflammatory response in which there is a rapid and massive release of cytokines into the bloodstream, leading to dangerously low blood pressure, high fever and shivering (abstract, [0003]-[0004], [0081], [0088]). Novik teaches administering apoptotic cell supernants to treat said cytokine release syndrome in a subject in need who is being treated with CAR-T therapy (abstract; claims 20-26).
Novik teaches incorporating additional immune modulating therapeutic agents with the efficacious apoptotic cell supernant ([0170]-[0172], [0187]-[0188]). Administration of the SYK kinase inhibitor fostamatinib is taught by Novik as a suitable immune modulatory agent to combine with the apoptotic cell supernant regimen to treat the afflicted patient ([0170]-[0172], [0187]-[0188]).
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As evidenced by CAS Registry Database, fostamatinib is art-recognized as the compound of claim 9 and 17.
Therefore, one of ordinary skill in the art of treating a subject comprising cytokine release syndrome who is a neoplastic patient being treated with CAR-T therapy, said artisan would have found it prima facie obvious to treat said patient comprising administering a therapeutically effective amount of an apoptotic cell supernant as Novik teaches that said apoptotic cell supernant is efficacious at treating cytokine release syndrome in the afflicted patient.
Secondly, said skilled artisan would have found it prima facie obvious to select the immune modulating SYK kinase inhibitor fostamatinib and combine the to the apoptotic cell supernant regimen in view of Novik in order to arrive at the presently claimed methodology. MPEP 2144.07 discloses rationales for a conclusion of obviousness including art recognized suitability for an intended purpose. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). In the present case, Novik teaches that fostamatinib is a suitable immune modulatory agent to combine with the apoptotic cell supernant regimen to treat the subject receiving CAR-T therapy who comprises cytokine release syndrome. Accordingly, said artisan would have readily predicted that the therapeutic combination comprising the apoptotic cell supernant and fostamatinib would have effectively treated cytokine release syndrome in the subject receiving CAR-T therapy.
However, Novik does not specifically teach administering the regimen of an apoptotic cell supernant and fostamatinib with a corticosteroid such as prednisone to treat cytokine release syndrome in the afflicted patient receiving CAR-T cell therapy.
Jensen teaches treating patients comprising cytokine release syndrome and a fever as a result of receiving CAR-T cell therapy comprising administration of a therapeutically effective amount of the corticosteroid prednisone (claims 85-87, 103-109).
Therefore, one of ordinary skill in the art of treating patients comprising cytokine release syndrome and a fever as a result of receiving CAR-T cell therapy as taught by Novik, said artisan would have found it prima facie obvious incorporate the corticosteroid prednisone to the therapeutic regimen of an apoptotic cell supernant and fostamatinib of Novik in view of Jensen in order to arrive at the presently claimed methodology.
Motivation to incorporate prednisone to the therapeutic regimen logically flows from the fact that both prednisone and the combination of an apoptotic cell supernant and fostamatinib were each individually taught in the prior art as having the same utility of treating cytokine release syndrome as a result of receiving CAR-T cell therapy and, in turn, raises the reasonable expectation of success, that when combined, a composition comprising an apoptotic cell supernant, fostamatinib and prednisone would be efficacious at treating cytokine release syndrome as a result of receiving CAR-T cell therapy. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06).
Regarding the limitation directed to wherein the administration of fostamatinib ameliorates the sign or symptom of cytokine release syndrome, such as a fever compared to the severity of the sign or symptom prior to administration of the compound (claims 12-13), Applicant is reminded that properties that accrue from the process step of administering the therapeutic regimen of an apoptotic cell supernant, fostamatinib and prednisone to a patient comprising cytokine release syndrome as a result of receiving CAR-T cell therapy are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the therapeutically effective amount of fostamatinib administered in the therapeutic regimen of an apoptotic cell supernant, fostamatinib and prednisone to a patient comprising cytokine release syndrome as a result of receiving CAR-T cell therapy as taught by the combination of Novik and Jensen above does not ameliorate the sign or symptom of a fever in the cytokine release syndrome patient receiving CAR-T cell therapy.
Applicant traverses. Applicant asserts that the teachings of Novik no longer read on the amended claim as the amended claims embrace the transitional phrase “consisting essentially thereof” which does not allow for additional unrecited elements or method steps, while Novik requires the combination of apoptotic cell supernants with fostamatinib to treat CRS in a subject in need. Applicant’s further argues that the teachings of Jensen fails to cure the deficiencies of Novik as Jensen does not teach nor suggest the claimed features of claims 9 and 17.
Response to Arguments
Applicant’s arguments, filed 10/06/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that Novik no longer read on the amended claim as the amended claims embrace the transitional phrase “consisting essentially thereof” which does not allow for additional unrecited elements or method steps, such as the combination of apoptotic cell supernants with fostamatinib to treat CRS in a subject in need as recited in Novak, this argument is unavailing. Applicant is reminded of MPEP 2111.03 wherein for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). In the present case, Applicant has not defined the scope of the transitional phrase “consisting essentially thereof” in the specification. Nor is there any disclosure in the specification about what constitutes a material change in the basic and novel characteristic of the invention. As such, for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103 "consisting essentially of" will be construed as equivalent to "comprising” which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In the present case, the claim embraces additional, unrecited elements such as apoptotic cell supernants of Novik.
Secondly, regarding Applicant’s contention that the Jensen fails to cure the deficiencies of Novik as Jensen does not teach nor suggest the claimed features of claims 9 and 17, this argument is also unpersuasive. Applicant is reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In the present case as disclosed above, Novik rendered obvious the treatment of cytokine release syndrome in a patient who is a neoplastic patient being treated with CAR-T therapy comprising administering a therapeutically effective amount of an apoptotic cell supernant and the claimed SYK kinase inhibitor fostamatinib, as Novik teaches that said apoptotic cell supernant is efficacious at treating cytokine release syndrome in the afflicted patient and fostamatinib is a suitable immune modulatory agent to combine with the apoptotic cell supernant regimen to treat the subject receiving CAR-T therapy who comprises cytokine release syndrome.
As Jensen teaches treating patients comprising cytokine release syndrome and a fever as a result of receiving CAR-T cell therapy comprising administration of a therapeutically effective amount of the corticosteroid prednisone, said skilled artisan would have sought to incorporate prednisone to the therapeutic regimen logically flows from the fact that both prednisone and the combination of an apoptotic cell supernant and fostamatinib were each individually taught in the prior art as having the same utility of treating cytokine release syndrome as a result of receiving CAR-T cell therapy and, in turn, raises the reasonable expectation of success, that when combined, a composition comprising an apoptotic cell supernant, fostamatinib and prednisone would be efficacious at treating cytokine release syndrome as a result of receiving CAR-T cell therapy. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06).
Claim(s) 9, 11-12, 14-16 remain rejected under 35 U.S.C. 103 as being unpatentable over the combination of Braselmann (Journal of Pharmacology and Experimental Therapeutics Vol. 319 pages 998-1008. Published 2006), Reddy (WO2018/187294 published 10/11/2018 with priority to U.S. Provisional Application 62480868 filed 04/03/2017) and Singh (WO2006/078846 published 07/27/2006).
Claim interpretation is as follows: Claim 9 is directed to method of claim 1 for treating and/or preventing cytokine release syndrome (CRS), the method consisting essentially of administering to a subject experiencing, or at risk of developing, CRS an effective amount of a compound, wherein the compound is
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or a salt and/or solvate thereof.
Applicant is reminded of MPEP 2111.03 wherein for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). In the present case, Applicant has not defined the scope of the transitional phrase “consisting essentially thereof” in the specification. Nor is there any disclosure in the specification about what constitutes a material change in the basic and novel characteristic of the invention.
Braselmann teaches compound R-406 as a potent inhibitor of spleen tyrosine kinase (SYK) (abstract, title, Figure 1f).
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Compound 406 of Braselmann corresponds to the following structural limitations: R17 and R18 are each C1 alkyl, C19 and R20 combine to form C(O), Y is O, Z1 is CH, Z2 is N, R21 is H, R22 is H, R5 is halo, R2 is C6-C14 optionally substituted aryl and R23 is H. Braselmann teaches that compound R406 inhibited basophil activation in patients (pages 1005-1006 left col., Figures 5a-5c).
The difference between the present claims and that of Braselmann is that Braselmann does not teach treating cytokine release syndrome in a subject in need comprising administering the art-recognized SYK kinase inhibitor. Nor does Braselmann teach wherein R-406 further comprises a phosphonooxyalkyl group.
Reddy teaches compounds of Formula (I) as potent inhibitors of spleen tyrosine kinase (SYK) (abstract, Table 7). SYK kinase is a kinase that triggers IgE and IgG receptor mediated signaling in mast cells, basophils and macrophages, leading to cytokine release (page 1 line 20-25, page 274 line 5 to page 276 ). Reddy teaches compounds of Formula (I) are potent inhibitors of SYK kinase, including Example 189 “COMPOUND A” (page 335, Table 7). Reddy also teaches that chimeric antigen receptor (CAR) T-cells have been shown to have immune-related toxicities and the use of CAR T-cells is limited by potential severe toxicity. CAR T-cell therapy can damage normal tissue by specifically targeting tumor associated antigen that is also expressed on those tissues, and that cytokine release syndrome, an inflammatory response caused by cytokines released by infused CAR T-cells can lead to widespread reversible organ dysfunction. Reddy teaches that cytokine release syndrome is the most common type of toxicity caused by CAR T-cell therapy (page 428 lines 20-30).
As shown in Table 14 and Figure 3, Reddy teaches that COMPOUND A is efficacious at inhibiting pro-inflammatory cytokines (IL-18) and can treat cytokine release syndrome in a subject in need when combined with immunotherapies such as CAR-T cell therapy (page 4 lines 10-20, page 393 line 5 to page 394 line 10, page 427, lines 25-30 to page 428, Figure 3, claims 1, 9-10). Oral administration of said SYK kinase inhibitor is embodied within the methodology of Reddy (page 36 lines 5-15). Reddy further teaches therapeutically effective amounts of said SYK kinase inhibitor are from 5 mg/kg to 70 mg/kg, and said compound can be administered in a dosage of 10 mg or 50 mg or 100 mg, once or twice per day (page 391). Said therapeutically effective dose of the SYK kinase inhibitor methodology embraced within Reddy overlaps with the therapeutically effective amount embodied within page 35 lines 15-30 of the instant specification. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Therefore, one of ordinary skill in the art knowing that compound of Formula (I) is a potent SYK kinase inhibitor and is effective at inhibiting basophil activation in patients as taught by Braselmann, said artisan would have found it prima facie obvious to administer the art-recognized SYK kinase inhibitor to treat cytokine release syndrome in a subject being treated with immunotherapies such as CAR-T cell therapy in view of Reddy.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, it was known in the prior art of Reddy that administration of SYK kinase inhibitors are efficacious at inhibiting pro-inflammatory cytokines and treating cytokine release syndrome in a subject when receiving immunotherapies such as CAR-T cell therapy. Accordingly, said artisan would have readily predicted that substitution of the art-recognized SYK kinase inhibitor in the regimen of Reddy from Formula (I) to R-406 of Braselmann, said artisan would have readily predicted that the administration of the resulting SYK kinase inhibitor would have treated cytokine release syndrome in the afflicted patient.
However, the combination of Braselmann and Reddy do not specifically teach administering the compound of Formula (I) wherein R21 is a phosphonooxyalkyl group.
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Singh (WO2006/078846 published 07/27/2006) teaches phosphate prodrugs of the SYK inhibitor of Formula (I) such as compound 4 above are also potent inhibitors of SYK kinase mediated disorders and are more water soluble versions of R-406 of Braselmann. Singh teaches that compounds 4 comprises improved aqueous solubility, which yields better dissolution in the gut, thereby facilitating oral administration ([0024]-[0026] claims 2, 26).
Therefore, one of ordinary skill in the art of treating cytokine release syndrome in a subject knowing that R-406 is a potent SYK kinase inhibitor and that oral administration of SYK kinase inhibitors is an efficacious methodology to treat cytokine release syndrome in a subject as taught by Braselmann and Reddy, said skilled artisan would have found it prima facie obvious to substitute the SYK kinase inhibitor R-406 in the regimen of Braselmann and Reddy for compound 4 of Singh in order to arrive at the presently claimed methodology. MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, considering compound 4 of Singh is a more orally available version of R-406 of Braselmann, said artisan would have substituted R-406 in the methodology of Braselmann and Reddy for compound 4 with a better oral absorption profile as taught by Singh, arriving at the presently claimed methodology with a reasonable expectation of success.
Regarding the limitation directed to wherein the administration of the compound of Formula (I) ameliorates the sign or symptom of cytokine release syndrome compared to the severity of the sign or symptom prior to administration of the compound (claim 12), Applicant is reminded that properties that accrue from the process step of administering the therapeutically effective amount of the SYK kinase inhibitor to a patient comprising cytokine release syndrome as a result of receiving CAR-T cell therapy as embodied within the teachings of Braselmann, Reddy and Singh above, said properties are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the administered therapeutically effective amount of SYK kinase inhibitor of Formula (I) administered in the therapeutic regimen to a patient comprising cytokine release syndrome as a result of receiving CAR-T cell therapy as taught by the combination of Braselmann, Reddy and Singh above does not ameliorate the sign or symptom in the cytokine release syndrome patient receiving CAR-T cell therapy.
Applicant traverses. Applicant asserts that Braselmann does not teach R406 has potential for modulating SYK activity or treating cytokine release syndrome in a subject in need and the combination of Reddy and Singh do not provide elements missing in Braselmann. Applicant argues that neither Reddy nor Singh teach treating cytokine release syndrome with R406. Applicant asserts that Reddy is directed to the treatment of cancers with JAK-STAT inhibitors of Formula (I), and that Singh does not mention treatment of cytokine release syndrome with fostamatinib or R406. Applicant concludes that there is no guidance to replace a compound of Formula (I) or compound A in Reddy for another SYK kinase inhibitor, much less R406 or a reason as to why a skilled artisan would have modified a prior art compound to arrive at the claimed invention.
Response to Arguments
Applicant’s arguments, filed 10/06/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that Braselmann does not teach R406 has potential for modulating SYK activity, the examiner is unpersuasive. Braselmann teaches that R406 is a potent and orally available SYK kinase inhibitor (abstract, title). Regarding Applicant’s contention that Braselmann does not teach treating cytokine release syndrome with R406, Applicant is reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208, USPQ 871 (CCPA 1981). As set forth above, the rejection of record is based on the combined teachings of Braselmann, Reddy and Singh. As disclosed in the rejection above, it was known in the prior art of Reddy that administration of SYK kinase inhibitors are efficacious at inhibiting pro-inflammatory cytokines and treating cytokine release syndrome in a subject when receiving immunotherapies such as CAR-T cell therapy. Considering Braselmann teaches that R406 is a potent and orally available SYK kinase inhibitor, and that Singh teaches that compound 4/fostamatinib above is also a potent inhibitor of SYK kinase mediated disorders and are more water soluble versions of R-406 of Braselmann, said artisan would have readily predicted that substitution of the art-recognized SYK kinase inhibitor in the regimen of Reddy from Formula (I) to the water-soluble version of R-406 of Braselmann and Singh, said artisan would have readily predicted that the administration of the resulting SYK kinase inhibitor fostamatinib would have treated cytokine release syndrome in the afflicted patient.
Secondly, regarding Applicant’s contention that the teachings of Reddy are directed to the treatment of cancers with SYK kinase inhibitors of Formula (I) and not treating cytokine release syndrome in a subject in need comprising administering the claimed R406 prodrug, this argument is unavailing. Applicant is reminded of MPEP 2123 in which patents are relevant as prior art for all that they contain and that nonpreferred and alternative embodiments constitute prior art. In the present case,
Reddy teaches that SYK kinase is a kinase that triggers IgE and IgG receptor mediated signaling in mast cells, basophils and macrophages, leading to cytokine release (page 1 line 20-25, page 274 line 5 to page 276 ). Reddy teaches compounds of Formula (I) are potent inhibitors of SYK kinase, including Example 189 “COMPOUND A” (page 335, Table 7). Reddy also teaches that chimeric antigen receptor (CAR) T-cells have been shown to have immune-related toxicities and the use of CAR T-cells is limited by potential severe toxicity. CAR T-cell therapy can damage normal tissue by specifically targeting tumor associated antigen that is also expressed on those tissues, and that cytokine release syndrome, an inflammatory response caused by cytokines released by infused CAR T-cells can lead to widespread reversible organ dysfunction. Reddy teaches that cytokine release syndrome is the most common type of toxicity caused by CAR T-cell therapy (page 428 lines 20-30).
As shown in Table 14 and Figure 3, Reddy teaches that SYK kinase inhibitors (COMPOUND A) are efficacious at inhibiting pro-inflammatory cytokines (IL-18) and can treat cytokine release syndrome in a subject in need when combined with immunotherapies such as CAR-T cell therapy (page 4 lines 10-20, page 393 line 5 to page 394 line 10, page 427, lines 25-30 to page 428, Figure 3, claims 1, 9-10). As such, in view of the teachings of Reddy above, said skilled artisan would have readily predicted that administration of a SYK kinase inhibitor would have effectively treated cytokine release syndrome in a subject in need when combined with immunotherapies such as CAR-T cell therapy.
Regarding Applicant’s contention that there is no guidance in the combined prior art to replace a compound of Formula (I) of Reddy with another SYK kinase inhibitor, much less specifically fostamatinib or R406, this argument is misguided. Applicant is reminded of MPEP 2143 wherein rationales that support a conclusion of obviousness include (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, it was known in the prior art that SYK kinase is a therapeutic target for treating cytokine release syndrome and that administration of SYK kinase inhibitors is an efficacious strategy to treat cytokine release syndrome in a subject in need when combined with immunotherapies such as CAR-T cell therapy. As Braselmann teaches that R406 is a potent and orally available SYK kinase inhibitor, coupled with the knowledge that Singh teaches compound 4/fostamatinib above is a potent inhibitor of SYK kinase mediated disorders and are more water soluble versions of R-406 of Braselmann, said artisan would have readily predicted that substitution of the art-recognized SYK kinase inhibitor in the regimen of Reddy from Formula (I) to the water-soluble version of R-406 of Braselmann and Singh, said artisan would have readily predicted that the administration of the resulting SYK kinase inhibitor would have treated cytokine release syndrome in the afflicted patient. Furthermore, Applicant has failed to provide objective evidence that there is unpredictability in the field of treating cytokine release syndrome comprising the administration of a SYK kinase inhibitor.
NEW CLAIMS
Claim(s) 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Novik (WO2016/132366 published 08/25/2016) and Jensen (WO2017/165571 published 09/28/2017) as applied to claims 9, 12-17, 19-21 above, in view of Leonhardt (Leukemia Vol. 26 pages 1617-1629 published 2012) .
As disclosed above, the combination of Novik and Jensen render obvious the treatment of cytokine release syndrome in a neoplastic patient with the administration of a therapeutically effective amount of a composition containing an apoptotic cell supernant, fostamatinib and the corticosteroid prednisone as prednisone and the combination of an apoptotic cell supernant and fostamatinib were each individually taught in the prior art as having the same utility of treating cytokine release syndrome as a result of receiving CAR-T cell therapy.
However, the combination of Novik and Jensen do not specifically teach wherein the patient with cytokine release syndrome comprises graft versus host disease.
Leonhardt (Leukemia Vol. 26 pages 1617-1629 published 2012) teaches treating graft-vs-host disease in a subject in need comprising administering the SYK kinase inhibitor fostamatinib (abstract). Leonhardt teaches that fostamatinib reduces acute graft-vs-host disease in the afflicted patient while also improving survival (page 1623 right col.).
Therefore, one of ordinary skill in the art knowing that administration of the SYK kinase inhibitor fostamatinib along with an apoptotic cell supernant and prednisone is art-recognized as efficacious at inhibiting cytokine release syndrome in a neoplastic subject, said skilled artisan would have found it prima facie obvious to administer the fostamatinib SYK kinase inhibitor regimen to a patient with graft-vs-host disease further comprising cytokine release syndrome in view of Leonhardt.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, Leonhardt teaches that the SYK kinase inhibitor fostamatinib reduces acute graft-vs-host disease in the afflicted patient while also improving survival. Accordingly, said skilled artisan would have readily predicted that the administered fostamatinib cytokine release syndrome treating regimen of Novik and Jensen to a patient with graft-vs-host disease would also reduce acute graft-vs-host disease and improve survival in the afflicted patient.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/GEORGE W KOSTURKO/ Examiner, Art Unit 1621