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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 3, 2026 has been entered.
Applicant’s Response Dated February 3, 2026
In the Response dated February 3, 2026, claims 1-3, 11-13, and 20-21 were amended and claim 16 was canceled. Claims 1-5, 7-15, and 17-22 are pending. An action on the merits of claims 1-5, 7-15, and 17-22 is contained herein.
The rejection of claims 1-5, 7-15, and 17-22 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dietrich US 2019/0249258 A1 (Dietrich) has been rendered moot in view of applicant’s amendment dated February 3, 2026. Dietrich does not teach a method comprising administering to the subject an inhibitor of methylation. Therefor the rejection has been withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 7-15, and 17-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dietrich US 2019/0249258 A1 (Dietrich) and Daver, Naval, et al. "Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes." Leukemia 32.5 (2018): 1094-1105 (Daver) in combination.
Claims 1-5, 7-10 are drawn to a method of treating, inhibiting, reducing, ameliorating, and/or preventing an immunogenic cancer or metastasis in a subject comprising:
(a) obtaining a tissue sample from the subject;
(b) assaying an increase in the amount of methylation of one or more co-stimulatory genes and/or a decrease in the amount of methylation of one or more immune checkpoint genes in the tissue sample relative to a normal control tissue; and
(c) administering to the subject an immunotherapy and an inhibitor of methylation.
Claims 11-15 and 17-22 are drawn to of initiating or resuming assessing the suitability of an immunotherapy and an inhibitor of methylation treatment regimen for the treatment an immunogenic cancer or metastasis in a subject comprising:
(a) obtaining a tissue sample from the subject; and
(b) assaying an increase in the amount of methylation of one or more co-stimulatory genes and/or a decrease in the amount of methylation of one or more immune checkpoint genes in the tissue sample relative to a normal control tissue; and
(c) initiating or resuming the subject on an immunotherapy and an inhibitor of methylation treatment regimen.
Dietrich teaches a method of treating a patient with a malignant disease with an immunotherapy, the method comprising determining presence, absence or level of methylation of at least one CCG dinucleotide of an immunoregulatory gene (e.g., b. assaying the amount of methylation of…in the tissue sample) of cells of the malignant disease and/or of T lymphocytes interacting with said cells of the malignant disease (e.g., a. obtaining a tissue sample from the subject), wherein said immunoregulatory gene encodes an immune checkpoint selected from B7 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2 BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor, selecting a pharmaceutical compound for immunotherapeutic treatment of said patient on the basis of the result of said DNA methylation analysis, and administering said pharmaceutical compound to said patient (e.g., c. administering to the subject an immunotherapy…normal control tissue is detected). See claim 38. Dietrich teaches, in a variant, the immunoregulatory gene is selected from the genes encoding the B7 protein and its receptor CD80 and CTLA4 [0089].
As used therein, the term “malignant disease” or “malignancy” includes those diseases that are characterized by a disease progression that is progressively destructive and may also lead to the death of the patient [0022]. Malignant diseases include malignant formation of new tissue, such as neoplasms or tumors, wherein malignancy may be characterized by uncontrolled, space-consuming, displacing, infiltrative and/or invasive growth. Malignant tumors are usually able to form secondary tumors (metastases). Malignant tumors include for example carcinomas, sarcomas, melanomas, gliomas, blastomas, seminomas and teratomas. Malignant diseases also include haematological malignancies, i.e. malignant diseases affecting the blood system or the haematopoietic system, such as leukaemias, lymphomas, myeloproliferative disorders and myelodysplastic syndromes. Leukemias include a group of malignant diseases in which immature hematopoietic cells have changed malignantly, proliferate excessively and lead to an accumulation of cells in the peripheral blood. Lymphomas comprise diseases in which cells of the lymphatic system are malignantly degenerated.
Dietrich teaches that the application of DNA methylation analysis of an immunoregulatory gene to predict the response to immunotherapy was tested on a cohort of 23 patients with malignant melanoma [0187]. Patients received immunotherapy with pembrolizumab. This compound is a monoclonal antibody directed against the PDCD1 receptor encoded by the immunoregulatory gene PDCD1. By interacting with the PDCD1 receptor, the antibody prevents the binding of the corresponding ligands encoded by CD274 and PDCD1LG2 and thus alters the immunoregulatory effect of both PDCD1 and CD274 and/or PDCD1LG2. FIG. 5 shows the Kaplan-Meier analysis of overall survival of 528 patients with squamous cell carcinomas of the head and neck stratified by DNA methylation analysis of the PDCD1 gene locus [0048]. Dietrich teaches that the gene CD274 or CD274 molecule, respectively, is also known under the synonyms PDCD1L1, B7-H, B7-H1, PDCD1LG1, PD-L1, PDL1 and B7E1 [0091]. CD274 is an immunoregulatory gene encoding a B7 protein, which is an immune checkpoint in the sense of the invention
Dietrich teaches that the DNA methylation analysis may include determining the presence, absence or level of methylation of at least one CpG dinucleotide contained in the immunoregulatory gene [0074]. It is also possible to analyze several CpG dinucleotides of the immunoregulatory gene. These dinucleotides can also be distributed over different parts of the immunoregulatory gene to be investigated. In preferred variants, the methylation of at least one CpG dinucleotide from each of at least two different immunoregulatory genes is determined. Dietrich teaches that the determination of the DNA methylation of the immunoregulatory gene is not particularly limited [0075]. Dietrich teaches that a person skilled in the art can easily determine suitable methods on the basis of the disclosure. Dietrich teaches that the result of the DNA methylation analysis or the methylation of the immunoregulatory gene can then be compared with a reference value, for example, to determine the prognosis and/or the likelihood of response of the patient to immunotherapy [0080]. The determination of suitable reference values is routine in medical laboratory practice.
Dietrich teaches a method for predicting the response of a patient with a malignant disease to immunotherapy [0011]. The method is characterized in that a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or of T lymphocytes interacting with said cells of the malignant disease is performed and, on the basis of the result, the prognosis is determined and/or the response to the immunotherapy is predicted (prediction). Dietrich further teaches a method for individualized selection of a pharmaceutical compound for immunotherapeutic treatment of a patient with a malignant disease, the method comprising performing a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes interacting with said cells of the malignant disease, wherein said immunoregulatory gene encodes an immune checkpoint selected from 137 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2, BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor, and selecting the pharmaceutical compound on the basis of the result of said DNA methylation analysis. See claim 31. FIG. 8 shows the Kaplan-Meier analysis of overall survival of 470 patients with malignant melanoma, stratified by DNA methylation analysis and mRNA expression analysis of the immunoregulatory genes CD274 (A) (as in FIG. 7), PDCD1LG2 (B), PDCD1 (C), BTLA (D), LAG3 (E), TIGIT (F), CD40 (G), CTLA4 (H) and TNFRSF9 (I). Group II (high risk group): high DNA methylation and low mRNA expression; Group IV (low risk group): low methylation and high mRNA expression; Group I+III (medium risk group): high mRNA expression and high DNA methylation or low mRNA expression and low DNA methylation [0051].
FIG. 19 shows the corresponding determination of DNA methylation of the immunoregulatory gene PDCD1 in accordance with the invention of Dietrich [0192]. In the group of patients 1 to 12 who showed a response, an average of 59% methylation of the PDCD1 gene was found in the tumor samples. This methylation was significantly higher with a p-value of 0.008 in a t-test than the methylation in the tumors of the patients who showed progression of the disease and who had a mean methylation of 22%. The level of DNA methylation of the PDCD1 gene therefore also correlates with the response to immunotherapy and allows for the DNA methylation of PDCD1 to be used to identify those patients who are likely to respond to therapy before starting the therapy. For example, the tumors of nine of the twelve (75%) responding patients (patients 1 to 12) exhibited a DNA methylation of the PDCD1 gene of over 25% and could thus be correctly identified as responding patients. The patient with a complete tumor decline due to immunotherapy (patient 1) showed the highest methylation of all investigated samples (98%) and could therefore most reliably be identified. In contrast, nine of the eleven (82%) patients (patients 13-23) who did not respond to therapy exhibited PDCD1 methylation below 25% and were correctly identified as patients who do not respond to the selected immunotherapy with pembrolizumab. In the future, using the method according to the present invention such patients could for instance be exempted from immunotherapy with pembrolizumab and its side effects.
Dietrich further teaches a method for assessing prognosis of a patient with a malignant disease and/or predicting response of a patient with a malignant disease to immunotherapy, the method comprising performing a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes interacting with said cells of the malignant disease, wherein said immunoregulatory gene encodes an immune checkpoint selected from B7 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNTRSF4, TNTRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2 BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor, and assessing the prognosis and/or predicting the response to immunotherapy on the basis of the result of said DNA methylation analysis. See Claim 16. As used therein, the term “prognosis” means a conclusion about the condition of a patient with a malignant disease or the change in the patient's condition in the future [0024]. This can include both the condition of patients in the absence of a therapeutic intervention and the condition of patients who are already receiving or have received therapy. Prognosis in the sense of the invention also encompasses the conclusion about the condition or the change of the condition, if the patient receives a therapy in the future.
Dietrich differs from the instantly claimed invention in that Dietrich does not teach a method further comprising administering to the subject an inhibitor of methylation; however, this deficiency would have been obvious in view of the teachings of Daver.
In the instant case, the references may be combined to show obviousness because Dietrich and Daver are each drawn to a method of treating a patient with a malignant disease with an immunotherapy. They are from the same field of endeavor, and/or are reasonably pertinent to a method of treating, inhibiting, reducing, ameliorating, and/or preventing an immunogenic cancer or metastasis in a subject.
Daver teaches that hypomethylating agents (HMAs), such as azacitidine and decitabine, have demonstrated diverse immune-modulating activities on tumor infiltrating lymphocytes and on leukemic cells (Fig. 1) (pages 1097-1099). An important mechanism of tumor immune response evasion by cancer cells lies in their ability to alter the expression of tumor-associated antigens, resulting in deficient antigen presentation. HMAs have favorable effects on anti-tumor immune response by upregulating a range of immunomodulatory pathway-related genes including the expression of cancer testis antigens (CTAs) [including melanoma-associated antigens (MAGE-1) and NY-ESO-1], increasing the expression of HLA class 1 on tumor cells allowing for improved tumor recognition, upregulating co-stimulatory molecules (CD28, CD40L), and upregulating IFN-gamma pathway viral defense genes (IRF7, IFI27, IFI44, DDX41, STAT11, IF16, and others).
Daver teaches that a number of trials combining HMAs with PD-1/PD-L1- based therapies have recently started enrollment for AML and MDS including azacitidine with the anti-PD-1 antibody nivolumab (NCT02397720), azacitidine with or without the anti-PD-L1 antibody durvalumab (NCT02775903), and azacitidine with or without the anti-PD-L1 antibody atezolizumab (NCT02508870) (Table 1) (Fig. 2) (page 1100). Daver teaches that it is becoming increasingly clear that the heavy systemic disease burden, the immunosuppressive effect of the tumor microenvironment, and the moderate overexpression of immune checkpoints co-stimulatory receptors on T cells and ligands on tumor cells, result in low single-agent activity with immune checkpoint inhibitors in hematologic malignancies including follicular lymphoma, MM, AML, and MDS (page 1102). The immune checkpoint inhibitors are best exploited in combination strategies with other standard therapies in these hematologic malignancies. Such rationally designed combination approaches have shown significant improvements in response rates and PFS. Induced expression of immune checkpoint pathway-related genes (PD-1, PD-L1, PD-L2) by HMA, leading to ‘‘exhaustion’’ of T cells may be restored by concomitant PD-1/PD-L1 blockade. At the same time, frequently described evasion mechanisms to immune checkpoint blockade therapy such as MHC downregulation, decreased tumor antigen expression, and loss or decreased co-stimulatory ligand expression may be abrogated by the anti-tumor immunity enhancing effects of HMAs. Consistent with these preclinical observations, antiPD-1/PD-L1 antibodies in combination with HMAs are being evaluated in clinical trials in patients with AML and MDS with early encouraging results. Efforts at optimization of study designs, development of double checkpoint combinations, identification of biomarkers of response to facilitate selection of patients best suited for these therapies, and identification and management of immune-mediated toxicities are ongoing, and will hopefully further improve outcomes.
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
In the instant case, it would have been prima facie obvious to combine an immune checkpoint inhibitor employed in the treatment method of Dietrich with a hypomethylating agent (HMA), such as azacitidine and decitabine, in view of the teachings of Daver. As evidenced by Daver, checkpoint inhibitors and HMAs were known in the art to be useful in the treatment of malignant disorders. Daver teaches combining HMAs with PD-1/PD-L1-based therapies. Daver teaches that the immune checkpoint inhibitors are best exploited in combination strategies with other standard therapies in these hematologic malignancies. Such rationally designed combination approaches have shown significant improvements in response rates and PFS. Induced expression of immune checkpoint pathway-related genes (PD-1, PD-L1, PD-L2) by HMA, leading to ‘‘exhaustion’’ of T cells may be restored by concomitant PD-1/PD-L1 blockade. All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Thus, one of ordinary skill in the art would have expected that a combination of an immune checkpoint inhibitor and a hypomethylating agent (HMA), such as azacitidine and decitabine, would be useful in treating a malignant disorder.
All of the instant limitations are taught by the combination of Dietrich and Daver. A person of ordinary skill in the art would have had a reason to combine the teachings of Dietrich and Daver. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Dietrich and Daver. Thus, claims 1-5, 7-15, and 17-22 would have been obvious based on the preponderance of the evidence.
Conclusion
Claims 1-5, 7-15, and 17-22 are pending. Claims 1-5, 7-15, and 17-22 are rejected. No claims are allowed.
Contacts
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272-0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/