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 1 and 16 have undergone amendments. Thus, Claims 1, 16-22, 24-25, and 27, submitted on 27 February 2026, represent all claims currently under consideration.
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.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 27 February 2026, is acknowledged and has been considered.
EXAMINER’S COMMENT
The Examiner acknowledges that Box 4 (Ex parte Qualye) of the Office Action Summary was erroneously checked in the Office Action mailed 28 November 2025 and apologizes for any confusion.
Response to Amendment
The 35 U.S.C. § 112(b) rejection of Claim 1 is withdrawn. Applicant has amended the claim to include the limitation that the piperazinyl ring is optionally substituted with “one or two substituents independently chosen from alkyl”.
Response to Arguments
The 35 U.S.C. § 103 rejection of Claims 1, 16-22, 24-25, and 27 over Owens in view of Crawford is withdrawn. Applicant claims that the cited references do not teach or suggest the claimed methods of treating a disease chosen from sepsis and cytokine release syndrome as there is no motivation to combine the teachings, and there is no reasonable expectation of success. Applicant claims that one of ordinary skill in the art would not be motivated to combine the teachings of Owens with Crawford as Crawford does not provide any specific teaching or guidance that would guide or motivate one of ordinary skill in the art towards using BTK inhibitors for the treatment of sepsis or CRS as the disclosure of Crawford focuses on the treatment of cancer. The Examiner finds this argument persuasive. There is only one mention of sepsis within the disclosure of Crawford within a laundry list of other inflammatory conditions, and provides no specific data demonstrating that BTK inhibition is useful for the treatment of sepsis or CRS. Crawford rather provides data (See Paragraphs 0340-0356) which demonstrates the utility in inhibiting the growth of B-cell lymphoma cell lines for the treatment of proliferative diseases, which are distinct from sepsis and CRS.
The 35 U.S.C. § 103 rejection of Claims 1, 16-22, 24-25, and 27 over Owens in view of Crawford and Gill is maintained. The Examiner has considered Applicant’s arguments but does not find them persuasive. Applicant claims that one of ordinary skill in the art would not be motivated to combine the BTK inhibitor of Owens with the methods of treating CRS using BTK inhibition as taught by Gill due to the compounds having disparate structures. The Examiner does not find this argument persuasive. Owens claims their compounds as inhibitors of BTK which are useful in the inhibition of this protein for the treatment of disease, which is the same pathway which Gill inhibits using ibrutinib, a BTK inhibitor. Compound 31 of Owens has an IC50 against BTK of 0.0015 µM (Page 91), with Example 3 (Page 92) stating that all compounds tested had IC50 values of between 1.4 and 0.08 µM in the blockade of CD69 expression in human whole blood samples. The inhibition of CD69 is a functional effect of the inhibition of BTK, which the artisan would recognize. The artisan would have a reasonable expectation of success that as the compounds of Owens, specifically compound 31, which is demonstrated to inhibit BTK, would reasonably provide inhibition of BTK in vivo and be capable of treating CRS as Gill demonstrates that inhibition of BTK, albeit with a different compound, is capable of treating CRS in an in vivo relevant model of CRS.
Claim Rejections - 35 USC § 103- REJECTIONS MAINTAINED
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 16-22, 24-25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Owens (WO 2014/049899; Publication Date: 13 March 2014) in view of Crawford (US 2013/0116245; Publication Date: 9 May 2013) and Gill (WO 2018/013918; Publication Date: 18 January 2018).
Owens (See IDS, 11 May 2023) discloses compounds that are tyrosine kinase inhibitors, particularly BTK inhibitors, and are useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer, inflammatory diseases, and the like. Also provided are pharmaceutical compositions containing such compounds (Abstract). Table 3 of the specification of the examined application describes the compounds of Owens, and these compounds correspond to the compounds specifically claimed in Claim 16 of the examined application. Compound 31
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(Page 86 of Owens) has variable R3 as fluorine, with variable R8 as oxetan-3-yl. Table 2 (Page 90-91) shows that this compound is a potent inhibitor of BTK in vitro. The compounds of the invention can be given as a mixture of R and S isomers thereof, or an individual E or Z isomer of any of the compounds of the invention (Page 12, Lines 29-30). Another embodiment disclosed is a pharmaceutical composition comprising a compound of a compound of the invention and a pharmaceutically acceptable excipient (Page 22, Lines 2-5). Another embodiment disclosed herein is a method of treating a disease treatable by inhibition of a tyrosine kinase such as BLK, BMX, HER2, HER4, ITK, TEC, BTK, and TXK, such as BTK, in a patient in need of such treatment which method comprises administering to the patient a pharmaceutical composition comprising a compound of the invention. In one embodiment, the disease is chosen from autoimmune, inflammatory diseases, and cancer (Page 22, Lines 6-14). In yet another embodiment disclosed herein is the use of a compound and/or pharmaceutically acceptable salt in the manufacture of a medicament for treating an inflammatory disease in a patient in need thereof in which the activity of BTK or other tyrosine kinases contribute to the pathology and/or symptoms of the disease. In one embodiment, the tyrosine kinase protein is BTK. In another embodiment, the disease is chosen from respiratory, cardiovascular, and proliferative disease (Page 36, Lines 12-18). The compounds and/or pharmaceutically acceptable salts of the present disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present disclosure or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. When a compound and/or pharmaceutically acceptable salt of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred (Page 41, Lines 18-27). When the patient is suffering from or at risk of suffering from an autoimmune disease, an inflammatory disease, or an allergy disease, a compound of the present disclosure may be used in with one or more of the following therapeutic agents in any combination: immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, leflunomide, aurofin, sulfasalazine, minocycline, TNF-alpha binding proteins, abatacept, anakinra, interferon beta, interferon gamma, interleukin 2, antihistamines, antileukotriends, beta-agonists, theophylline, and anticholinergics (Page 42, Line 22- Page 43, Line 3).
Owens fails to teach the treatment of cytokine release syndrome using BTK inhibition.
Gill (See IDS, 3 October 2025) provides compositions and methods for treating diseases associated with expression of an antigen or for treating or preventing cytokine release syndrome by administering a CAR therapy with a kinase inhibitor, e.g., JAK-STAT inhibitor and/or BTK inhibitor (Abstract). The present disclosure is based on the discovery that a BTK inhibitor, such as ibrutinib, can improve or prevent cytokine release syndrome after a CD19 CAR therapy for C cell neoplasms (Page 2, Lines 23-24). Provided herein is a method of preventing cytokine release syndrome in a subject in need thereof, comprising administering a BTK inhibitor (e.g., ibrutinib), alone or in combination with the CAR therapy, to the subject, thereby preventing CRS in the subject (Page 5, Lines 1-6). In embodiments, the BTK inhibitor is a small molecule, e.g., ibrutinib, GDC-0834, RN-486, CGI-560, CGI-1764, HM-71224, CC-292, ONO-4059, CNX-774, or LFM-A13. In embodiments, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof (Page 21, Line 30- Page 22, Line 3). Example 2 (Page 409) demonstrates that ibrutinib improves cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B cell neoplasms. The authors established a clinically relevant model of CRS, and determined that addition of ibrutinib to drinking water resulted in significant reductions in IL-6, IFNg, TNFα, IL-2, and GM-CSF (Page 412).
Gill and Owens do not teach the use of anti-CD20 antibodies for the treatment of inflammatory conditions in combination with BTK inhibitors.
Crawford teaches compounds useful for inhibiting Btk kinase, and for treating disorders such as inflammation mediated by Btk kinase. Methods of using the compound and treatment of such disorders are disclosed (Abstract). A large body of evidence supports the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein based therapeutics such as Rituxan developed to deplete B-cells represent an approach to the treatment of a number of autoimmune and/or inflammatory diseases. Because of Btk’s role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (Paragraph 0004). The invention includes a method for treating a disease or disorder which method comprises administering a compound of the invention to a patient with a disease or disorder selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism/endocrine functional disorders, and neurological disorders which are mediated by Bruton’s tyrosine kinase (Paragraph 0011). Inflammatory disorders amendable to treatment with compounds of the invention encompass disorders associated with reactions of the specific defense system as well as with reactions of the non-specific defense system (Paragraph 0050). Examples of inflammation that result, at least in part, from a reaction of the non-specific defense system include inflammation associated with conditions such as acute respiratory distress syndrome and cytokine-induced toxicity (Paragraph 0052). Included in the definition of “chemotherapeutic agents” which can be used with the compounds of the invention include therapeutic antibodies, including rituximab (Paragraph 0062).
Owens, Crawford and Gill are considered analogous to the claimed invention as all are involved in the treatment of inflammatory conditions mediated by aberrant activity of B cells and Bruton’s tyrosine kinase using BTK inhibitors. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to apply the compounds and formulations of Owens for the treatment of cytokine release syndrome, and further apply this treatment to include anti-CD20 antibodies such as rituximab as Crawford teaches that these antibodies are useful for the treatment of inflammatory conditions when used in conjunction with Btk inhibitors as the depletion of B-cells can represent an approach in the treatment of inflammatory diseases. The combination of these teachings is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)) wherein the known methods are the inhibition of Btk using the compounds of Owens, applied for the specific treatment of the cytokine release syndrome as taught by Gill, predictably resulting in a treatment for CRS. The artisan would be motivated to combine these teachings as the compounds of Owens are demonstrated Btk inhibitors, and Gill demonstrates that using the BTK inhibitor ibrutinib results in a reduction in cytokines associated with cytokine release syndrome in a clinically relevant in vivo model of CRS.
Regarding Claims 18-20, the claimed compound is identical to compound 31 of by Owens. The description provided by Owens further states that compounds can be administered as mixtures of the (E) and (Z) isomers, or as purified forms. As such, the selection of “at least 85%” as the (E) isomer is prima facie obvious as 85% falls within the range of a purified (E) isomer as described by Owens (See MPEP § 2144.05 I).
Regarding Claim 21, the methods of Owens can be optionally performed with a second therapeutic agent and as such, the administration of the compounds of the invention for the treatment of the claimed conditions in place of a corticosteroid therapy would be prima facie obvious.
Regarding Claim 25, Owens does not explicitly state that the methods and compounds of the invention are used to treat humans. However, it would be prima facie obvious to one of ordinary skill in the art to tailor the methods of using these formulations in order to treat the claimed conditions in humans as it flows from the art of Owens that these compounds and methods have utility in the treatment of human conditions and pathology.
Conclusion
Claims 1, 16-22, 24-25, and 27 are rejected.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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