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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/7/26 has been entered.
Claims 1, 4-10, 13-23, 26-31, and 33 are pending.
Claims 1, 4, 8-10, 16-22, 26-31, and 33 have been amended by Applicant.
Claims 1, 4-10, 13-23, 26-31, and 33 are currently under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Office Action contains New Rejections.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections
Claim Rejections - 35 USC § 103
Claims 1, 4-10, 13-23, and 26-31 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lowy et al (US 2017/0327590 A1; 11/16/17) in view of Dracopoli et al (US 2020/0157642 A1; 5/21/20; 2/21/23 IDS), Goodman et al (Genome Medicine, 2020, 12(45): 1-13; 2/21/23 IDS), Paulson et al (International Immunology, 2019, 31(7): 465-475), Lipson et al (Journal for ImmunoTherapy, 2017, 5(23): 1-5; 7/7/26 IDS), Cabrera et al (Immunobiology, 185(5): 440-452), and Sabbatino et al (Journal of ImmunoTherapy of Cancer, 2018, 6(126): 1-8).
Lowy et al teaches an anti-PD-1 antibody checkpoint inhibitor immunotherapeutic antibody comprising SEQ ID NOs:9-10, which are identical to instant SEQ ID NOs:9-10, and wherein the antibody is the human antibody cemiplimab (same as “REGN2810” at [0020) and comprises all recited SEQ ID NOs ([0209], in particular). Lowy et al further teaches antibodies comprise heavy and light chains inter-connected by disulfide bonds ([0090], in particular). Lowy et al further teaches a method of treating cancer, including basal cell carcinoma (BCC), comprising administering said antibody as a monotherapy or in combination with another therapy, such as radiation therapy, to a patient with cancer ([0007], [0222], and [0224], in particular). Lowy et al further teaches said method wherein the BCC is metastatic BCC ([0061], in particular). Lowy et al further teaches said method wherein “large tumors” are treated and that large tumors “typically correlates with higher tumor burden or tumor load” ([0077], in particular). Lowy et al further teaches said method wherein the patient with BCC and has been treated with HHI and shown progressive disease ([0012], in particular). Lowy et al further teaches said method wherein the antibody is administered at dose of 5mg to 1500mg, such as doses of 200mg, 250mg, or 350mg ([0135], in particular). Lowy et al further teaches said method wherein the antibody is administered at dose of 1mg/kg to 20mg/kg of the patient’s body weight, such as 1mg/kg, 3mg/kg, or 10mg/kg of the patient’s body weight ([0136], in particular). Lowy et al further teaches said method wherein the doses are administered 0.5-12 weeks after the immediately preceding dose, such as 2 or 3 weeks after an immediately preceding dose ([0016], in particular). Lowy et al further teaches said method wherein the antibody is administered intravenously ([0116], in particular). Lowy et al further teaches a kit comprising the antibody and instructions ([0023], in particular).
Lowry et al does not specifically teach the patient with cancer has been selected as having a high tumor mutation burden (TMB) of 10 mutations/Mb or that the patient does not exhibit downregulated MHC. However, these deficiencies are made up in the teachings of Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, and Sabbatino et al.
By examining TMB in a population of patients with numerous tumor types (including BCC) treated with PD-1 and PD-l1 immunotherapies (Table 1, in particular), Dracopoli et al teaches high TMB is associated with better response to immunotherapy because the tumor carries more somatic mutations and has a higher chance of presenting an immunogenic neopeptide ([0006], in particular). Dracopoli et al further teaches loss of heterozygosity (LOH) of MHC class I occurs in several tumors and LOH at MHC correlates with shorter survival of the patients with checkpoint inhibitors ([0008], in particular). Dracopoli et al further teaches a method of treating a tumor comprising (a) selecting a patient with cancer (such as melanoma), wherein the patient has a tumor with a high TMB and wherein the patient does not exhibit downregulated MHC as measured by lack of LOH of MHC Class I, and (b) administering to the patient a therapeutically effective amount of an anti-PD-1 antibody checkpoint inhibitor immunotherapeutic antibody such as pembrolizumab (see [0012]-[0013] and claims 21, 25, 27, and 28, in particular). Dracopoli et al further teaches TMB is described as mutations/Mb ([0006], in particular) and is determined in tumor samples ([0011], in particular) that can be obtained by biopsy ([0128], in particular). Dracopoli et al teaches such treating includes causing regression of disease ([0112], in particular).
Goodman et al teaches immune checkpoint blockade (ICB) with antibodies inhibiting PD-1 or PD-L1 can stimulate immune responses against cancer (Abstract, in particular). Goodman et al further teaches higher TMB correlate with better treatment outcomes, including higher response rates and longer progression-free survival and overall survival, in diverse cancers treated with immunotherapies (left column on page 2, in particular). Goodman et al further teaches higher progression-free survival in cancer patients with high TMB/more efficient MHC presentation treated with immune checkpoint blockade immunotherapy, as compared to the level of progression-free survival in cancer patients with high TMB/less efficient MHC presentation treated with immune checkpoint blockade (Abstract, in particular). Goodman et al defines high TMB as greater than or equal to 10 mutations/Mb (right column on page 3, in particular). Goodman et al further teaches that neoantigens, which are generated by mutations, are presented by MHC-1 and tumors that present neoantigens efficiently respond to (ICB) when TMB is ≥ 10 mutations/mb (right column on page 9, in particular).
Paulson et al teaches tumors must present T-cell antigens bound to MHC to respond to immunotherapies (left column on page 469, in particular).
Lipson et al cites Cabrera et al as teaching BCCs have been shown to demonstrate low levels of MHC-1 expression and that the low MHC-1 expression may suppress anti-tumor immunity and allow for immune escape (paragraph spanning pages 2-3, in particular). Cabrera et al teaches all samples of healthy skin and epithelium near BCC tumors show high levels of HLA class I and class II antigen (same as human MHC I and MHC II) whereas 38% of BCC tumors show complete absence (Abstract, in particular).
Sabbatino et al teaches a BCC patient that is not responsive to the anti-PD-1 inhibitor nivolumab with tumor cells that lack human MHC class I (HLA class I) expression (Figure 3, in particular). Sabbatino et al further teaches lack of the human MHC class I expression by BCC patients treated with an anti-PD-1 inhibitor immunotherapeutic nivolumab “can justify the lack of clinical response to nivolumab” and that human MHC class I down-regulation is “widely recognized as a mechanism of tumor immune escape and it has been associated to cancer immunotherapy resistance” (right column on page 5, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising selecting a patient with a cancer of Lowy et al (such as locally advanced BCC and/or BCC that has been treated with HHI and shown progressive disease of Lowy et al) for treatment of Lowy et al comprising intravenously administering the anti-PD-1 antibody checkpoint inhibitor immunotherapeutic antibody cemiplimab of Lowry et al at doses and dosing schedules of Lowy et al as a monotherapy or in combination with radiation wherein a tumor biopsy is collected from the patient and a high TMB is measured in the tumor biopsy and wherein the patient does not exhibit downregulated MHC as measured by expression of MHC Class I because Dracopoli et al (which evaluated many tumor types, including BCC, with PD-1/PD-L1 immunotherapy treatment, see Table 1) teaches high TMB is associated with better response to immunotherapy ([0006], in particular), Goodman et al teaches that neoantigens are generated by mutations and are presented by MHC-1 and tumors that present neoantigens efficiently respond to (ICB) when TMB is ≥ 10 mutations/mb (right column on page 9, in particular), Paulson et al teaches tumors must present T-cell antigens bound to MHC to respond to immunotherapies, Lipson et al in view of Cabrera et al indicate some (not all) BCCs demonstrate low levels of MHC-1 expression and that the low MHC-1 expression may suppress anti-tumor immunity and allow for immune escape, and Sabbatino et al teaches lack of the human MHC class I expression by BCC patients treated with an anti-PD-1 inhibitor immunotherapeutic nivolumab “can justify the lack of clinical response to nivolumab” and that human MHC class I down-regulation is “widely recognized as a mechanism of tumor immune escape and it has been associated to cancer immunotherapy resistance”.
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein a TMB of greater than or equal to 10 mutations/Mb of Goodman et al is used as a cut-off to determine a high TMB because Goodman et al teaches a high TMB greater than or equal to 10 mutations/Mb and efficient presentation of neoantigens by MHC-1 as correlating with ICB efficacy (right column on page 9, in particular). Further, Goodman et al teaching higher progression-free survival in cancer patients with high TMB/more efficient MHC presentation (which clearly would not occur if MHC was not expressed) treated with immune checkpoint blockade immunotherapy, as compared to the level of progression-free survival in cancer patients with high TMB/less efficient MHC presentation treated with immune checkpoint blockade, wherein greater than or equal to 10 mutations/Mb is used as a measure of high TMB supports the predictability of the combined method that uses high TMB (greater than or equal to 10 mutations/Mb) and lack of downregulation of MHC Class I to select cancer patients for treatment with the immune checkpoint blockade cemiplimab of Lowry et al.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4-10, 13-23, 26-31, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lowy et al (US 2017/0327590 A1; 11/16/17) in view of Dracopoli et al (US 2020/0157642 A1; 5/21/20), Goodman et al (Genome Medicine, 2020, 12(45): 1-13), Paulson et al (International Immunology, 2019, 31(7): 465-475), Lipson et al (Journal for ImmunoTherapy, 2017, 5(23): 1-5; 7/7/26 IDS), Cabrera et al (Immunobiology, 185(5): 440-452), and Sabbatino et al (Journal of ImmunoTherapy of Cancer, 2018, 6(126): 1-8), as applied to claims 1, 4-10, 13-23, and 26-31 above, and further in view of Caruso (Cancer Discovery, 2018, 8(9):1052) and Taramelli et al (Cancer Research, 1986, 46: 433-439).
Teachings of Lowy et al, Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, and Sabbatino et al are discussed above.
Lowy et al, Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, and Sabbatino et al do not specifically teach measuring expression of MHC class I in the tumor biopsy wherein at least 35% of the tumor biopsy cells are positive for MHC-I expression. However, these deficiencies are made up in the teachings of Caruso and Taramelli et al.
In melanoma, Caruso teaches melanoma patients with 50% or fewer melanoma cells exhibiting MHC class I presentation had worse overall survival to another immunotherapeutic checkpoint inhibitor (middle column, in particular).
Taramelli et al teaches measuring percentage of tumor cells expressing MHC Class I in a tumor biopsy, wherein approximately 80% of tumor (melanoma) biopsies comprise cancer cells where greater than 50% of the cancer cells exhibit MHC Class I expression, approximately 10% of tumor (melanoma) biopsies comprise cancer cells where 11-50% of the cancer cells exhibit MHC Class I expression, and approximately 10% of tumor (melanoma) biopsies comprise cancer cells where less than 10% of the cancer cells exhibit MHC Class I expression (Chart 1, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Lowy et al, Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, and Sabbatino et al wherein a tumor biopsy comprising BCC cells is collected from the patient, TMB and expression of MHC Class I are measured in tumor cells of the tumor biopsy and patients with tumor biopsies comprising tumor cells with a tumor mutation burden of greater than or equal to 10 mutations/Mb and expressing MHC Class I (including biopsies with at least 50% of the tumor cells MHC Class I) are selected for and treated by the combined method because a tumor mutation burden of greater than or equal to 10 mutations/Mb and expression of MHC class I in BCC tumor cells correlates with response to anti-PD-1 of the combined method and Caruso teaches melanoma patients with 50% or fewer melanoma cells (a tumor where anti-PD-1 also function as an immune checkpoint inhibitor) exhibiting MHC class I presentation had worse overall survival to another immunotherapeutic checkpoint inhibitor. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
Claims 1, 4-10, 13-23, 26-31, and 33 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 31, 33, and 35-58 of copending Application No. 18/046576 in view of Lowy et al (US 2017/0327590 A1; 11/16/17) in view of Dracopoli et al (US 2020/0157642 A1; 5/21/20), Goodman et al (Genome Medicine, 2020, 12(45): 1-13), Paulson et al (International Immunology, 2019, 31(7): 465-475), Lipson et al (Journal for ImmunoTherapy, 2017, 5(23): 1-5; 7/7/26 IDS), Cabrera et al (Immunobiology, 185(5): 440-452), Sabbatino et al (Journal of ImmunoTherapy of Cancer, 2018, 6(126): 1-8), Caruso (Cancer Discovery, 2018, 8(9):1052), and Taramelli et al (Cancer Research, 1986, 46: 433-439). The copending claims differ from the instant claims in that the copending claims do not specifically recite the patient with cancer treated with cemiplimab (anti-PD-1 checkpoint inhibitor immunotherapy) has been selected as having a high tumor mutation burden (TMB) of 10 mutations/Mb or that the patient does not exhibit downregulated MHC. However, these deficiencies are made up in the teachings of Lowy et al, Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, Sabbatino et al, Caruso, and Taramelli et al.
Teachings of Lowy et al, Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, Sabbatino et al, Caruso, and Taramelli et al are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the copeding method wherein a BCC patient for the copending method is selected for treatment with the copending method by collecting a tumor biopsy from the patient and a high TMB is measured in the tumor biopsy and wherein the patient does not exhibit downregulated MHC as measured by expression of MHC Class I in the tumor biopsy sample because Dracopoli et al teaches high TMB is associated with better response to immunotherapy ([0006], in particular), Goodman et al teaches that neoantigens are generated by mutations and are presented by MHC-1 and tumors that present neoantigens efficiently respond to (ICB) when TMB is ≥ 10 mutations/mb (right column on page 9, in particular), Paulson et al teaches tumors must present T-cell antigens bound to MHC to respond to immunotherapies, Lipson et al in view of Cabrera et al indicate some (not all) BCCs demonstrate low levels of MHC-1 expression and that the low MHC-1 expression may suppress anti-tumor immunity and allow for immune escape, and Sabbatino et al teaches lack of the human MHC class I expression by BCC patients treated with an anti-PD-1 inhibitor immunotherapeutic nivolumab “can justify the lack of clinical response to nivolumab” and that human MHC class I down-regulation is “widely recognized as a mechanism of tumor immune escape and it has been associated to cancer immunotherapy resistance”.
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein a TMB of greater than or equal to 10 mutations/Mb of Goodman et al is used as a cut-off to determine a high TMB because Goodman et al teaches a high TMB greater than or equal to 10 mutations/Mb and efficient presentation of neoantigens by MHC-1 as correlating with ICB efficacy (right column on page 9, in particular). Further, Goodman et al teaching higher progression-free survival in cancer patients with high TMB/more efficient MHC presentation (which clearly would not occur if MHC was not expressed) treated with immune checkpoint blockade immunotherapy, as compared to the level of progression-free survival in cancer patients with high TMB/less efficient MHC presentation treated with immune checkpoint blockade, wherein greater than or equal to 10 mutations/Mb is used as a measure of high TMB supports the predictability of the combined method that uses high TMB (greater than or equal to 10 mutations/Mb) and lack of downregulation of MHC Class I to select cancer patients for treatment with the immune checkpoint blockade cemiplimab of Lowry et al.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of the copending claims, Lowy et al, Dracopoli et al, Goodman et al, Paulson et al, Lipson et al, Cabrera et al, Sabbatino et al, Caruso, and Taramelli et al wherein a tumor biopsy comprising BCC cells is collected from the patient, TMB and expression of MHC Class I are measured in tumor cells of the tumor biopsy and patients with tumor biopsies comprising tumor cells with a tumor mutation burden of greater than or equal to 10 mutations/Mb and expressing MHC Class I (including biopsies with at least 50% of the tumor cells MHC Class I) are selected for and treated by the combined method because a tumor mutation burden of greater than or equal to 10 mutations/Mb and expression of MHC class I in BCC tumor cells correlates with response to anti-PD-1 of the combined method and Caruso teaches melanoma patients with 50% or fewer melanoma cells (a tumor where anti-PD-1 also function as an immune checkpoint inhibitor) exhibiting MHC class I presentation had worse overall survival to another immunotherapeutic checkpoint inhibitor.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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