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
This office action is in reply to the application 18/854,263 filed on 04 October 2024, 371 of PCT/US2023/017704 filed on 06 April 2023, with PRO 63/328,348 field 07 April 2022. Claims 1, 12-13, 15, 17-26, 28, 31-32, and 35-36 amended. Claims 2-11, 14, 16, 27, 30, 33-34, and 37-51 are canceled. Currently, claims 1, 12-13, 15, 17-26, 28-29, 31-32, and 35-36 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 19 November 2025 was filed after the mailing date of the application on 04 October 2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
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.
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 non-obviousness.
Claims 1 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Fraser et al. (Rapid discovery and structure-activity relationships of pyrazolopyrimidines that potently suppress breast cancer cell growth via SRC kinase inhibition with exceptional selectivity over ABL kinase, J. Med. Chem. 2016, 59, 4697-4710; entered into the IDS on 19 November 2025) in view of Mahajan et al. (Src family protein tyrosine kinases induce autoactivation of Bruton’s tyrosine kinase, Mol. Cell. Biol. 1995, 15, 10, 5304-5311).
Fraser discloses structure 11a, illustrated below, as a potent inhibitor of Src (pg. 4701, Fig. 4a):
PNG
media_image1.png
281
123
media_image1.png
Greyscale
They do not, however, teach the use of structure 11a for treating a B-cell cancer as a Btk inhibitor where the cancer harbors a Btk mutation.
Mahajan rectifies this deficiency by teaching that mutations in the Btk gene can lead to human X-linked agammaglobulinemia (XLA) and murine X chromosome-linked immunodeficiency (xid) (pg. 5304, left col.), that co-expression of Btk with Src family protein tyrosine kinases normally expressed in B-cells (Yes, Lck, Fgr and Src) resulted in Btk tyrosine phosphorylation and Btk enzyme activation (pg. 5309, right col.), and that communication between Src protein tyrosine kinases and Btk is maintained in xid pleckstrin homology mutant of Btk but not XLA (pg. 5310, left col.).
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of disclosed structure 11a, a potent inhibitor of Src and Src family enzymes, to indirectly inhibit activation of Btk enzymes due to the signaling relationship demonstrated by Mahajan which are implicated in both XLA and xid, B-cell-related diseases.
Regarding the limitation of claim 12 is met with the obviousness argument presented in paragraphs 5-8.
Claims 15 and 17-22 are rejected under 35 U.S.C. 103 as being unpatentable over Fraser and Mahajan as applied to claims 1 and 12 above, and further in view of Wen et al. (Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances, Leukemia 2021, 35, 312-332).
Fraser discloses structure 11a as a potent Src inhibitor while Mahajan teaches the indirect signaling relationship between Src and Btk.
They do not, however, teach where the cancer is selected from a group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin’s lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia.
Wen overcomes this paucity by teaching that B-cell malignancies include non-Hodgkin lymphomas and chronic lymphocytic leukemia, with common subtypes including chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, multiple myeloma, marginal zone lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia, with Bruton’s tyrosine kinase inhibitors developed as therapeutic agents for non-Hodgkin’s lymphoma (pg. 312).
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider utilizing structure 11a as a potential agent for treating B-cell malignancies, such as those taught by Wen, because of the relationship between Src and Btk established by Mahajan.
Regarding the limitations of claim 17 are met as Wen teaches that all irreversible inhibitors are covalently bound to cysteine 481 of Btk and therefore are susceptible to mutations such as cysteine to serine mutations at the C481 site, leading to drug resistance (pg. 325). A suggested strategy to overcome these resistances include developing next-generation non-covalent Btk inhibitors that do not interact with Cys481, to combine Btk inhibitors with PI3K, SYK, or BCL-2 inhibitors, or to treat with other therapies such as chimeric antigen receptor T-cell immunotherapies (pg. 326, left col.).
Concerning the limitations of claim 18 are met as Wen teaches Btk Cys481 mutations including C481S mutations (pg. 325).
Pertaining to the limitations of claim 19 are met as Wen teaches that chronic lymphocytic leukemia/small lymphocytic leukemia patients who progress on covalent Btk inhibitor Ibrutinib can meet resistance through mutations in Ibrutinib binding, Btk Cys481, gatekeeper, Btk Thr484, and SH2, Btk Thr316 domains of Btk (pg. 325).
With respect to the limitations of claim 20 are met as Wen teaches that chronic lymphocytic leukemia/small lymphocytic leukemia patients who progress on covalent Btk inhibitor Ibrutinib can meet resistance through mutations in Ibrutinib binding, Btk Cys481, gatekeeper, Btk Thr484, and SH2, Btk Thr316 domains of Btk (pg. 325).
With regards to the limitations of claim 21 are met as Wen teaches resistance arising from patients being treated with Ibrutinib (pg. 325).
With concern to the limitations of claim 22 are met as Wen teaches that marginal zone leukemia is a heterogenous B-cells malignancy arising from the post-germinal center marginal zone B-cells (pg. 323, left col.).
Claim 24-29, 31-32, and 35-36 is rejected under 35 U.S.C. 103 as being unpatentable over Fraser, Mahajan and Wen as applied to claims 1, 12, 15, and 17-22 above, and further in view of Unciti-Broceta et al. (Compounds, WO 2016/185160 A1, 2016; entered into the IDS on 19 November 2025).
Fraser discloses structure 11a as a potent Src inhibitor while Mahajan teaches the indirect signaling relationship between Src and Btk.
They do not, however, teach where the inhibitor is administered orally, subcutaneously, intraperitoneally, or intravenously.
Unciti-Broceta addresses this by teaching various forms of administration of pharmaceutical compositions to patients of structure 11a, known as compound 506 in this prior art, including oral, rectal, nasal, intrabronchial, topical (buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration (pg. 36, lines 20-23).
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider various forms of administration of structure 11a as taught by Unciti-Broceta.
Regarding the limitations of claim 25 are met as Unciti-Broceta teaches the use of drug combinations in therapy, that drugs in general are more effective when used in combination, and the major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease or delay the emergence of resistance (pg. 39, lines 20-33).
Concerning the limitations of claim 26 are met as Unciti-Broceta teaches the use of drug combinations in therapy, that drugs in general are more effective when used in combination, and the major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease or delay the emergence of resistance (pg. 39, lines 20-33).
Pertaining to the limitations of claim 28 are met as Unciti-Broceta teaches that a person of ordinary skill in the art can easily determine an appropriate dose of one of the compositions, including compound 506, to administered to a subject without undue experimentation, that a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability, and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
With respect to the limitations of claim 29 are met as the cancers are taught by Wen (pg. 312).
With regards to the limitations of claim 31 are met as Wen teaches Btk Cys481 mutations including C481S mutations (pg. 325).
With concern to the limitations of claim 32 are met as Fraser teaches structure 11a, Mahajan teaches the signaling relationship between Src and Btk, Wen teaches the various cancers and associated drug resistances arising from point mutations, and Unciti-Broceta teaches administration of structure 11a.
Regarding the limitations of claim 35 are met as Wen teaches resistance arising from patients being treated with Ibrutinib (pg. 325).
Concerning the limitations of claim 36 are met as Wen teaches treating Btk mutation cancers with Ibrutinib, Acalabrutinib, and Zanubrutinib, and strategies to overcome acquired resistance including developing next-generation non-covalent Btk inhibitors that do not interact with Cys481, to combine Btk inhibitors with PI3K, SYK, or BCL-2 inhibitors to inhibit the activation of bypass signaling, and to treat with other novel therapies such as chimeric antigen receptor T-cell immunotherapies (pg. 326, left col.). This is reinforced by Unciti-Broceta who teaches the use of drug combinations in therapy, that drugs in general are more effective when used in combination, and the major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease or delay the emergence of resistance (pg. 39, lines 20-33).
Allowable Subject Matter
Claims 13 and 23 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Reasons for Indicating Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: the compound in claim 13 is exemplified only in Temps et al. (Tyrosine kinase inhibitors, WO 2023/017264 A1, 2023; entered into the IDS on 19 November 2025) which is after the claimed priority date of the instant application. Regarding claim 23, the prior art is nebulous on homozygous Btk mutations, rendering a case of obviousness difficult.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a non-statutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 13 is provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claim 9 of co-pending Application No. 18/291,890 in view of Mahajan et al. (Src family protein tyrosine kinases induce autoactivation of Bruton’s tyrosine kinase, Mol. Cell. Biol. 1995, 15, 10, 5304-5311). Mahajan teaches that mutations in the Btk gene can lead to human X-linked agammaglobulinemia (XLA) and murine X chromosome-linked immunodeficiency (xid) (pg. 5304, left col.), that co-expression of Btk with Src family protein tyrosine kinases normally expressed in B-cells (Yes, Lck, Fgr and Src) resulted in Btk tyrosine phosphorylation and Btk enzyme activation (pg. 5309, right col.), and that communication between Src protein tyrosine kinases and Btk is maintained in xid pleckstrin homology mutant of Btk but not XLA (pg. 5310, left col.). As such, disclosed Src inhibitor by Temps et al. (Tyrosine kinase inhibitors, WO 2023/017264 A1, 2023) may act as potent indirect Btk inhibitors.
This is a provisional non-statutory double patenting rejection.
Summary
Claims 1, 12, 15, 17-22, 24-26, 28-29, 31-32 and 35-36 are rejected under 35 U.S.C. 103. Claim 13 is rejected under non-statutory double patenting. Claim 23 is objected to as being dependent on a rejected base claim.
Conclusion
Claims 1, 12-13, 15, 17-22, 24-26, 28-29, 31-32 and 35-36 are rejected. Claim 23 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights