DETAILED OFFICE 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 .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 refers to “the cells in the biological sample” of claim 1, but claim 1 does not require that the sample contain cells. Certain samples, such as plasma, are cell-free. Clarification is required.
Claim 21 requires that the survivin antigen is administered at, for example, about 0.1 mg/mL. It is unclear what volume is represented in the denominator. Clarification is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 52 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The Alice/Mayo analysis (see MPEP 2106(III)) proceeds as follows:
Step 1: YES, a process.
Step 2A prong 1: YES, a step of identifying a subject as likely to benefit from a particular combination therapy. This is an abstract idea relating the results of an assay for PD-L1 or PD-1 with a likelihood of success in providing the combination therapy. The “identifying” step can be performed wholly mentally, so it is a judicial exception.
Step 2A prong 2: NO, this judicial exception is not integrated into a practical application. A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the judicial exception. MPEP 2106.04(d). There are no additional elements beyond the “identifying” step other than a step of assaying biological samples from patients with hematologic malignancy for PD-L1 or PD-1 expression. This step does not integrate the mental step into any particular practical application because mere physical or tangible implementation of an exception does not guarantee eligibility. See MPEP 2106.04(d)(I). The active “assaying” step only serves to generally link the use of the judicial exception to a particular technological environment. For example, claim 52 contains no active step downstream of the “identifying” step. See MPEP 2106.04(d)(2) (citing Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 126 USPQ2d 1266 (Fed. Cir. 2018)). Claim 52’s active steps also do not appear to improve any existing technological process. See MPEP 2106.04(d)(I).
Step 2B: NO, the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. Assaying biological samples from patients with hematologic malignancy for PD-L1 or PD-1 expression was well-understood, routine, and conventional as of the claim’s effective filing date. Applicants state at paragraph 43 of the as-filed specification that PD-L1 is expressed in diffuse large B cell lymphoma (DLBCL). This representation is supported by the prior and contemporaneous art. For example:
Cogswell (US 20130309250; reference A) teaches assaying PD-L1 expression on the surface of cells in samples from various lymphomas (paragraph 12);
Kowanetz et al. (US 20150071910; reference B) teaches assaying PD-L1 expression in samples from various lymphomas using immunohistochemical and PCR methods (paragraph 408);
Couto et al. (US 20150346208; reference C) teaches PD-L1-expression-based prognostic assays for Hodgkin’s lymphoma, among other cancers (paragraph 190);
Freeman et al. (US 20160272712; reference D) teaches PD-L1 expression is diagnostic for cancers including Hodgkin’s lymphoma and B-cell lymphoma (paragraph 275);
Langermann et al. (US 20140044738; reference E) teaches PD-1 is a marker of T-cell lymphoma (paragraph 200);
Silvestre et al. (US 20170157188; reference F) teaches PD-1 is a marker of T-cell lymphoma based on FACS-based binding assays (paragraphs 195, 197); and
Bedoya et al. (US 20170306416; reference G) teaches assaying PD-1 in samples from subjects with hematological cancers (paragraph 359).
Because the active step of detecting PD-L1 or PD-1 expression in a biological sample from a subject with a hematologic malignancy was well-understood, routine, and conventional, the answer at Step 2B is NO.
For these reasons, the broadest reasonable interpretation of claim 52 fails to present patent-eligible subject matter and is rejected under 35 U.S.C. 101.
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.
Claims 1, 7-9, 32, 38, and 49-51 are rejected under 35 U.S.C. 103 as being unpatentable over Reichert (US 20180237524; reference H) in view of Desai (US 20180256551; reference I) as evidenced by Fowler (US 20040175827; reference J).
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies including diffuse large B-cell lymphoma (DLBCL; examined claim 50) and non-Hodgkin's lymphoma (NHL; examined claim 49) after carrying out the assay. (Paragraph 15.) Regarding claims 7 and 8, Reichert teaches administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody, for cancer treatment. (Paragraphs 10, 15, 78, 80, 100.) Regarding claim 9, Reichert teaches administering 200 mg of pembrolizumab. (Paragraph 142.) Regarding claims 32 and 38, Reichert teaches administering an additional active agent in combination, serially or simultaneously with pembrolizumab. (Paragraph 78.)
Reichert does not teach that the therapeutically effective amount of additional active agent coadministered with pembrolizumab is a therapeutically effective amount of a T cell activation therapeutic. Regarding claims 33 and 35, Reichert does not teach that the coadministered active agent is one that interferes with DNA replication, e.g. cyclophosphamide. Regarding claim 51, Reichert does not teach treating a relapsed/refractory DLBCL.
Desai likewise teaches treating hematopoietic malignancies including lymphoma, leukemia, and myeloma by administering the anti-PD-1 antibody pembrolizumab. (Paragraph 68.) Desai teaches that hematological malignancies can be treated with an effective amount of an immunomodulator that may be IL-2. (Paragraph 66.) Fowler is cited solely as evidence that IL-2 is a T cell stimulator. (Paragraph 49.) As such, Desai’s IL-2 is reasonably a “T cell activation therapeutic.” Regarding claim 51, Desai teaches that his methods can treat relapsed or refractory hematological malignancies, including B-cell lymphomas. (Paragraphs 9, 14, 15, 41, 58, 98.)
It would have been obvious to add Desai’s IL-2 to Reichert’s method of first detecting PD-L1 in a sample from a subject and then administering pembrolizumab (a PD-1 inhibitor) to treat a hematological cancer in the subject. This is so because Reichert and Desai each teach that their agents are useful for treating that condition. Coadministering pembrolizumab and IL-2 would have yielded the predictable result of treating hematological cancers. See MPEP 2143(I)(A) (combining prior-art elements); MPEP 2143(I)(E) (obvious to select from finite number of identified, predictable solutions to solve a known problem); MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by prior art to be useful for the same purpose) (citing In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)).
Regarding claim 51, the skilled artisan would have had a reasonable expectation of success in treating relapsed/refractory DLBCL with the method of Reichert in view of Desai because Reichert teaches treating DLBCL with pembrolizumab and Desai teaches that his method treats relapsed/refractory lymphomas. “Obviousness does not require absolute predictability, but at least some degree of predictability is required.” MPEP 2143.02(II). Based on the extensive teachings of Desai about treating relapsed/refractory lymphomas generally, the person of ordinary skill in the art would have reasonably predicted that the same method would treat relapsed/refractory DLBCL.
Claims 1, 7-9, 16, 18, 21-25, 27, 28, 32, 33, 35, 38, 48, 42, 45, 49, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Reichert (US 20180237524) in view of Mansour (2018, US Patent 10,022,441; reference K).
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies including diffuse large B-cell lymphoma (DLBCL; examined claim 50) and non-Hodgkin's lymphoma (NHL; examined claim 49) after carrying out the assay. (Paragraph 15.) Regarding claims 7 and 8, Reichert teaches administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody, for cancer treatment. (Paragraphs 10, 15, 78, 80, 100.) Regarding claim 9, Reichert teaches administering 200 mg of pembrolizumab. (Paragraph 142.) Regarding claims 32 and 38, Reichert teaches administering an additional active agent in combination, serially or simultaneously with pembrolizumab. (Paragraph 78.)
Reichert does not teach that the therapeutically effective amount of additional active agent coadministered with pembrolizumab is a survivin antigen, for example those having an amino acid sequence selected from SEQ ID NOs: 2-9. Reichert does not teach the amounts in claim 21. Reichert does not teach the compositions of claims 22-25, 27, or 28. Regarding claims 33 and 35, Reichert does not teach coadministering an agent that interferes with DNA replication, for example cyclophosphamide. Regarding claims 38, 42, 45, and 48, Reichert does not teach the claimed administration regimens.
Mansour teaches coadministration of a survivin-antigen vaccine and cyclophosphamide for treating cancer, for example lymphoma and leukemia. (Column 1, lines 40-65; column 48, lines 7-10.) Regarding claim 18, Mansour’s peptides have sequences as set forth in SEQ ID NOs: 1-8, which are identical to examined sequences 2-9, respectively. (Column 2, lines 1-6.) Regarding claim 21, Mansour exemplifies a vaccine comprising 1 mg of each of five synthetic peptides per mL of vaccine. (Column 25, lines 7-11.) Regarding claim 22, Mansour’s survivin-antigen vaccine is formulated with liposomes and a carrier comprising a continuous phase of a hydrophobic substance. (Column 24, lines 12-15.) Regarding claims 23 and 24, Mansour’s composition further comprises a T-helper epitope, for example that having SEQ ID NO:9, which is identical to examined SEQ ID NO:10. (Column 24, lines 17-24.) Regarding claims 25 and 27, Mansour’s composition further comprises an adjuvant, specifically a polyI:C polynucleotide (which, by definition, is either DNA or RNA). (Column 24, lines 24-25.) Regarding claim 28, the carrier in the composition may be mannide oleate in a mineral oil solution. (Column 39, lines 23-26.)
Regarding the dosing and timing regimen in claim 38, Mansour teaches providing about 25-300 mg/day, about 50-100 mg/day, or about 100 mg/day of cyclophosphamide, or 50 mg per dose; by definition, this must be provided either before, after, or concurrently with the survivin-antigen vaccine since those are the only three possible timing options; cyclophosphamide may also be administered 1-5 times daily, or more. (Column 2, line 42; column 44, lines 42-44; column 55, lines 25-28.) Regarding claim 42, Mansour teaches providing the active agent (i.e., DNA-replication-interfering agent) is administered about one week before providing the survivin-antigen vaccine, or it may be provided daily (i.e., “maintenance doses”) or twice daily for about one week, or it may be provided about one week before administration of the survivin-antigen vaccine. (Column 1, lines 53-65; column 45, lines 1-11.) Regarding claim 45, Mansour teaches metronomic treatment of one daily dose for a week on alternating weekly intervals; Mansour also teaches providing the active agent for a week, then not at all for a week, and repeating that cycle. (Column 46, lines 6-67.) Regarding claim 48, Mansour teaches providing the survivin-antigen vaccine every one, two, or three weeks and further discloses that “[t]he frequency and duration of the administration of the vaccine may however be adjusted as desired for any given subject,” for example continuing for an indefinite amount of time. (Column 1, lines 60-62; column 47, lines 1-17.)
Regarding claims 16 and 18, it would have been obvious to provide Mansour’s survivin-antigen vaccine along with Reichert’s pembrolizumab because both are taught to be useful in the treatment of cancers. Combining these agents would have yielded a predictable result, namely treating leukemia or lymphoma. See MPEP 2143(I)(A) (combination of prior-art elements) and 2144.06(I) (prima facie obvious to combine two compositions known for the same purpose to achieve that same purpose).
Regarding claim 21, it would have been obvious to provide the survivin-antigen vaccine at about 1 mg of each individual peptide antigen per mL of vaccine because Mansour exemplifies such a composition.
Regarding claims 22-25, 27, and 28, these formulations would have been obvious given Mansour’s explicit teachings that they are suitable for formulating the survivin-antigen vaccine for administration to a subject.
Regarding claims 33 and 35, Mansour teaches and exemplifies administering his survivin-antigen vaccine along with cyclophosphamide, which he teaches interferes with DNA replication. Making the combination would therefore have been obvious.
Regarding the dosing and timing regimens in claims 38, 42, 45, and 48, Mansour teaches all of the claimed intervals and amounts and further suggests that the timing may be optimized for a given patient, likely indefinitely. Selecting the dose and timing for a given patient would therefore have been obvious based on Mansour’s express teachings and on the express suggestion to optimize within the disclosed doses and timings.
Claims 1, 7-9, 16, 18, 21, 32, 33, 35, 38, 42, 45, 48, 50, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Berinstein et al. (6/12/19, Hematological Oncology 37 (S2) Supplement 569, abstract OT23; reference U; “Berinstein 1”) in view of Reichert (US 20180237524). Berinstein 1 and Reichert are both available as prior art under 35 U.S.C. 102(a)(1) outside the grace period.
Berinstein 1 teaches treating diffuse large B cell lymphoma (DLBCL) by administering 200 mg pembrolizumab every 3 weeks; 50 mg cyclophosphamide daily on alternating weeks; and 0.5 mL DPX-Survivac 21 days apart and up to six 0.1 mL subsequent doses every two months. (“Methods,” paragraph 1.) Berinstein 1 teaches that DPX-Survivac is a T-cell activating therapy and pembrolizumab is an inhibitor of PD-1. (“Introduction,” paragraph 2.) Berinstein 1 teaches that the treatment is efficacious for relapsed DLBCL that is refractory to autologous stem cell transplant. (“Introduction,” paragraph 1.) Berinstein 1 teaches carrying out a tumor biopsy prior to commencing the three-agent treatment. (Figure, bottom line.)
Berinstein 1 does not teach detecting the expression of PD-L1 in the tumor biopsy prior to starting the therapy.
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies including diffuse large B-cell lymphoma (DLBCL; examined claim 50) after carrying out the assay by administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody. (Paragraphs 10, 15, 78, 80, 100.)
It would have been obvious to select PD-L1 as the biomarker assayed in Berinstein 1’s tumor biopsy because Reichert teaches that PD-L1 is a biomarker for cancers including DLBCL. The skilled artisan would have expected that administering pembrolizumab to a PD-L1-positive cancer would have a therapeutic effect by inhibiting PD-1/PD-L1 signaling.
Claims 22-25, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Berinstein 1 in view of Reichert as applied to claims 1, 7-9, 16, 18, 21, 32, 33, 35, 38, 42, 45, 48, 50, and 51 above, as evidenced by Mansour et al. (US Patent 10,022,441).
The teachings of Berinstein 1 and Reichert are relied upon as above.
Berinstein 1 and Reichert do not specify the contents of Berinstein 1’s DPX-Survivac composition.
Mansour teaches coadministration of a survivin-antigen vaccine, DPX-Survivac, and cyclophosphamide for treating cancer, for example lymphoma and leukemia. (Column 1, lines 40-65; column 48, lines 7-10.) Regarding claim 18, Mansour’s DPX-Survivac contains peptides having sequences as set forth in SEQ ID NOs: 1-8, which are identical to examined sequences 2-9, respectively. (Column 2, lines 1-6.) Regarding claim 21, Mansour’s DPX-Survivac comprises 1 mg of each of five synthetic peptides per mL of vaccine. (Column 25, lines 7-11.) Regarding claim 22, Mansour’s DPX-Survivac is formulated with liposomes and a carrier comprising a continuous phase of a hydrophobic substance. (Column 24, lines 12-15.) Regarding claims 23 and 24, Mansour’s DPX-Survivac further comprises a T-helper epitope, for example that having SEQ ID NO:9, which is identical to examined SEQ ID NO:10. (Column 24, lines 17-24.) Regarding claims 25 and 27, Mansour’s DPX-Survivac further comprises an adjuvant, specifically a polyI:C polynucleotide (which, by definition, is either DNA or RNA). (Column 24, lines 24-25.) Regarding claim 28, the carrier in DPX-Survivac may be mannide oleate in a mineral oil solution. (Column 39, lines 23-26.)
Given the teachings of Mansour as to the identity of DPX-Survivac, the skilled artisan would have understood that Berinstein 1 administers the same vaccine composition referenced in examined claims 22-25, 27, and 28. The person of ordinary skill in the art would therefore have recognized that the structural requirements of claims 22-25, 27, and 28 are met by Berinstein 1.
Claims 1, 7-9, 16, 18, 21, 32, 33, 35, 38, 42, 45, 48, 50, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Berinstein et al. (11/13/19, Blood 134 (Supplement_1): 3236; reference V; “Berinstein 2”) in view of Reichert (US 20180237524). Reichert is available as prior art under 35 U.S.C. 102(a)(1) outside the grace period. Berinstein 2 is available as prior art under 35 U.S.C. 102(a)(1) inside the grace period because it was published within one year of the claims’ effective filing date and names authors who are not inventors on this application.
Berinstein 2 teaches treating diffuse large B cell lymphoma (DLBCL) by administering 200 mg pembrolizumab every 3 weeks; 50 mg cyclophosphamide twice daily on alternating weeks; and 0.5 mL DPX-Survivac 21 days apart and up to six 0.1 mL subsequent doses every two months. (“Introduction,” paragraph 1; “Methods,” paragraph 1.) Berinstein 2 teaches that DPX-Survivac is a T-cell activating therapy and pembrolizumab is an inhibitor of PD-1. (“Introduction,” paragraph 2.) Berinstein 2 teaches that the treatment is efficacious for relapsed DLBCL that is refractory to autologous stem cell transplant. (“Introduction,” paragraph 1.) Berinstein 2 teaches carrying out a tumor biopsy prior to commencing the three-agent treatment. (Figure, bottom line.)
Berinstein 2 does not teach detecting the expression of PD-L1 in the tumor biopsy prior to starting the therapy.
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies including diffuse large B-cell lymphoma (DLBCL; examined claim 50) after carrying out the assay by administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody. (Paragraphs 10, 15, 78, 80, 100.)
It would have been obvious to select PD-L1 as the biomarker assayed in Berinstein 2’s tumor biopsy because Reichart teaches that PD-L1 is a biomarker for cancers including DLBCL. The skilled artisan would have expected that administering pembrolizumab to a PD-L1-positive cancer would have a therapeutic effect by inhibiting PD-1/PD-L1 signaling.
Claims 22-25, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Berinstein 2 in view of Reichert as applied to claims 1, 7-9, 16, 18, 21, 32, 33, 35, 38, 42, 45, 48, 50, and 51 above, as evidenced by Mansour et al. (US Patent 10,022,441).
The teachings of Berinstein 2 and Reichert are relied upon as above.
Berinstein 2 and Reichert do not specify the contents of Berinstein 1’s DPX-Survivac composition.
Mansour teaches coadministration of a survivin-antigen vaccine, DPX-Survivac, and cyclophosphamide for treating cancer, for example lymphoma and leukemia. (Column 1, lines 40-65; column 48, lines 7-10.) Regarding claim 18, Mansour’s DPX-Survivac contains peptides having sequences as set forth in SEQ ID NOs: 1-8, which are identical to examined sequences 2-9, respectively. (Column 2, lines 1-6.) Regarding claim 21, Mansour’s DPX-Survivac comprises 1 mg of each of five synthetic peptides per mL of vaccine. (Column 25, lines 7-11.) Regarding claim 22, Mansour’s DPX-Survivac is formulated with liposomes and a carrier comprising a continuous phase of a hydrophobic substance. (Column 24, lines 12-15.) Regarding claims 23 and 24, Mansour’s DPX-Survivac further comprises a T-helper epitope, for example that having SEQ ID NO:9, which is identical to examined SEQ ID NO:10. (Column 24, lines 17-24.) Regarding claims 25 and 27, Mansour’s DPX-Survivac further comprises an adjuvant, specifically a polyI:C polynucleotide (which, by definition, is either DNA or RNA). (Column 24, lines 24-25.) Regarding claim 28, the carrier in DPX-Survivac may be mannide oleate in a mineral oil solution. (Column 39, lines 23-26.)
Given the teachings of Mansour as to the identity of DPX-Survivac, the skilled artisan would have understood that Berinstein 2 administers the same vaccine composition referenced in examined claims 22-25, 27, and 28. The person of ordinary skill in the art would therefore have recognized that the structural requirements of claims 22-25, 27, and 28 are met by Berinstein 2.
Claims 3 and 4 are rejected under each of (A) Reichert in view of Desai as evidenced by Fowler as applied to claims 1, 7-9, 32, 38, and 49-51; (B) Reichert in view of Mansour as applied to claims 1, 7-9, 16, 18, 21-25, 27, 28, 32, 33, 35, 38, 48, 42, 45, 49, and 50; (C) Berinstein 1 in view of Reichert as applied to claims 1, 7-9, 16, 18, 21, 32, 33, 35, 38, 42, 45, 48, 50, and 51; and (D) Berinstein 2 in view of Reichert as applied to claims 1, 7-9, 16, 18, 21, 32, 33, 35, 38, 42, 45, 48, 50, and 51, each combination taken further in view of Cogswell et al. (US 20150125463; reference L).
The teachings of combinations (A), (B), (C), and (D) are relied upon as above.
Combinations (A), (B), (C), and (D) do not teach that PD-L1 expression is detected in at least 1%, at least 5%, or at least 10% of cells in the biological sample, for example tumor cells.
Cogswell teaches that samples are considered PD-L1-positive if 5% of tumor cells exhibit PD-L1 staining. (Paragraph 331.)
It would have been obvious for the person of ordinary skill in the art to examine cells in the PD-L1 assay step of Reichert (which is part of each of combinations (A), (B), (C), and (D)) for at least 5% of cells being PD-L1 positive because Reichert teaches treating cancer and links PD-L1 expression to cancer. The skilled artisan would have understood based on Cogswell that 5% of cells being PD-L1 positive is a known threshold for a diagnosis of cancer.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Reichert (US 20180237524) in view of Lennerz et al. (2014, Cancer Immunology, Immunotherapy 63: 381-394; reference W) and Savoldo et al. (US 20170335290; reference M).
Claim 52 is a method of identifying a particular subject comprising detecting PD-L1 in a biological sample of the subject and identifying the subject as likely to benefit from a combination treatment comprising a PD-L1 or PD-1 inhibitor and a T-cell activation therapeutic. The transitional phrase “comprising” is inclusive or open-ended and does not exclude additional, unrecited method steps. MPEP 2111.03(I). As such, methods with additional assay steps lie within the scope of claim 52.
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies after carrying out the assay. (Paragraph 15.) Reichert teaches administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody, for cancer treatment. (Paragraphs 10, 15, 78, 80, 100.)
Reichert does not teach identifying a subject as likely to benefit from a combination treatment comprising a PD-L1 or PD-1 inhibitor and a T-cell activation therapeutic.
Lennerz teaches assaying solid tumors from patients for expression of survivin. (Page 383, column 1.) Lennerz teaches that the survivin-derived multi-epitope vaccine EMD640744 activates T cells and renders them able to recognize native survivin in tumor tissues. (Page 386, column 2; page 391, column 2.) Lennerz concludes that EMD640744 is immunologically efficacious. (Abstract.)
Savoldo teaches that survivin is expressed in some leukemias and lymphomas. (Paragraph 19.)
It would have been obvious to carry out Reichert’s PD-L1 expression assay and Lennerz’s survivin expression assay on a sample from a subject with a hematologic malignancy in order to determine whether the subject’s tumor produces both of these cancer biomarkers. The skilled artisan would have expected success in making the determination because Reichert and Savoldo teach that PD-L1 and survivin, respectively, are expressed in hematopoietic malignancy.
It would have been further obvious to identify the subject as likely to benefit from a combination treatment comprising Reichert’s pembrolizumab (a PD-1 inhibitor) and Lennerz’s EMD640744 (a T cell activation therapeutic) based on positive results from both assays because Reichert establishes that pembrolizumab was known to treat PD-L1-positive cancers, while Lennerz teaches that EMD640744 activates T cells in recipients and enables them to recognize survivin-expressing cancer cells. The skilled artisan would have concluded based on such a double-positive result that the subject would benefit from receiving both agents.
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 1, 7-9, 16, 18, 21-25, 27, 28, 32, 33, 35, 38, 42, 45, and 48-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-8, and 10-14 of U.S. Patent No. 10,022,441 in view of Reichert (US 20180237524) and Mansour (US 20160067335; reference A2).
The ’441 patent claims a method for treating cancer in a subject by first administering a therapeutically effective amount of cyclophosphamide (an agent that interferes with DNA replication), then a therapeutically effective amount of a vaccine comprising at least one survivin antigen (a T cell activation therapeutic). (Claim 1.) Specifically, the ’441 patent administers cyclophosphamide on a metronomic schedule wherein the agent is administered during the first week of an at-least-two-week cycle, then not during the second week, and repeating the cycle. (Claim 1.) The ’441 patent then administers the survivin-antigen vaccine a week after beginning the metronomic regimen. (Claim 1.) Regarding examined claim 18, the ’441 patent claims peptide antigens of SEQ ID NOs: 1-8, which are identical to examined SEQ ID NOs: 2-9. (Claim 6.) Regarding examined claims 22-25, 27, and 28, the ’441 patent claims that the vaccine is a composition comprising the same components; see ’441 claims 10-14.
The ’441 patent does not claim treating a hematological cancer in a subject. The ’441 patent does not claim detecting PD-L1 in a biological sample of the subject. The ’441 patent does not claim administering an inhibitor of PD-L1 or PD-1, for example according to the regimen of examined claim 9. The ’441 patent does not claim the amount of survivin antigen in examined claim 21 or the administration regimen in examined claim 48.
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies including diffuse large B-cell lymphoma (DLBCL; examined claim 50) and non-Hodgkin's lymphoma (NHL; examined claim 49) after carrying out the assay. (Paragraph 15.) Regarding examined claims 7 and 8, Reichert teaches administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody, for cancer treatment. (Paragraphs 10, 15, 78, 80, 100.) Regarding examined claim 9, Reichert teaches administering 200 mg of pembrolizumab. (Paragraph 142.) Regarding examined claims 32 and 38, Reichert teaches administering an additional active agent in combination, serially or simultaneously with pembrolizumab. (Paragraph 78.)
Mansour teaches coadministration of a survivin-antigen vaccine and cyclophosphamide for treating cancer, for example lymphoma and leukemia. (Paragraphs 4-5, 270.) Regarding examined claim 18, Mansour’s peptides have sequences as set forth in SEQ ID NOs: 1-8, which are identical to examined sequences 2-9, respectively. (Paragraphs 9-10.) Regarding claim 21, Mansour exemplifies a vaccine comprising 1 mg of each of five synthetic peptides per mL of vaccine. (Paragraph 114.) Regarding claim 22, Mansour’s survivin-antigen vaccine is formulated with liposomes and a carrier comprising a continuous phase of a hydrophobic substance. (Paragraph 212.) Regarding claims 23 and 24, Mansour’s composition further comprises a T-helper epitope, for example that having SEQ ID NO:9, which is identical to examined SEQ ID NO:10. (Paragraphs 10, 110.) Regarding claims 25 and 27, Mansour’s composition further comprises an adjuvant, specifically a polyI:C polynucleotide (which, by definition, is either DNA or RNA). (Paragraphs 10, 110.) Regarding claim 28, the carrier in the composition may be mannide oleate in a mineral oil solution. (Paragraph 209.)
Regarding the dosing and timing regimen in claim 38, Mansour teaches providing about 25-300 mg/day, about 50-100 mg/day, or about 100 mg/day of cyclophosphamide, or 50 mg per dose; by definition, this must be provided either before, after, or concurrently with the survivin-antigen vaccine since those are the only three possible timing options; cyclophosphamide may also be administered 1-5 times daily, or more. (Paragraphs 246, 335, 336.) Regarding claim 42, Mansour teaches providing the active agent (i.e., DNA-replication-interfering agent) is administered about one week before providing the survivin-antigen vaccine, or it may be provided daily (i.e., “maintenance doses”) or twice daily for about one week, or it may be provided about one week before administration of the survivin-antigen vaccine. (Paragraphs 6, 245.) Regarding claim 45, Mansour teaches metronomic treatment of one daily dose for a week on alternating weekly intervals; Mansour also teaches providing the active agent for a week, then not at all for a week, and repeating that cycle. (Paragraph 259.) Regarding claim 48, Mansour teaches providing the survivin-antigen vaccine every one, two, or three weeks and further discloses that “[t]he frequency and duration of the administration of the vaccine may however be adjusted as desired for any given subject,” for example continuing for an indefinite amount of time. (Paragraphs 6, 261.)
It would have been obvious to combine the cyclophosphamide and survivin-antigen vaccine of the ’441 patent with Reichert’s pembrolizumab to treat a hematological cancer in a subject because Mansour and Reichert, respectively, teach that these agents are useful for that purpose. Making the combination would have given the predictable outcome of the hematological cancer being treated in the subject. See MPEP 2143(I)(A) (combination of prior-art components); MPEP 2144.06(I) (prima facie to combine two components known for a given purpose for that same purpose).
It would have been further obvious to assay PD-L1 expression in a biological sample of the ’441 patent’s subject because Reichert teaches that PD-L1 is a known biomarker of cancer. The skilled artisan would have predicted that subjects identified as having PD-L1 expression would respond to therapy that inhibits PD-1/PD-L1 signaling.
It would have been obvious to provide the ’441 patent’s survivin-antigen vaccine and cyclophosphamide according to the examined claims’ dosing and treatment regimens because Mansour teaches that all of these parameters were known for administering those agents to treat cancer, including hematological cancers.
Claims 3 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-8, and 10-14 of U.S. Patent No. 10,022,441 in view of Reichert (US 20180237524) and Mansour (US 20160067335) as applied to claims 1, 7-9, 16, 18, 21-25, 27, 28, 32, 33, 35, 38, 42, 45, and 48-51 above, further in view of Cogswell et al. (US 20150125463).
The claims of the ’441 patent and the teachings of Reichert and Mansour are relied upon as above.
The ’441 patent does not claim, and Reichert and Mansour do not teach, that PD-L1 expression is detected in at least 1%, at least 5%, or at least 10% of cells in the biological sample, for example tumor cells.
Cogswell teaches that samples are considered PD-L1-positive if 5% of tumor cells exhibit PD-L1 staining. (Paragraph 331.)
It would have been obvious for the person of ordinary skill in the art to examine cells in the PD-L1 assay step of Reichert for at least 5% of cells being PD-L1 positive because Reichert teaches treating cancer and links PD-L1 expression to cancer. The skilled artisan would have understood based on Cogswell that 5% of cells being PD-L1 positive is a known threshold for a diagnosis of cancer.
Claims 1, 7-9, 16, 18, 21-25, 27, 28, 32, 33, 35, 38, 42, 45, and 48-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-6, 10-15, 17-21, and 24 of U.S. Patent No. 10,729,766 in view of Reichert (US 20180237524) and Mansour (US 20160067335).
The ’766 patent claims a method for treating cancer in a subject by first administering at least two doses of a therapeutically effective amount of cyclophosphamide (an agent that interferes with DNA replication), then a therapeutically effective amount of a vaccine comprising at least one survivin antigen (a T cell activation therapeutic). (Claim 1.) Specifically, the ’766 patent administers cyclophosphamide on a metronomic schedule wherein the agent is administered during the first week of an at-least-two-week cycle, then not during the second week, and repeating the cycle. (Claims 11-13.) The ’766 patent then administers the survivin-antigen vaccine a week after beginning the metronomic regimen. (Claim 6.) Regarding examined claim 18, the ’766 patent claims peptide antigens of SEQ ID NOs: 1-8, which are identical to examined SEQ ID NOs: 2-9. (Claims 1, 24.) Regarding examined claims 22-25, 27, and 28, the ’766 patent claims that the vaccine is a composition comprising the same components; see ’441 claims 10-14.
The ’766 patent does not claim treating a hematological cancer in a subject. The ’766 patent does not claim detecting PD-L1 in a biological sample of the subject. The ’766 patent does not claim administering an inhibitor of PD-L1 or PD-1, for example according to the regimen of examined claim 9. The ’766 patent does not claim the amount of survivin antigen in examined claim 21 or the administration regimen in examined claim 48.
Reichert teaches detecting the expression of PD-L1 in tumor-tissue samples removed from a patient with cancer, wherein PD-L1 is in fact detected. (Paragraphs 15, 68-72.) Reichert teaches that PD-L1 is a preferred biomarker for numerous cancers. (Paragraph 60.) Reichert teaches treating numerous hematologic malignancies including diffuse large B-cell lymphoma (DLBCL; examined claim 50) and non-Hodgkin's lymphoma (NHL; examined claim 49) after carrying out the assay. (Paragraph 15.) Regarding examined claims 7 and 8, Reichert teaches administering a therapeutically effective amount of pembrolizumab, an anti-PD-1 antibody, for cancer treatment. (Paragraphs 10, 15, 78, 80, 100.) Regarding examined claim 9, Reichert teaches administering 200 mg of pembrolizumab. (Paragraph 142.) Regarding examined claims 32 and 38, Reichert teaches administering an additional active agent in combination, serially or simultaneously with pembrolizumab. (Paragraph 78.)
Mansour teaches coadministration of a survivin-antigen vaccine and cyclophosphamide for treating cancer, for example lymphoma and leukemia. (Paragraphs 4-5, 270.) Regarding examined claim 18, Mansour’s peptides have sequences as set forth in SEQ ID NOs: 1-8, which are identical to examined sequences 2-9, respectively. (Paragraphs 9-10.) Regarding claim 21, Mansour exemplifies a vaccine comprising 1 mg of each of five synthetic peptides per mL of vaccine. (Paragraph 114.) Regarding claim 22, Mansour’s survivin-antigen vaccine is formulated with liposomes and a carrier comprising a continuous phase of a hydrophobic substance. (Paragraph 212.) Regarding claims 23 and 24, Mansour’s composition further comprises a T-helper epitope, for example that having SEQ ID NO:9, which is identical to examined SEQ ID NO:10. (Paragraphs 10, 110.) Regarding claims 25 and 27, Mansour’s composition further comprises an adjuvant, specifically a polyI:C polynucleotide (which, by definition, is either DNA or RNA). (Paragraphs 10, 110.) Regarding claim 28, the carrier in the composition may be mannide oleate in a mineral oil solution. (Paragraph 209.)
Regarding the dosing and timing regimen in claim 38, Mansour teaches providing about 25-300 mg/day, about 50-100 mg/day, or about 100 mg/day of cyclophosphamide, or 50 mg per dose; by definition, this must be provided either before, after, or concurrently with the survivin-antigen vaccine since those are the only three possible timing options; cyclophosphamide may also be administered 1-5 times daily, or more. (Paragraphs 246, 335, 336.) Regarding claim 42, Mansour teaches providing the active agent (i.e., DNA-replication-interfering agent) is administered about one week before providing the survivin-antigen vaccine, or it may be provided daily (i.e., “maintenance doses”) or twice daily for about one week, or it may be provided about one week before administration of the survivin-antigen vaccine. (Paragraphs 6, 245.) Regarding claim 45, Mansour teaches metronomic treatment of one daily dose for a week on alternating weekly intervals; Mansour also teaches providing the active agent for a week, then not at all for a week, and repeating that cycle. (Paragraph 259.) Regarding claim 48, Mansour teaches providing the survivin-antigen vaccine every one, two, or three weeks and further discloses that “[t]he frequency and duration of the administration of the vaccine may however be adjusted as desired for any given subject,” for example continuing for an indefinite amount of time. (Paragraphs 6, 261.)
It would have been obvious to combine the cyclophosphamide and survivin-antigen vaccine of the ’766 patent with Reichert’s pembrolizumab to treat a hematological cancer in a subject because Mansour and Reichert, respectively, teach that these agents are useful for that purpose. Making the combination would have given the predictable outcome of the hematological cancer being treated in the subject. See MPEP 2143(I)(A) (combination of prior-art components); MPEP 2144.06(I) (prima facie to combine two components known for a given purpose for that same purpose).
It would have been further obvious to assay PD-L1 expression in a biological sample of the ’766 patent’s subject because Reichert teaches that PD-L1 is a known biomarker of cancer. The skilled artisan would have predicted that subjects identified as having PD-L1 expression would respond to therapy that inhibits PD-1/PD-L1 signaling.
It would have been obvious to provide the ’766 patent’s survivin-antigen vaccine and cyclophosphamide according to the examined claims’ dosing and treatment regimens because Mansour teaches that all of these parameters were known for administering those agents to treat cancer, including hematological cancers.
Claims 3 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-8, and 10-14 of U.S. Patent No. 10,729,766 in view of Reichert (US 20180237524) and Mansour (US 20160067335) as applied to claims 1, 7-9, 16, 18, 21-25, 27, 28, 32, 33, 35, 38, 42, 45, and 48-51 above, further in view of Cogswell et al. (US 20150125463).
The claims of the ’766 patent and the teachings of Reichert and Mansour are relied upon as above..
The ’766 patent does not claim, and Reichert and Mansour do not teach, that PD-L1 expression is detected in at least 1%, at least 5%, or at least 10% of cells in the biological sample, for example tumor cells.
Cogswell teaches that samples are considered PD-L1-positive if 5% of tumor cells exhibit PD-L1 staining. (Paragraph 331.)
It would have been obvious for the person of ordinary skill in the art to examine cells in the PD-L1 assay step of Reichert for at least 5% of cells being PD-L1 positive because Reichert teaches treating cancer and links PD-L1 expression to cancer. The skilled artisan would have understood based on Cogswell that 5% of cells being PD-L1 positive is a known threshold for a diagnosis of cancer.
Conclusion
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/Lora E Barnhart Driscoll/ Primary Examiner, Art Unit 3991