CTNF 18/561,331 CTNF 97184 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Status of the Claims Claims 1-26 and 28-29 are pending and examined herein. Specification The Specification is objected to because it contains disclosures of nucleic acid sequences that are not accompanied by SEQ ID NOS, specifically, nucleic acid sequences with 10 or more nucleotides in Table 3. Even if those sequences are included in the sequence listing, a sequence identifier must accompany each sequence each time it appears in the specification. 37 C.F.R. 1.821 (a) and (c); M.P.E.P. 2422.01-03. 37 C.F.R. 1.831 Requirements for patent applications filed on or after July 1, 2022, having nucleotide and/or amino acid sequence disclosures. (c) Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing XML" in accordance with paragraph (a) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by "SEQ ID NO:" or the like in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a)), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a)) in the Brief Description is clear. MPEP 2412.04. Claim Objections 07-29-01 AIA Claim 10 is objected to because of the following informalities: Claim 10 contains abbreviation H3K36me3. Abbreviations should be completely spelled out in their first occurrence . Appropriate correction is required. Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 Claim 19 is 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 19 recites the PD-1 antagonist is a pembrolizumab variant. The metes and bounds of the claim are not clear because the specification fails to define common structural features of these variants (e.g., insertions, deletions, or substitutions). Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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 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. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15 AIA Claim s 1-7, 11-13, 17-18, 20-23, 26, and 28-29 are rejected under 35 U.S.C. 102( a)(1) and 35 U.S.C. 102 (a)(2 ) as being anticipated by Bhagavatheeswaran et al . (IDS; PGPub 2021/0101980) . Regarding claim 1 , Bhagavatheeswaran teaches a method of treating a human patient with cancer which comprises: determining if a sample collected from the patient has reduced activity or amount of a SET domain containing 2 (SETD2) biomarker – specifically, the reference teaches “a method of identifying a subject suitable for a therapy of an anti-PD-1 antibody or antigen-binding portion thereof comprising measuring a TMB status of a biological sample of the subject, wherein the TMB status is a high TMB thereby the subject is identified as being suitable for the therapy of an anti-PD-1 antibody or antigen-binding portion thereof” ([0009]). Additionally, the reference teaches “The anti-PD-1 antibody for use of claim 5 or 6, wherein the genomic profiling assay comprises one or more genes selected from the group consisting of SETD2” (claim 7, pg. 79, col. 2). Additionally, the reference teaches antibodies such as nivolumab and pembrolizumab that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway ([0004]). The blocking function of the antibodies indicates that they act as antagonists, and treating the patient with reduced activity or amount of the SETD2 biomarker with a treatment regimen that comprises administration of a therapeutically effective amount of a programmed death 1 receptor (PD-1) antagonist – specifically, the reference teaches “a method for treating a subject afflicted with a tumor comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding portion thereof, wherein the tumor has a tumor mutational burden (TMB) status that is a high TMB” ([0008]). Regarding claim 2 , Bhagavatheeswaran teaches “the biological sample is a tumor tissue biopsy” ([0016]). A sample of a tumor tissue is a cancerous sample. Regarding claim 3 , Bhagavatheeswaran teaches that the reduced activity or amount is reduced copy number of SETD2 DNA “the tumor has one or more genomic alterations comprising: (g) a copy number alteration (CNA)” (claim 4) and the reduced activity or amount of SETD2 biomarker is determined as compared to a non-cancerous sample from the patient – “The tumor DNA can be compared with DNA from patient-matched normal tissue to eliminate germline mutations or polymorphisms” ([0152]). Regarding claims 4-5 , Bhagavatheeswaran teaches a sample collected from the patient has a somatic mutation in a SETD2 nucleic acid - specifically, the reference teaches “The anti-PD-1 antibody for use of claim 5 or 6, wherein the genomic profiling assay comprises one or more genes selected from the group consisting of SETD2” (claim 7) and “the tumor has one or more genomic alterations comprising: a nonsynonymous mutation” (claim 4). The reference does not explicitly teach the patient has a somatic mutation, but the examples of tumors: renal cell carcinoma, ovarian cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, bladder cancer, lung cancer, and melanoma ([0018]) provide evidence that the patient has a somatic mutation because the disclosed cancers occur in non-reproductive cells. The examples of tumors also provide evidence that the somatic mutation is identified in a cancerous sample of the patient, meeting the limitation of claim 5 reciting the somatic mutation is identified in a cancerous sample of the patient. Regarding claims 6-7 , Bhagavatheeswaran teaches that the somatic mutation is a loss-of-function mutation – “A "nonsense mutation" herein refers to a nonsynonymous point mutation in which a codon is changed to a premature stop codon that leads to truncation of the resulting protein” ([0179]). The premature stop codon truncation often leads to a loss of protein function. Regarding claims 11, 17 and 20 , Bhagavatheeswaran teaches the anti-PD-1 antibody is nivolumab or pembrolizumab ([0020]), meeting the limitations of claims 17 reciting pembrolizumab and claim 20 reciting nivolumab. Both nivolumab and pembrolizumab are monoclonal antibodies meeting the limitation of claim 11 reciting the PD-1 antagonist is a monoclonal antibody. Regarding claims 12-13 , Bhagavatheeswaran teaches the PD-1 antagonist, or antigen binding fragment thereof, specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; and the PD-1 antagonist also blocks binding of human PD-L2 to human PD-1. Specifically, the reference teaches nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2)” ([0006]). Regarding claim 18 , Bhagavatheeswaran teaches the pembrolizumab is administered at 200 mg every three weeks “the anti-PD-1 antibody or antigen-binding portion thereof is administered as a flat dose. In one embodiment, the anti-PD-I antibody or antigen binding portion thereof is administered as a flat dose of at least about 200 mg” and “the anti-PD-1 antibody or antigen-binding portion thereof is administered as a flat dose about once every 1, 2, 3, or 4 weeks” ([0022]). Regarding the limitation of intravenous administration, the reference teaches “Preferred routes of administration for the immunotherapy, e.g., the anti-PD-1 antibody or the anti-PD-L1 antibody, include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion” ([0122]). Regarding claims 21-22 , Bhagavatheeswaran teaches that the patient has not been previously treated with anti-PD-1 or anti-PD-L1 therapy. Specifically, in Example 1, the reference teaches “In a multicohort phase 1 study in previously untreated patients with NSCLC (CheckMate), preliminary data in the nivolumab monotherapy cohort (n=20) showed durable responses and a favorable safety profile” ([0391]). Additionally, the reference teaches nivolumab binds specifically to the Programmed Death-1 (PD-1) receptor and blocks the inhibitory PD-1/PD-1 ligand pathway ([0004]). Regarding claims 23, 26, and 29 , Bhagavatheeswaran teaches the cancer is renal cell carcinoma, bladder cancer, and melanoma “the tumor is selected from renal cell carcinoma, ovarian cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, bladder cancer, lung cancer, and melanoma” ([0019]). Regarding claim 28 , Bhagavatheeswaran teaches therapeutic agents of the present disclosure can be constituted in a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier ([0369]). Non-functional printed matter does not distinguish claimed product. Where the only difference between a prior art product and a claimed product is printed matter (i.e., instructions), which is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. MPEP 2112.01(III) . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: Determining the scope and contents of the prior art. Ascertaining the differences between the prior art and the claims at issue. Resolving the level of ordinary skill in the pertinent art. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Bhagavatheeswaran et al . (IDS; PGPub 2021/0101980), as applied to claim 1 above, in view of Pfister et al . (WO 2014/188201) . Regarding claims 8 and 10 , Bhagavatheeswaran teaches that some mutations associated with cancers are somatic mutations with a loss-of-function ([0179]). Regarding claims 8 and 10 , Bhagavatheeswaran fails to teach the sample has a reduced amount of SETD2 protein, reduced methylation level of the SETD2 protein substrate lysine-36 of histone H3, or reduced levels of SETD2 mRNA as compared to a noncancerous sample from the patient; and the methylation level of its substrate lysine-36 of histone H3 is detected by an antibody to H3K36me3. Regarding claims 8 and 10 , Pfister teaches methods of treating cancers which comprise a decreased amount of H3K36me3 (pg. 1, par. 1). Pfister also teaches reduced methylation level of the SETD2 protein substrate lysine-36 of histone H3 and an antibody to H3K36me3. Specifically, Pfister teaches that SETD2 uniquely catalyzes the tri-methylation of H3K36 (pg. 1, par. 3), some cancers comprise a decreased amount of H3K36me3 (par. 4), and the amount of H3K36me3 can be measured using immunohistochemistry, western blotting, mass spectrometry or fluorescence activated cell sorting using antibodies against H3K36me3 (pg. 12, last par.). It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bhagavatheeswaran by employing the detection of decreased amount of H3K36me3 as taught by Pfister as an obvious matter of combining prior art elements according to known methods to yield predictable results. Bhagavatheeswaran teaches that some mutations associated with cancer are somatic mutations with a loss of SETD2 function and Pfister teaches measuring SETD2 activity loss by measuring amount of H3K36me3. One of ordinary skill in the art would have expected to obtain predictable results because Pfister teaches measuring SETD2 activity loss by measuring amount of H3K36me3, and a specific method for measuring a reduced amount of SETD2 protein cannot not affect the cancer treatment . 07-21-aia AIA Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Bhagavatheeswaran et al . (IDS; PGPub 2021/0101980), as applied to claims 1 and 3 above . Regarding claim 9 , Bhagavatheeswaran teaches “the genomic alteration comprises a copy number alteration (CNA)” ([0010]). A change in copy number of any gene often leads to a change in the expression level of a protein encoded by this gene. Regarding claim 9 , Bhagavatheeswaran does not specifically teach the amount of SETD2 protein is measured by an immunohistochemistry (IHC) assay with an anti-SETD2 antibody. However, the reference teaches that the presence of PD-L1 polypeptide is determined by immunohistochemistry (IHC) ([0226]) and the IHC assay is performed using an anti-PD-LI monoclonal antibody to bind to the PD-L1 polypeptide ([0227]). It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bhagavatheeswaran by employing SETD2 polypeptide as a target, as an obvious matter of combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have expected to obtain predictable results because immunohistochemistry with target-specific antibodies is well-known method for protein analysis. Bhagavatheeswaran does not specifically teach the reduced activity or amount is reduced amount of SETD2 protein (as recited in parent claim 3). However, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to use the method of Bhagavatheeswaran by employing SETD2 polypeptide as a biomarker (Bhagavatheeswaran, claim 7), as an "obvious to try" approach of choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. Namely, the genomic alteration comprising a copy number alteration (Bhagavatheeswaran, [0010]) can lead to three outcomes related to the expression levels: no change, increase, or decrease. One of ordinary skill in the art would have expected to obtain predictable results because detection of SETD2 polypeptide using immunohistochemistry with anti-SETD2 antibody can detect all three possible expression outcomes with reasonable chances of success . 07-21-aia AIA Claim s 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Bhagavatheeswaran et al . (IDS; PGPub 2021/0101980), as applied to claim 1 above, in view of Petit et al . (U.S. Patent No. 9907849) . Regarding claims 14-16 , Bhagavatheeswaran teaches a method of treating a human patient with cancer comprising an anti-PD-1 antibody ([0009]). Regarding claims 14-16 , Bhagavatheeswaran fails to teach specific protein sequences of light and heavy chains. Regarding claims 14-16 , Petit teaches combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and the use of the combination therapies for the treatment of prostate cancer (Abstract). Regarding claim 14 , Petit teaches a PD-1 antagonist antibody that comprises: (a) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 1, 2 and 3, respectively and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8, respectively. Specifically, Petit teaches: SEQ ID NO:15 (Fig. 4) comprises SEQ ID NOs: 1, 2 and 3 of instant invention (Search results, 12 May, 2026; us-18-561-331-1fus2fus3.align450.rai, result #1), and SEQ ID NO:13 (Fig. 3) comprises SEQ ID NOs: 6, 7 and 8 of instant invention (Search results, 12 May, 2026; us-18-561-331-6fus7fus8.align450.rai, result #2). Regarding claim 15 , Petit teaches a PD-1 antagonist antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain variable region comprising SEQ ID NO: 4. Specifically, Petit teaches: SEQ ID NO:15 (Fig. 4) comprises SEQ ID NO: 4 of instant invention (Search results, 12 May, 2026; us-18-561-331-4.rai, result #1), and SEQ ID NO:13 (Fig. 3) comprises SEQ ID NO: 9 of instant invention (Search results, 12 May, 2026; us-18-561-331-9.rai, result #1). Regarding claim 16 , Petit teaches a PD-1 antagonist antibody that comprises two heavy chains and two light chains, and wherein each heavy chain comprises SEQ ID NO: 10 and each light chain comprises SEQ ID NO:5. Specifically, Petit teaches: SEQ ID NO:18 (Fig. 5) comprises SEQ ID NO: 5 of instant invention (Search results, 12 May, 2026; us-18-561-331-5.rai, result #1), and SEQ ID NO:14 (Fig. 3) comprises SEQ ID NO: 10 of instant invention (Search results, 12 May, 2026; us-18-561-331-10.rai, result #1). It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bhagavatheeswaran by employing the specific sequences as taught by Petit as an obvious matter of simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have expected to obtain predictable results because Bhagavatheeswaran is silent on specific sequences of the PD-1 antagonist and Petit teaches an antagonist of Programmed Death 1 receptor (PD-1) and its use for the treatment of prostate cancer . 07-21-aia AIA Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Bhagavatheeswaran , as applied to claim 1 above, in view of Denker et al . (WO 2016141218) . The teachings of Bhagavatheeswaran have been set forth above. Regarding claim 19 , Bhagavatheeswaran fails to teach the PD-1 antagonist is a pembrolizumab variant. Regarding claim 19 , Denker teaches combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and the use of the combination therapies for the treatment of cancer (Abstract). Denker also teaches the PD-1 antagonist is a pembrolizumab variant. Specifically, Denker teaches “The PD-1 antagonist in the combination therapy preferably is pembrolizumab, a pembrolizumab variant” ([00181]). It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bhagavatheeswaran by employing pembrolizumab variants as anti-PD-1 monoclonal antibodies as taught by Denker , as an obvious matter of simple substitution of one known anti-PD-1 monoclonal antibody for another to obtain predictable results. One of ordinary skill in the art would have expected to obtain predictable results because both references teach pembrolizumab as an anti-PD-1 monoclonal antibody for cancer therapy . 07-21-aia AIA Claim s 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Bhagavatheeswaran , as applied to claim 1 above, in view of Bilic et al . (IDS; PGPub 2018/0371093) . The teachings of Bhagavatheeswaran have been set forth above. Regarding claims 24-25 , Bhagavatheeswaran teaches the tumor is selected from renal cell carcinoma ([0019]). Bhagavatheeswaran fails to teach the cancer is clear cell renal cell carcinoma and the cancer is non-clear cell renal cell carcinoma. Regarding claims 24-25 , Bilic teaches antibody molecules that specifically bind to PD-1 and can be used to treat or prevent cancerous or infectious conditions and disorders (Abstract). Bilic also teaches cell and non-clear renal cell carcinomas. Specifically, Bilic teaches treatment of both clear cell renal cell carcinoma and non-clear cell renal cell carcinoma with a PD-1 antagonist “the cancer is kidney cancer, e.g., a renal cell carcinoma (e.g., a clear cell renal cell carcinoma (CCRCC) or a non-clear cell renal cell carcinoma (nccRCC)” ([0011]). It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the method of Bhagavatheeswaran to treating clear cell renal cell carcinoma and non-clear cell renal cell carcinoma with the PD-1 antagonist as taught by Bilic , as an obvious matter of applying a known technique (method of Bhagavatheeswaran) to known cancers (Bilic) ready for improvement to yield predictable results. One of ordinary skill in the art would have expected to obtain predictable results because Bhagavatheeswaran already teaches renal cell carcinoma and Bilic teaches treating both clear cell renal cell carcinoma and non-clear cell renal cell carcinoma with the PD-1 antagonist. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). 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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form. /ALEXANDER ALEXANDROVIC VOLKOV/ Examiner, Art Unit 1677 /REBECCA M GIERE/Primary Examiner, Art Unit 1677 Application/Control Number: 18/561,331 Page 2 Art Unit: 1677 Application/Control Number: 18/561,331 Page 3 Art Unit: 1677 Application/Control Number: 18/561,331 Page 4 Art Unit: 1677 Application/Control Number: 18/561,331 Page 5 Art Unit: 1677 Application/Control Number: 18/561,331 Page 6 Art Unit: 1677 Application/Control Number: 18/561,331 Page 7 Art Unit: 1677 Application/Control Number: 18/561,331 Page 8 Art Unit: 1677 Application/Control Number: 18/561,331 Page 9 Art Unit: 1677 Application/Control Number: 18/561,331 Page 10 Art Unit: 1677 Application/Control Number: 18/561,331 Page 11 Art Unit: 1677
Prosecution Insights