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
The Amendments and Remarks filed 3/12/26 in response to the Office Action of 9/15/25 are acknowledged and have been entered.
Claims 1, 4-10, 13-23, and 26-33 are pending.
Claims 1, 20-23, 26, 27, and 32 have been amended by Applicant.
Claims 1, 4-10, 13-23, and 26-33 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Withdrawn
The rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn.
The provisional double patenting rejection over claims of Application No. 17/433003 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Goodman et al (Genome Medicine, 2020, 12(45): 1-13), and Taramelli et al (Cancer Research, 1986, 46: 433-439) is withdrawn.
The rejection of claims on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10457725 B2 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Goodman et al (Genome Medicine, 2020, 12(45): 1-13), and Taramelli et al (Cancer Research, 1986, 46: 433-439) is withdrawn.
The rejection of claims on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11505600 B2 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Goodman et al (Genome Medicine, 2020, 12(45): 1-13), and Taramelli et al (Cancer Research, 1986, 46: 433-439) is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 102
Claim(s) 32 remains rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lowy et al (US 2017/0327590 A1; 11/16/17).
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 cemiplimab (same as “REGN2810” at [0020) and comprises all recited SEQ ID NOs ([0209], in particular). Lowy et al further teaches a kit comprising the antibody and instructions ([0023], in particular).
Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, as in the instant situation, the printed matter will not distinguish the claimed product from the prior art. In re Nagi, 367 F .3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed.). MPEP 2112.01.
Response to Arguments
In the Reply of 3/12/26, Applicant argues Lowy et al does not teach a kit including a combination of an antibody or antigen binding fragment that specifically binds PD-1 and the instructions defined in claim 32 because Lowy et al does not teach the use of an antibody or antigen binding fragment that specifically binds PD-1 for treatment of BCC, where the BCC is characterized by a TMB of greater than or equal to 10 mutations/Mb and the patient does not exhibit downregulated MHC. Applicant further argues Lowy et al does not tech that an antibody or an antigen binding fragment according to claim 32 can be used for treating a cancer characterized by a TMB of great than or equal to 10 mutations/Mb in a patient that does not exhibit downregulated MHC. Applicant further argues the use directed by the instructions in the claimed kit is novel over the teachings of Lowy et al and the combination of the printed matter and a substrate of claim 32 create a new, previously unknown functional relationship that enables treatment of a defined population of patients suffering from BCC.
The amendments to the claims and the arguments found in the Reply of 3/12/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that Lowy et al does not teach a kit including a combination of an antibody or antigen binding fragment that specifically binds PD-1 and the instructions defined in claim 32 because Lowy et al does not teach the use of an antibody or antigen binding fragment that specifically binds PD-1 for treatment of BCC, where the BCC is characterized by a TMB of greater than or equal to 10 mutations/Mb and the patient does not exhibit downregulated MHC, the examiner disagrees. The antibodies of Loy et al are equivalent to antibodies that specifically bind PD-1 for treatment of BCC, where the BCC is characterized by a TMB of greater than or equal to 10 mutations/Mb and a patient does not exhibit downregulated MHC.
In regards to the argument Lowy et al does not tech that an antibody or an antigen binding fragment according to claim 32 can be used for treating a cancer characterized by a TMB of great than or equal to 10 mutations/Mb in a patient that does not exhibit downregulated MHC, the ability of the antibodies of Lowy et al to be used for treating a cancer characterized by a TMB of great than or equal to 10 mutations/Mb in a patient that does not exhibit downregulated MHC is inherent.
In regards to the argument that a use directed by the instructions in the claimed kit is novel over the teachings of Lowy et al and the combination of the printed matter and a substrate of claim 32 create a new, previously unknown functional relationship that enables treatment of a defined population of patients suffering from BCC, the examiner disagrees. It is first noted the claims are drawn a kit comprising products and not a “use”. It is acknowledged claim 32 recites an intended use; however, the kit comprising antibody and instructions of Lowy et al ([0023], in particular) is equivalent to a recited kit with a recited intended use. Further, in the instant case, there is a lack of a functional relationship between the claimed antibodies and the claimed instructions. The instant case with antibodies and instructions is analogous to that of a set of chemicals and a printed set of instructions. As stated at MPEP 2111.05: “…where the printed matter and product do not depend upon each other, no functional relationship exists. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864.”
Claim Rejections - 35 USC § 103
Claims 1, 4-10, 13-23, and 26-32 remain 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) and Goodman et al (Genome Medicine, 2020, 12(45): 1-13; 2/21/23 IDS).
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 cemiplimab (same as “REGN2810” at [0020) and comprises all recited SEQ ID NOs ([0209], in particular). Lowy et al further teaches a method of treating cancer, such as cutaneous squamous cell carcinoma (CSC), basal cell carcinoma (BCC), Merkel cell carcinoma, and melanoma 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 and Goodman 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).
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 lack of LOH 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), Dracopoli et teaches LOH of MHC class I occurs in several tumors and LOH at MHC correlates with shorter survival of patients with checkpoint inhibitors ([0008], in particular) Dracopoli et al teaches a method of treating a tumor comprising (a) selecting a patient with cancer, 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 (see [0012]-[0013] and claims 21, 25, 27, and 28, in particular), and Goodman et al 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).
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 describes “efficient MHC presentation” as a biomarker for response to immune checkpoint blockade and patients with “efficient MHC presentation” would be expected not to exhibit downregulated MHC (as recited by the instant claims) because downregulation of MHC would inhibit MHC presentation. Further, Goodman et al teaching 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, 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 as measured by lack of LOH 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.
Response to Arguments
In the Reply of 3/12/26, Applicant argues cited references do not teach or suggest a method comprising selecting a patient that has BCC, a tumor with a TMB of greater than or equal to 10 mutation/Mb and does not exhibit downregulated MHC. Applicant further argues Dracopoli and Goodman (and Taramelli et al of the below rejection) do not teach treatment of BCC or an antibody as defined by claim 1. Applicant further argues the combined teachings of the cited references fail to provide a reasonable expectation of success requisite for establishing prima facie obviousness. Applicant further states that Applicant has surprisingly found that, even for patients with advanced BCC where such patients do not exhibit downregulated MHC and have a tumor with a TMB of greater than equal to 10 mutations/Mb, administering an antibody or antigen binding fragment thereof as defined in claim 1 to such patients is surprisingly effective. Applicant further argues that, given the known difficulty of treating patients with advanced BCC, one of ordinary skill in the art would have had no expectation the methods recited in claims 1, 3-10, 13-26, and 33 or the kit recited in claim 32 could be successfully implemented. Applicant further cites Example 1, [00154], and Figure 9 of the specification as teaching (i) BCC patients of “Group 2” treated with cemiplimuab that had a TMB ≥ 10 mutations/Mb achieved a higher ORR than BCC patients of Group 2 that did not have a TMB ≥ 10 mutations/Mb and (ii) that the median proportion of MHC+ cells/tumor in high TMB patient was markedly higher in those that responded to cempilimab than those with high TMB that did not respond to cemiplimab. Applicant further argues the claims are non-obvious because the claimed methods of using the recited anti-PD-1 antibody or antigen binding fragment thereof to treat BCC tumors having TMB ≥ 10 mutations/Mb and comprising cells that are positive for MHC expression achieve unexpectedly high therapeutic efficacy.
The amendments to the claims and the arguments found in the Reply of 3/12/26 have been carefully considered, but are not deemed persuasive. In regard to the arguments (i) cited references do not teach or suggest a method comprising selecting a patient that has BCC, a tumor with a TMB of greater than or equal to 10 mutation/Mb and does not exhibit downregulated MHC, (ii) the combined teachings of the cited references fail to provide a reasonable expectation of success requisite for establishing prima facie obviousness, and (iii) that, given the known difficulty of treating patients with advanced BCC, one of ordinary skill in the art would have had no expectation the methods recited in claims 1, 3-10, 13-26, and 33 or the kit recited in claim 32 could be successfully implemented, the examiner disagrees. As stated above, 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 lack of LOH 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), teaches LOH of MHC class I occurs in several tumors and LOH at MHC correlates with shorter survival of patients with checkpoint inhibitors ([0008], in particular) and Dracopoli et al teaches a method of treating a tumor comprising (a) selecting a patient with cancer, 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 (see [0012]-[0013] and claims 21, 25, 27, and 28, in particular), and Goodman et al 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). 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 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 describes “efficient MHC presentation” as a biomarker for response to immune checkpoint blockade and patients with “efficient MHC presentation” would be expected not to exhibit downregulated MHC (as recited by the instant claims) because downregulation of MHC would inhibit MHC presentation. Further, Goodman et al teaching 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, 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 as measured by lack of LOH of MHC Class I to select cancer patients for treatment with the immune checkpoint blockade cemiplimab of Lowry et al.
In regards to the argument Dracopoli and Goodman (and Taramelli et al of the below rejection) do not teach treatment of BCC or an antibody as defined by claim 1, the cited references are not limited to Dracopoli and Goodman (or Dracopoli, Goodman, and Taramelli et al). The cited references also include Lowy.
The examiner acknowledges Example 1, [00154], and Figure 9 of the specification as teaching (i) BCC patients of “Group 2” treated with cemiplimuab that had a TMB ≥ 10 mutations/Mb achieved a higher ORR than BCC patients of Group 2 that did not have a TMB ≥ 10 mutations/Mb and (ii) that the median proportion of MHC+ cells/tumor in high TMB patient was markedly higher in those that responded to cempilimab than those with high TMB that did not respond to cemiplimab.
In regard to the arguments Applicant has surprisingly found that administering an antibody or antigen binding fragment thereof as defined in claim 1 to such patients is surprisingly effective for patients with advanced BCC where such patients do not exhibit downregulated MHC and have a tumor with a TMB of greater than equal to 10 mutations/Mb and that the claims are non-obvious because the claimed methods of using the recited anti-PD-1 antibody or antigen binding fragment thereof to treat BCC tumors having TMB ≥ 10 mutations/Mb and comprising cells that are positive for MHC expression achieve unexpectedly high therapeutic efficacy, the examiner disagrees. High therapeutic efficacy is expected by administering anti-PD-1 immunotherapeutic checkpoint antibody to subject with BCC tumors with high TMB (≥ 10 mutations/Mb) comprising cells positive for MHC expression based on teachings of Dracopoli and Goodman 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 population of patients with checkpoint inhibitors ([0008], in particular). Further, 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) and that 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 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). 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). Further, Goodman describes “efficient MHC presentation” as a biomarker for response to immune checkpoint blockade and patients with “efficient MHC presentation” would be expected not to exhibit downregulated MHC (as recited by the instant claims) because downregulation of MHC would inhibit MHC presentation. Further, Goodman et al teaching 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, 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 as measured by lack of LOH of MHC Class I to select cancer patients for treatment with the immune checkpoint blockade cemiplimab of Lowry et al.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4-10, 13-23, and 26-33 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) and Goodman et al (Genome Medicine, 2020, 12(45): 1-13) as applied to claims 1, 4-10, 13-23, and 26-32 above, and further in view of Taramelli et al (Cancer Research, 1986, 46: 433-439).
Teachings of Lowy et al, Dracopoli et al, and Goodman et al are discussed above.
Lowy et al, Dracopoli et al, and Goodman 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 Taramelli et al.
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). Those tumor biopsies of Taramelli et al exhibiting MHC Class I in less than 10% of tumor cells of the biopsy would predictably include those with LOH of MHC Class I because LOH of MHC Class I is the loss of alleles encoding MHC Class I.
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, and Goodman et al wherein LOH of MHC Class I is determined by measuring expression of MHC Class I in tumor cells of the tumor biopsies and patients with tumor biopsies comprising tumor cells expressing MHC Class I (including biopsies with at least 50% of the tumor cells MHC Class I) are treated by the combined method because measuring expression of MHC Class I in tumor cells of the biopsy provides an indication that LOH of MHC Class I is not present because LOH of MHC Class I is the loss of alleles encoding MHC Class I and loss of alleles encoding MHC Class I would lead to a loss of expressing of MHC Class I. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 3/12/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 101
Claim 33 remains rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. Abstract ideas include mathematical concepts (including mathematical relationships, formulas, equations, and calculations), mental processes (including concepts performed in the human mind), and certain methods of organizing human activity (including managing personal behavior, relationships, or interactions between people). The rationale for this determination is explained below:
Claim 33 is directed to abstract idea because the claim recites an abstract idea (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “abstract idea” is: the “selecting” step (a mental process). The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, methods of the encompassed claim do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) encompass methods that are limited to well-understood, routine and conventional limitations of collecting a tumor biopsy, measuring TMB in the biopsy, and measuring the expressing of MHC Class I in the biopsy, and a recited generic treatment step in the preamble (“Step 2B”). Steps of collecting a tumor biopsy, measuring TMB in the biopsy, and measuring the expressing of MHC Class I in the biopsy are well-known in the prior art (see above prior art rejections). Further treating a subject with cancer is well-known in the art. Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance). It is acknowledged that claim 33 recites an optional treatment step of administering a specific antibody or fragment thereof that specifically binds PD-1; however, the claim encompasses methods wherein the antibody is not administered (see “…if the tumor biopsy exhibits….” at the third to last line of claim 33).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
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Further, the specification acknowledges assays for detecting expression of MHC in tumor cells and TMB are known in the art ([0044]-[0045], in particular). Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods encompassed by the instant claims are well-known, routine, and conventional. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting expression) are routinely performed in the art to obtain data regarding expression and treat subjects. Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013).
Response to Arguments
In the Reply of 3/12/26, Applicant argues this rejection should be withdrawn because embodiments of the claim that require administering the antibody or antigen-biding fragment thereof are significantly more than the recited judicial exception.
The amendments to the claim and the arguments found in the Reply of 3/12/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that this rejection should be withdrawn because embodiments of the claim that require administering the antibody or antigen-biding fragment thereof are significantly more than the recited judicial exception, the examiner disagrees for the reasons stated above. The claim encompasses embodiments wherein the antibody or antigen-biding fragment thereof are not administered.
Double Patenting
Claims 1, 4-10, 13-23, and 26-33 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), 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, and Taramelli et al.
Teachings of Lowy et al, Dracopoli et al, Goodman et al, 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 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 lack of LOH of MHC Class I because Dracopoli et al teaches high TMB is associated with better response to immunotherapy ([0006], in particular), Dracopoli et teaches LOH of MHC class I occurs in several tumors and LOH at MHC correlates with shorter survival of patients with checkpoint inhibitors ([0008], in particular) and Dracopoli et al teaches a method of treating a tumor comprising (a) selecting a patient with cancer, 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 (see [0012]-[0013] and claims 21, 25, 27, and 28, in particular).
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said method wherein a TMB of greater than or equal to 10 mutations/Mb is used as a cut-off to determine a high TMB because Goodman et al defines high TMB as greater than or equal to 10 mutations/Mb (right column on page 3, in particular). Further, Goodman describes “efficient MHC presentation” as a biomarker for response to immune checkpoint blockade and patients with “efficient MHC presentation” would be expected not to exhibit downregulated MHC (as recited by the instant claims) because downregulation of MHC would inhibit MHC presentation. Further, Goodman et al teaching 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, wherein greater than or equal to 10 mutations/Mb is used as a measure of high TMB supports the predictability of the method using high TMB (greater than or equal to 10 mutations/Mb) and lack of downregulation of MHC class I as measured by lack of LOH of MHC Class I to select cancer patients for treatment with the immune checkpoint blockade cemiplimab of the copending claims.
As evidenced by Taramelli et al, greater than 50% of the tumor cells of the biopsies of the method, which do not exhibit downregulated MHC as measured by lack of LOH of MHC Class I, would predictably be positive for MHC Class I expression because Taramelli et al teaches 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). Those tumor biopsies of Taramelli et al exhibiting MHC Class I in less than 10% of tumor cells of the biopsy would predictably include those with LOH of MHC Class I because LOH of MHC Class I is the loss of alleles encoding MHC Class I.
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method wherein LOH of MHC Class I is determined by measuring expression of MHC Class I in tumor cells of the tumor biopsies and patients with tumor biopsies comprising tumor cells expressing MHC Class I (including biopsies with at least 50% of the tumor cells MHC Class I) are treated by the method because measuring expression of MHC Class I in tumor cells of the biopsy provides an indication that LOH of MHC Class I is not present because LOH of MHC Class I is the loss of alleles encoding MHC Class I and loss of alleles encoding MHC Class I would lead to a loss of expressing of MHC Class I.
Further, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to combine the reagents of a method into a kit format with instructions in order to allow others to perform the method with guidance.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In the Reply of 3/12/26, Applicant repeats arguments above and requests this rejection be withdrawn. The amendments to the claims and the arguments found in the Reply of 3/12/26 have been carefully considered, but are not deemed persuasive. The rejection remains withdrawn for reasons of record.
Double Patenting
Claim 32 remains rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9987500 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims differ than the instant claim in that that the instant claim recites antibody of the patent claim is part of a kit comprising “instructions”. However, it would be obvious to provide the patent antibody in a kit comprising “instructions” for use in order to provide guidance to one using the antibody to bind PD-1, as recited by patent claims.
Response to Arguments
In the Reply of 3/12/26, Applicant repeats arguments above and requests this rejection be withdrawn. The amendments to the claims and the arguments found in the Reply of 3/12/26 have been carefully considered, but are not deemed persuasive. The rejection remains withdrawn for reasons of record.
Conclusion
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.
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