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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed June 6th, 2026, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory 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.
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Claims 170, and 173 – 178 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 10, 17 – 18, 21, 24, 26 – 27, and 29 of U.S. Patent No. US 9775844 B2 to Kutok et. al. (Kutok’844) in view of Bauman et. al. ((March 2014), Integrating Novel Therapeutic Monoclonal Antibodies Into the Management of Head and Neck Cancer, Cancer, 122, 624 – 632).
Kutok’844 recite a method of treating a PI3K-gamma mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof. See reference claim 1. See examined claim 170.
Additionally, Kutok’844 recite a method where the subject has a PI3K-gamma mediated disorder selected from cancer, an inflammatory disease, or an autoimmune disease. See reference claim 2. Kutok’844 recite a method where the disorder is cancer and the cancer is a solid tumor. See reference claim 3. Kutok’844 recite a method where the disorder is a cancer selected from a list that includes genitourinary cancer and head and neck cancer. See reference claim 4. Furthermore Kutok’844 recite a method were the subject is human. See reference claim 5.
Moreover, Kutok’844 recite a method where the therapeutically effective amount of the compound is about 2 mg per day, about 1-3 mg per day, about 1-5 mg per day, about 1-10 mg per day, about 0.5-20 mg per day, about 0.1-50 mg per day, about 0.1-75 mg per day, about 0. 1 - 1 00 mg per day, about 0.1-250 mg per day, about 0.1 -500 mg per day, about 0.1-1000 mg per day, about 1 -50 mg per day, about 1-75 mg per day, about 1-100 mg per day, about 1 -250 mg per day, about 1 -500 mg per day, about 1 - 1000 mg per day, about 10-50 mg per day, about 10-75 mg per day, about 10-100 mg per day, about 10-250 mg per day, about 10-500 mg per day, about 10-1000 mg per day, about 100-500 mg per day, or about 100-1000 mg per day. See reference claim 6. See examined claims 176 – 178. Moreover, Kutok’844 recite a method where the therapeutically effective amount of the compound is about effective amount of the compound is about 0.029 mg/kg, about 0.014-0.14 mg/kg, about 0.02-0.04 mg/kg, about 0.01-0.05 mg/kg, about 0.01-0.1 mg/kg, or about 0.01 -0.5 mg/k g. See reference claim 7. Furthermore, Kutok’844 recite a method where the compound is administered once every two days, once per day, and/ or twice per day. See reference claims 8 – 10.
Moreover, Kutok’844 recite a method which further comprises administering an immunomodulator to the subject where the immunomodulator is a PDL-1 inhibitor or an anti-PDL-1 antibody; wherein the PD-L1 inhibitor or the anti-PDL-1 antibody is YW243.55.S70, MDPL3280A, MSB0010718C, MDX-1105, or MEDI-4736; wherein the immunomodulator is a PD-1 inhibitor or an anti-PD-1 antibody; and where the PD-1 inhibitor or the anti-PD-1 antibody is nivolumab, pembrolizumab, ipilimumab, AMP-244, or AMP-5 14 (reference claim 29). See reference claims and 24, 26 – 31. See examined claims 170, and 173 – 175.
While the instant application recites a method of treating the specific cancer head and neck squamous cell carcinoma; the conflicting invention of Kutok’844 recites a method of treating a PI3K-gamma mediated disorder where the disorder is cancer broadly. Moreover, Kutok’844 recites, in dependent claims, the cancer is squamous cell carcinoma, a slightly narrowed genus, or head and neck cancer, that is another slightly narrowed genus; both of which encompasses the species head and neck squamous cell carcinoma. Furthermore, both the instant application and the invention of Kutok’844 recite the administration of
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in the conflicting methods as active steps. Furthermore, given the advanced skill level for one of ordinary skill in the pharmaceutical arts it would have been obvious to such artisan that the broad genus of cancer and slightly narrowed genus of squamous cell carcinoma and head and neck cancer includes the examined species head and neck squamous cell carcinoma.
However, Kutok’844 fails to recite a method of specifically treating head and neck squamous cell carcinoma cancer where the subject has been pre-treated or previously treated with one immunotherapy treatment. See examined claim 170.
Nevertheless, Bauman et. al. teach that head and neck squamous cell carcinoma (HNSCC), the sixth leading incident cancer worldwide, has been recognized as an immunosuppressive disease. See page 624 paragraph 1. Moreover, Bauman et. al. teach that HNSCC induces a tumor-permissive cytokine profile, qualitative and quantitative lymphocyte deficiencies, anergy in major immune effector cells, and poor antigen presentation. See page 624 paragraph 1. Furthermore, Bauman et. al. teach that in a phase 1 clinical trial of cetuximab, ipilimumab , that is a PD-1 antibody, and intensity-modulated radiotherapy in the management of locally advanced HNSCC is now accruing (NCT01860430). See page 629 column 1 paragraph 2. Additionally, Bauman et. al. teach that infiltration by PD-1-expressing T cells is associated with favorable prognosis in HPV-associated disease, that is HNSCC HPV associated disease; this paradox highlights the importance of prior immune response and the therapeutic potential of restoring it by PD-1 blockade. See page 629 column 2 paragraph 1. Furthermore, Bauman et. al. teach that the objective response rates in this heavily treated population were notable in renal cell carcinoma (27%), melanoma (28%), and NSCLC (18%). See page 629 column 2 paragraph 2. Additionally, Bauman et. al. teach the important preliminary observation the correlated objective response with PD-L1-positive tumors. See page 629 column 2 paragraph 2.
Therefore it would have been obvious to one of ordinary skill in the at before the effective filing date of the instant application to modify the invention of Kutok’844 for a method of treating the cancer species head and neck squamous cell carcinoma using a combination of the compound of the above structure and an anti-PD-1 antibody in view of Bauman et. al., that is to treat the subject that has been pre-treated or previously treated with one immunotherapy treatment. One of ordinary skill in the art would have been motivated to make this modification because head and neck squamous cell carcinoma (HNSCC), is an immunosuppressive disease. One of ordinary skill in the art would have had a reasonable expectation of success because infiltration by PD-1-expressing T cells is associated with favorable prognosis in HNSCC HPV associated disease.
Claims 179, and 181 – 185 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4, 6, 17, 24, 26 – 27, and 29 of U.S. Patent No. US 9775844 B2 to Kutok et. al. (Kutok’844) in view of Kitamura et. al. ((2011), Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives, Cancers, 3, 3055 – 3072).
Kutok’844 recite a method of treating a PI3K-gamma mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof. See reference claim 1. See examined claim 179.
Additionally, Kutok’844 recite a method where the subject has a PI3K-gamma mediated disorder selected from cancer, an inflammatory disease, or an autoimmune disease. See reference claim 2. Kutok’844 recite a method where the disorder is cancer and the cancer is a solid tumor. See reference claim 3. Kutok’844 recite a method where the disorder is a cancer selected from a list that includes genitourinary cancer. See reference claim 4. Furthermore Kutok’844 recite a method were the subject is human. See reference claim 5.
Moreover, Kutok’844 recite a method where the therapeutically effective amount of the compound is about 2 mg per day, about 1-3 mg per day, about 1-5 mg per day, about 1-10 mg per day, about 0.5-20 mg per day, about 0.1-50 mg per day, about 0.1-75 mg per day, about 0. 1 - 1 00 mg per day, about 0.1-250 mg per day, about 0.1 -500 mg per day, about 0.1-1000 mg per day, about 1 -50 mg per day, about 1-75 mg per day, about 1-100 mg per day, about 1 -250 mg per day, about 1 -500 mg per day, about 1 - 1000 mg per day, about 10-50 mg per day, about 10-75 mg per day, about 10-100 mg per day, about 10-250 mg per day, about 10-500 mg per day, about 10-1000 mg per day, about 100-500 mg per day, or about 100-1000 mg per day. See reference claim 6. See examined claims 183 – 185. Moreover, Kutok’844 recite a method where the therapeutically effective amount of the compound is about effective amount of the compound is about 0.029 mg/kg, about 0.014-0.14 mg/kg, about 0.02-0.04 mg/kg, about 0.01-0.05 mg/kg, about 0.01-0.1 mg/kg, or about 0.01 -0.5 mg/k g. See reference claim 7. Furthermore, Kutok’844 recite a method where the compound is administered once every two days, once per day, and/ or twice per day. See reference claims 8 – 10.
Moreover, Kutok’844 recite a method which further comprises administering an immunomodulator to the subject where the immunomodulator is a PDL-1 inhibitor or an anti-PDL-1 antibody; wherein the PD-L1 inhibitor or the anti-PDL-1 antibody is YW243.55.S70, MDPL3280A, MSB0010718C, MDX-1105, or MEDI-4736; wherein the immunomodulator is a PD-1 inhibitor or an anti-PD-1 antibody; and where the PD-1 inhibitor or the anti-PD-1 antibody is nivolumab, pembrolizumab, ipilimumab, AMP-244, or AMP-5 14 (reference claim 29). See reference claims and 24, 26 – 31. See examined claims 179, and 181 – 182.
While the instant application recites a method of treating the specific urothelial carcinoma; the conflicting invention of Kutok’844 recites a method of treating a PI3K-gamma mediated disorder where the disorder is cancer broadly. Moreover, Kutok’844 recites, in dependent claims, the cancer is genitourinary cancer, a slightly narrowed genus, which encompass the urothelial carcinoma. Furthermore, both the instant application and the invention of Kutok’844 recite the administration of
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in the conflicting methods as active steps. Furthermore, given the advanced skill level for one of ordinary skill in the pharmaceutical arts it would have been obvious to such artisan that the broad genus of cancer and slightly narrowed genus of genitourinary cancer includes the examined species urothelial carcinoma.
However, Kutok’844 fails to recite a method of specifically treating urothelial carcinoma where the subject is naïve to immunotherapy. See examined claim 179.
Nevertheless, Kitamura et. al. teach that since the first report of successful treatment by Morales and associates, bacillus Calmette-Guérin (BCG) immunotherapy has been the recommended standard treatment for high grade non-muscle-invasive bladder cancer (NMIBC). See page 3055 paragraph 1. Kitamura et. al. teach that cisplatin-based chemotherapy, e.g., MVAC (methotrexate/vinblastine/doxorubicin/cisplatin), GC (gemcitabine/cisplatin), etc. is a standard systemic therapy for muscle-invasive or metastatic bladder cancer, since urothelial cancer (UC) is chemosensitive. See page 3056 paragraph 1. Furthermore, Kitamura et. al. teach that up to 50% of patients are unfit for cisplatin-containing chemotherapy, either due to poor performance status and/or impaired renal function, or to comorbidity that prohibits high-volume hydration. See page 3056 paragraph 1. Additionally, Kitamura et. al. teach that high levels of tumor infiltration by CD83+ tumor-infiltrating dendritic cells (DCs) and CD68+ tumor-associated macrophages prior to BCG therapy were associated with an increased risk of recurrence. See page 3058 paragraph 1. Moreover, Kitamura et. al. teach that these results may be explained by a switch from a favorable Th1 response of DCs in patients exposed to few BCG instillations to a less favorable Th2 response on repeated BCG instillation. See page 3058 paragraph 1. Furthermore, Kitamura et. al. teach that the rationale for studies of active immunotherapy is supported by strong cellular immune responses when introducing cancer-specific CTLs from patients. See page 3061 paragraph 3.
Therefore it would have been obvious to one of ordinary skill in the at before the effective filing date of the instant application to modify the invention of Kutok’844 for a method of treating the cancer species urothelial carcinoma using a combination of the compound of the above structure and an anti-PD-1 antibody in view of Kitamura et. al., that is to treat the subject that is naïve to immunotherapy. One of ordinary skill in the art would have been motivated to make this modification to expand treatment options for patients that are unfit for cisplatin-containing chemotherapy, either due to poor performance status and/or impaired renal function, or to comorbidity that prohibits high-volume hydration. One of ordinary skill in the art would have had a reasonable expectation of success because high levels of tumor infiltration by CD83+ tumor-infiltrating dendritic cells (DCs) and CD68+ tumor-associated macrophages prior to BCG therapy were associated with an increased risk of recurrence.
Discussion of the Prior Art
Claims 170, 173 – 179, and 181 – 185 are direct to a method of treating head and neck cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody.
The closet prior art of International Publication Number US 2013/0267521 A1 to Castro et. al. (herein after Castro’521; cited on the IDS dated April 28th, 2023) teach compounds capable of selectively inhibiting one or more isoform(s) of class I PI3K without substantially affecting the activity of the remaining isoforms of the same class (page 1 paragraph 0010). Specifically, Castro’521 teach compounds of Formula (I)
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(page 23 paragraph 0221). More specifically, Castro’521 teach compound 154 of structure
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(page 160 paragraph 0922). Castro’521 teach that a patient can be treat with compounds of the disclosure, including compounds of reference formula (I), for the treatment of head and neck cancer (claim 170), squamous cell carcinoma, and renal cancer (page 90 paragraph 0632).
However, Castro’521 fails to teach a method wherein a compound of the formula:
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is administered in combination with an anti-PD-1 antibody. Moreover, neither Castro’521 nor the prior art provides a motivation for modifying prior art compound 154 to get the instant compound of structure
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. Given that the prior art of Castro’521 fails to anticipate or render obvious the method of the instant claims; instant claims 170 – 189 are free of the prior art.
Response to Arguments
Applicant's arguments filed June 6th, 2026 have been fully considered but they are not persuasive.
Applicant argues that solely for the purpose of expediating prosecution claim 170 was amended to include the limitations of claim 172 which was not subject the NSDP rejection. See applicants arguments page 5 paragraph 3. Moreover applicant argues that claim 179 was amended to include the limitations of claim 180 in the response to the office action dated October 21, 2025.
The examiner has since amended the rejections in view of Kitamura et. al. ((2011), Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives, Cancers, 3, 3055 – 3072) for examined claims 170, and 173 – 179, and in view of Kitamura et. al. ((2011), Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives, Cancers, 3, 3055 – 3072) for examined claims 179, and 181 – 185.
Conclusion
Claims 170, 173 – 179, and 181 – 185 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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