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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/11/2026 has been entered.
Claims Status
The claim amendment filed on 02/11/2026 has been entered.
Claims 21-40 are pending and currently under examination
Priority
This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No: 62/893,987, filed August 30, 2019. Accordingly, the priority date of claim set filed on Feb. 11, 2026, is determined to be August 30, 2019.
Claim Objections
Claims 25-27 are objected to because of the following informalities:
“The method of claim 21 comprising measuring” (Claim 25, ln 1) should be amended to “The method of claim 21, comprising”. (Claim 25)
“cytotoxic CD8+ T cell that expresses ZNF683 in the sample from the subject is a large CD8+ effector/effector memory (E/EM) cell” (Claim 26, ln 1-3) should be amended to “cytotoxic CD8+ T cell population that expresses ZNF683 in the sample from the subject is a large CD8+ effector/effector memory (E/EM) cell population”. (Claim 26)
“wherein the cytotoxic CD8+ T cell that expresses ZNF683 at a level higher than in the reference sample.” (Claim 27, ln 1-2) should be amended to “wherein the cytotoxic CD8+ T cell population that expresses ZNF683 in the sample from the subject is at a level higher than in the reference sample”. (Claim 27)
Appropriate correction is required.
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 21-40 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 21 is indefinite over the limitation “measuring an expression level of Zinc finger protein 683 gene (ZNF683) in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a sample from a subject having, or at risk of having, Richter's transformation (RT); and administering a PD-1 inhibitor to the subject to treat the subject with RT, when the expression level of ZNF683 in the subject is higher than an expression level of ZNF683 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample, wherein measuring is performed before administering” (ln). It is unclear whether the t “wherein measuring is performed before administering”(ln ) is specifically referring back to the “measuring an expression level of Zinc finger protein 683 gene (ZNF683) in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a sample from a subject having, or at risk of having, Richter's transformation (RT)” (ln ) and “administering a PD-1 inhibitor to the subject to treat the subject with RT” or if the limitation is regarding some other measurement and administration. Claims 22-40 depend on claim 21.
Claim 24 is indefinite over the limitation “wherein the reference sample is obtained from healthy normal tissue, cancer that received a clinical benefit from PD-1 inhibition, or cancer that did not receive a clinical benefit from PD-1 inhibition, or the reference sample is obtained from healthy normal tissue from the same subject as the test sample or one or more healthy normal tissues from different individuals” (ln 1-5). It is unclear if the limitations about “cancer that received a clinical benefit from PD-1 inhibition, or cancer that did not receive a clinical benefit from PD-1 inhibition”(ln 2-3) are they are obtained as test samples and optionally obtained as reference samples or whether they are obtained as only test samples. Furthermore, it is unclear if each limitation listed in ln-1-4 are considered alternatives of reference sample as the claim recites a number of “or” conjunctions in ln 2-4 between limitations, but not between all or just once before the last limitation. Please clarify and amend any grammatical errors recited in the claim.
Claim 24 recites the limitation "the test sample" in ln 4. “A test sample” is not recited in claim 21, in which claim 24 depends on. There is insufficient antecedent basis for this limitation in the claim.
Claim 28 is indefinite over the limitation “wherein the cytotoxic CD8+ T cell population expressing ZNF683 represents a first CD8+ T cell population” and “and the sample comprises a second CD8+ T cell population”. It is unclear whether the limitations about the first and second CD8+ T cell population is regarding the sample from the subject having or at risk of having RT, the reference sample or both the sample from the subject having or at risk of having RT and reference sample.
Claim 29 is indefinite over the limitation “wherein the cytotoxic CD8+ T cell population expressing ZNF683 represents a first CD8+ T cell population” and “and the sample comprises a second CD8+ T cell population”. It is unclear whether the limitations about the first and second CD8+ T cell population is regarding the sample from the subject having or at risk of having RT, the reference sample or both the sample from the subject having or at risk of having RT and reference sample.
Claim 40 is indefinite over the limitation “wherein the cytotoxic CD8+ T cell population expressing ZNF683 represents a first CD8+ T cell population, and the sample comprises a second CD8+ T cell population that are exhausted CD8+ T cells, wherein the exhausted CD8+ T cells express ZNF683 at a higher level than in a reference sample. It is unclear whether the limitations about the first and second CD8+ T cell population is regarding the sample from the subject having or at risk of having RT, the reference sample or both the sample from the subject having or at risk of having RT and reference sample. Furthermore, it is unclear whether the first and second CD8+ population comprise ZNF683.
Claims 21- 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the step of measuring an expression level of Zinc finger protein 683 gene (ZNF683) in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample in Claim 21. Claims 22-40 depend on claim 21.
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 21-26, 33 and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over Taghiloo et al. (“Taghiloo”; (2017). Blimp-1 Expression as an Exhaustion Transcription Factor in Chronic Lymphocytic Leukemia. Research Molecular Medicine, 5 (3): 5-10) in view of Reading et al. (“Reading”; (2018). The function and dysfunction of memory CD 8+ T cells in tumor immunity. Immunological reviews, 283(1), 194-212.) and Ding et al. (“Ding” (2017). Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, The Journal of the American Society of Hematology, 129(26), 3419-3427.)
Claim interpretations: The limitation(s) reciting “wherein the reference sample is obtained from healthy normal tissue, cancer that received a clinical benefit from PD-1 inhibition, or cancer that did not receive a clinical benefit from PD-1 inhibition, or the reference sample is obtained from healthy normal tissue from the same subject as the test sample or one or more healthy normal tissues from different individuals” in claim 24, is interpreted as claiming only one limitation as a reference sample within the list of limitations and the other limitation(s) as optional alternatives to the reference sample.
Taghiloo discloses “Background: Previously, it was shown that exhausted CD4+ and CD8+ T cells in chronic lymphocytic leukemia (CLL) co-express the two immune-inhibitory receptors, Tim-3 and PD-1. Present study investigated the expression of Blimp-1, a transcription factor involved in T cell exhaustion, in patients with CLL. Materials and Methods: Peripheral blood mononuclear cells were collected from 25 untreated CLL patients and 15 sex- and age-matched normal subjects. CLL patients were clinically classified according to the Rai staging system. The relative expression of Blimp-1 mRNA was determined by quantitative Real Time Polymerase Chain Reaction (qRT-PCR) after normalization with β-actin. Results: Expression of Blimp-1 mRNA was much higher in CLL patients than in normal controls (p=0.001). Moreover, Blimp-1 was more expressed in patients with advanced clinical stages of CLL compared to those with early stages of the disease (p=0.01). Interestingly, the Blimp-1 expression was correlated with the frequencies of exhausted Tim-3+/PD-1+/CD4+ and Tim-3+/PD-1+/CD8+ T cells in CLL patients. Conclusion: Our results highlight the role of Blimp-1 transcription factor in T cell exhaustion of CLL” (Abstract).
Regarding claim 21, Taghiloo teaches a method comprising “Peripheral blood was collected from 25 CLL patients who had not received any chemotherapy regimens” (Pg. 6, Patients and controls, Para. 1). Taghiloo teaches a method comprising ” The mRNA level of Blimp-1 was measured by quantitative Real Time PCR (qRT-PCR)” (Pg. 7, Quantitative Reverse-Transcriptase PCR). Taghiloo teaches a method comprising “Blimp-1 was measured in peripheral blood of CLL patients.” (Pg. 7, Quantitative Reverse-Transcriptase PCR, Para. 1). Taghiloo teaches a method comprising “Our results demonstrated that Blimp-1 was highly upregulated in CLL patients compared to normal subjects” (Pg. 7, Blimp-1 mRNA was highly expressed in CLL patients, Para. 1). Taghiloo teaches a method comprising “relative expression level of Blimp-1 was significantly higher in advanced clinical stages of CLL patients than that of early stages” (Pg. 8, Blimp-1 was more expressed in CLL patients at advanced clinical stages, Para. 1 ). Furthermore, Taghiloo teaches a method comprising “Blimp-1 mRNA expression was significantly correlated, not only with the frequency of Tim-3+/PD-1+/CD4+ T cells (r = 0.483, p = 0.01), but also with the frequency of Tim-3+/PD-1+/CD8+ T cells in CLL patients (r = 0.459, p = 0.02). These results suggest a potential role for Blimp-1 in the regulation of Tim-3 and PD-1 expression as an important inhibitory receptor in T cell exhaustion.” (Pg. 8, Col. 2, Para 1). Furthermore, Taghiloo highlights previous reports that “In our previous studies on CLL patients, we have shown that both CD4+ (23) and CD8+ T cells are exhausted and show functional defects. These exhausted T cells are characterized by overexpression of Tim-3 and PD-1 immune inhibitory receptors” (Pg. 6, Col. 1 last para.) and “high levels of Blimp-1 is correlated with the maintenance of the exhausted cells and appeared to control the expression of PD-1” (Pg. 9, Col. 1, first para.). Taghiloo also teaches that “although other transcription factors and pathways contributing to T cell exhaustion remained to be understood this study introduces Blimp-1 as a potential transcription regulator of T cell exhaustion in CLL” (Pg. 9, last para.). CLL patients read on a subject at risk of having, Richter's transformation (RT). “advanced clinical stages of CLL” reads on Richter’s Transformation (RT) to aggressive lymphoma. Blimp-1 and other transcription factors read on the similar transcriptional regulator Zinc Finger 683 (ZNF683)/ homolog of Blimp1 in T cells (Hobit). CD8+ T cells reads on cytotoxic CD8+ T cell population. CD4+ reads on cytotoxic CD4+ T cell population. Thus, Taghiloo suggests a method comprising measuring an expression level of ZNF683 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a sample from a subject having, or at risk of having, RT; wherein the expression level of ZNF683 in the subject is higher than an expression level of ZNF683 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample, and wherein measuring is performed before administering.
Furthermore, Taghiloo teaches that “This leads to a better understanding of underlying mechanisms of T cell exhaustion which could be helpful in finding new therapeutic strategies for CLL” (Pg. 9, last para.). One of skill in the art would be motivated to modify the method in new therapeutic strategies. Taghiloo does not explicitly teach i) ZNF683 and ii) administering a PD-1 inhibitor to the subject to treat the subject with RT.
i) Reading discloses that “The generation and maintenance of CD8+ T cell memory is crucial to long-term host survival, yet the basic tenets of CD8+ T cell immunity are still being established. Recent work has led to the discovery of tissue-resident memory cells and refined our understanding of the transcriptional and epigenetic basis of CD8+ T cell differentiation and dysregulation. In parallel, the unprecedented clinical success of immunotherapy has galvanized an intense, global research effort to decipher and de-repress the anti-tumor response. However, the progress of immunotherapy is at a critical juncture, since the efficacy of immuno-oncology agents remains confined to a fraction of patients and often fails to provide durable benefit. Unlocking the potential of immunotherapy requires the design of strategies that both induce a potent effector response and reliably forge stable, functional memory T cell pools capable of protecting from recurrence or relapse. It is therefore essential that basic and emerging concepts of memory T cell biology are rapidly and faithfully transposed to advance therapeutic development in cancer immunotherapy. This review highlights seminal and recent reports in CD8+ T cell memory and tumor immunology, and evaluates recent data from solid cancer specimens in the context of the key paradigms from preclinical models. We elucidate the potential significance of circulating effector cells poised downstream of neoantigen recognition and upstream of T cell dysfunction and propose that cells in this immunological 'sweet spot' may be key anti-tumor effectors.” (Abstract).
Regarding claim 21, Reading teaches that “complex molecular circuitries, which enact key transcription factors ... Blimp-1… to determine precursor fate and memory CD8+ T cells subset differentiation” (Pg. 196, Col. 2 Para. 2). Reading also teaches “several transcription factors are involved in the generation and maintenance of tissue-resident memory CD8+ T (Trm) cells ... Trm cell differentiation program is controlled by the expression of Blimp-1 and the homolog of Blimp-1 in T cells (Hobit) transcription factors” (Pg. 197, Col. 2, Para. 1). “the homolog of Blimp-1 in T cells (Hobit)” reads on ZNF683. One of skill in the art would be motivated to incorporate measuring the expression of ZNF683 to further understand other transcription factors and pathways contributing to T cell differentiation, with a reasonable expectation of success, since Blimp-1 and ZNF683 are homologs with similar cellular function and important transcriptional regulators of T-cell differentiation. A skilled artisan would expect a predictable outcome of increase expression of ZNF683 in CD8+ T cells involved in cancer. Thus, Taghiloo and Reading suggest a method of measuring expression levels of ZNF683 in a cytotoxic CD8+ T cell population and/or a cytotoxic CD4+ T cell population in a sample from a subject having, or at risk of having, RT; and when the expression level of ZNF683 in the subject is higher than an expression level of ZNF683 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample.
Both Taghiloo and Reading suggest understanding the differentiation and regulation of CD8+ T cell as well as the transcriptional regulators in disease as a part of new therapeutic strategies for responsive cancer immunotherapy. Thus, one of skill in the art would be motivated to strategically devise plan for therapy for patients with CLL and at risk for RT which would include measuring and evaluating the expression of key regulator for possible potent effector response prior to deciding if a particular treatment might be beneficial to a particular disease. While increased PD1 expression was mentioned, Taghiloo and Reading do not explicitly teach a method comprising administering a PD-1 inhibitor to the subject to treat the subject with RT.
ii) Ding discloses “This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1–blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a median follow-up time of 11 months, the median overall survival in the RT cohort was 10.7 months but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT and could change the landscape of therapy for RT patients if further validated” (Abstract).
Regarding claim 21, Ding teaches a method comprising “conducted an investigator-initiated phase 2 clinical trial (#NCT02332980) to evaluate the safety and clinical activity of the PD-1–blocking antibody pembrolizumab in relapsed or refractory CLL”, “included the use of pembrolizumab in RT” and “CLL patients with RT” (Pg. 3420, Col. 1, Para. 1; Abstract). Thus, Taghiloo, Reading and Ding suggest a method of treating a subject with Richter's transformation. Ding teaches a method comprising “pembrolizumab, was IV administered” (Pg. 3420, Col. 2, Para. 2, Study Design). “pembrolizumab” reads on PD-1 inhibitor. Thus, Taghiloo, Reading and Ding suggest a method comprising administering a PD-1 inhibitor to the subject to treat the subject with RT, when the expression level of ZNF683 in the subject is higher than an expression level of ZNF683 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample, wherein measuring is performed before administering.
Taghiloo, Reading and Ding are considered to be analogous to the claimed invention because they are in the same field exhausted CD8+ T cell regulation in cancer. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring an expression level of Blimp-1 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a sample from a subject having, or at risk of having, RT; wherein the expression level of Blimp-1 in the subject is higher than an expression level of Blimp-1 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample, and wherein measuring is performed before administering as taught by Taghiloo to incorporate measuring the expression level of the Blimp-1 homolog, ZNF683 in CD8+ T cells as taught by Reading and incorporate the method of administering a PD-1 inhibitor to the subject to treat the subject with Ras taught by Ding, to provide a method for treating a subject with RT with a PD-1 inhibitor, when the expression level of the ZNF683 in the subject is higher than the expression level of ZNF683 in a cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in a reference sample. Doing so would enhance the immune anti-tumor response in RT subjects.
The teachings of Taghiloo, Reading and Ding are documented above in the rejection of claim 21 under 35 U.S.C. 103. Claims 22, 24-33, 35 and 39 depend on claim 21. Claim 23 depends on claim 22, which depends on claim 21. Claim 37 depends on claim 36. Claims 36 and 38 depend on claim 35, which depends on claim 21.
Regarding claims 22-23, Ding teaches a method wherein ““blood” (Pg. 3421, Col. 1, Para. 2, Biomarker assessment). Blood reads on blood sample. Thus, Taghiloo, Reading and Ding suggest a method wherein the sample from the RT subject is a bone marrow sample, a tumor tissue sample, a tumor microenvironment sample, a plasma sample, or a blood sample; and wherein the sample from the RT subject is a bone marrow sample or a blood sample.
Regarding claim 24, Ding teaches a method comprising “normal and tumor samples” (Supplemental methods, Pg. 7, Para. 1), “normal” reads on reference sample is obtained from healthy normal tissue. Thus, Taghiloo, Reading and Ding suggest a method wherein the reference sample is obtained from healthy normal tissue, normal, or cancer that did not receive a clinical benefit from PD-1 inhibition, or the reference sample is obtained from healthy normal tissue from the same subject as the test sample or one or more healthy normal tissues from different individuals.
Regarding claims 25-26, Reading teaches “several transcription factors are involved in the generation and maintenance of tissue-resident memory CD8+ T (Trm) cells ... Trm cell differentiation program is controlled by the expression of Blimp-1 and the homolog of Blimp-1 in T cells (Hobit) transcription factors” (Pg. 197, Col. 2, Para. 1). “the homolog of Blimp-1 in T cells (Hobit)” reads on ZNF683. “CD8+ T (Trm) cells” reads on the cytotoxic CD8+ T cell population. “memory CD8+ T (Trm) cells” reads on large CD8+ effector/effector memory (E/EM) cells. Thus, Taghiloo, Reading and Ding suggest a method comprising measuring the expression level of ZNF683 in the cytotoxic CD8+ T cell population; and wherein the cytotoxic CD8+ T cell that expresses ZNF683 in the sample from the subject is a large CD8+ effector/effector memory (E/EM) cell.
Regarding claim 33, Ding teaches a method comprising "RS1 had a DOR of 11 months for single-agent pembrolizumab and then received local radiation directed to one site of progression" (Figure 1 (B) legend). Thus, Taghiloo, Reading and Ding suggest a method further comprising treating the subject with a chemotherapeutic agent, radiation therapy, cryotherapy, hormone therapy, or immunotherapy.
Regarding claims 35-36, Ding teaches a method wherein the “PD-1–blocking antibody” is “pembrolizumab” (Pg. 3420, Col. 1 Para. 1). “pembrolizumab” reads on a humanized monoclonal antibody. Thus, Taghiloo, Reading and Ding suggest a method wherein the PD-1 inhibitor comprises a small molecule inhibitor, RNA, interference (RNAi), microRNA (miRNA), an antibody, an antibody fragment, an antibody drug, conjugate, an aptamer, a chimeric antigen receptor (CAR), a T cell receptor, or any combination thereof; and wherein the PD-1 inhibitor comprises an antibody or antibody fragment, and wherein the antibody or antibody fragment comprises nivolumab, cemiplimab, pembrolizumab, avelumab, atezolizumab, or durvalumab.
Regarding claim 37, Ding teaches a method wherein “pembrolizumab” is “a humanized PD-1–blocking antibody” (Abstract). Thus, Taghiloo, Reading and Ding suggest a method a method wherein the antibody or antibody fragment is partially humanized, fully humanized, or chimeric.
Regarding claim 38, Ding teaches a method wherein “Fifteen (60%) patients had received prior ibrutinib” (Pg. 3421, Col. 1 Para. 3; Table 1-prior ibrutinib). Ding teaches a method wherein “RT patients treated with pembrolizumab after prior ibrutinib” (Pg. 3421-3422, last sent. to first sent.; Figure 1a). Ibrutinib is known in the art as a BTK inhibitor and is interpreted as a small molecule that can inhibit the BTK downstream signaling effect of PD1 expression. Thus, Thus, Taghiloo, Reading and Ding suggest a method wherein the small molecule that is the PD-1 inhibitor comprises ibrutinib.
Response to Arguments
Applicant's arguments filed 02/11/2026 have been considered but do not apply to the new grounds of rejections in view of Taghiloo, Reading and Ding. To clarify some instances argued in the response filed 02/11/2026 see responses to each argument made by Applicant below:
Applicants' argument: “Ding fails to teach all features of claim 21, and its disclosure is fundamentally different than the current application.” (Pg. 7)
Response: In response to applicant's argument stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicants' argument: “Ding does not teach or suggest identifying a biomarker having increased expression (in particular, PD-LI expression) that is predictive of response and thus useful to identify patients, prior to treatment, who would benefit from PD-I blockade. This is a fundamental deficiency of Ding and it is not rectified by the teachings of the cited secondary references.” (Pg. 8)
Response: In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., identifying a biomarker having increased expression (in particular, PD-LI expression) that is predictive of response) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, Ding did disclose that “We also included the use of pembrolizumab in RT because; 50% of patients with RT have TP53 disruption that typically associate with genomic instability, and cancers with high somatic mutation loads/genomic complexity tend to respond to PD-1 blockade” (Pg. 3420). Thus, there was an indication of identifying predictive marker(s) before treatment that would benefit from PD-1 blockade.
Applicants' argument: “Reading does not refer to what tissues or biological conditions led to this finding… Reading's teaching does not allow one of skill to understand that expression of ZNF683 in would be useful in identifying RT patients, prior to treatment, who would benefit from PD-1 blockade.” (Pg. 12)
Response: In response to applicant's argument stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Claims 27, 30 and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Taghiloo et al. (“Taghiloo”; (2017). Blimp-1 Expression as an Exhaustion Transcription Factor in Chronic Lymphocytic Leukemia. Research Molecular Medicine, 5 (3): 5-10) in view of Reading et al. (“Reading”; (2018). The function and dysfunction of memory CD 8+ T cells in tumor immunity. Immunological reviews, 283(1), 194-212.) and Ding et al. (“Ding” (2017). Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, The Journal of the American Society of Hematology, 129(26), 3419-3427.) as applied to claim 21 above, and further in view of Szabo et al. (“Szabo”; (2019). A single-cell reference map for human blood and tissue T cell activation reveals functional states in health and disease. bioRxiv, 555557.).
The teachings of Taghiloo, Reading and Ding are documented above in the rejection of claims 21-26, 33 and 35-39 under 35 U.S.C. 103. Claim 27 depends on claim 21. Taghiloo, Reading and Ding do not explicitly teach the limitations of claim 27.
Szabo discloses “Human T cells coordinate adaptive immunity by localization in diverse tissue sites, though blood T cells are the most readily studied. Here, we used single-cell RNA-seq to define the functional responses of T cells isolated from human lungs, lymph nodes, bone marrow, and blood to TCR-stimulation. We reveal how human T cells in tissues relate to those in blood, and define activation states for CD4+ and CD8+T cells across all sites, including an interferon-response state for CD4+T cells and distinct effector states for CD8+T cells. We further show how profiles of individual tumor-associated T cells can be projected onto this healthy reference map, revealing their functional state.” (Abstract)
Regarding claim 27, Szabo teaches “CD8+T cell-enriched modules included a Cytotoxic module containing genes associated with cytotoxicity (GNLY, GZMK) and … transcription factors associated with effector/memory differentiation (… ZNF683)… inhibitory molecules (… CD226 (TIGIT)…)” (Pg. 10, last 4 lines – Pg.11, first line). It would be obvious to the ordinary artisan to evaluate the expression of ZNF683 and CD226 in a patient and reference sample with the expectation of assessing if the level of transcription factor that drives CD8+ T cell differentiation and T cell activating receptor that drives an immune response in cytotoxic CD8+ T cells is high enough to regulate an anti-tumor immune response from the CD8+ T cells. Thus, Taghiloo, Reading, Ding and Szabo suggest a method wherein the cytotoxic CD8+ T cell that expresses ZNF683 at a level higher than in the reference sample also expresses CD226 at an expression level higher than expression of CD226 in the cytotoxic CD8+ T cell population and/or cytotoxic CD4+ T cell population in the reference sample.
Taghiloo, Reading Ding and Szabo considered to be analogous to the claimed invention because they are in the same field of CD8+ T cell regulation in cancer. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a subject with Richter’s transformation as taught by Taghiloo, Reading and Ding to incorporate the method of measuring the expression levels of ZNF683 and CD226 in CD8+ T cells as suggested by Szabo and provide assessment of functional states for human T cells (Pg. 11, Para. 1) in subjects. Doing so would allow for assessment of regulating transcription factors associated with CD8+ T cell differentiation and T cell activating receptor expression in patients and provide insight on immune response capability of the cytotoxic T cells.
Regarding claims 30 and 40, Szabo teaches a method wherein ZNF683 and KLRG1 are both expressed in CD8 Cytotoxic and some CD8 Cytokine T cells as shown in Figure 4A. (Fig. 4A). Thus, Taghiloo, Reading, Ding and Szabo suggest a method wherein the CD8+ T cell population expressing ZNF683 further expresses (a) a gene selected from the group consisting of KLRG1, CX3CR1 and LAG3 that is or are co-expressed with ZNF683, and/or (b) a gene selected from the group consisting of exhaustion/inhibitory markers CD160 and CD244; and wherein the cytotoxic CD8+ T cell population expressing ZNF683 represents a first CD8+ T cell population, and the sample comprises a second CD8+ T cell population that are exhausted CD8+ T cells, wherein the exhausted CD8+ T cells express ZNF683 at a higher level than in a reference sample.
Regarding claim 39, Szabo teaches a method wherein “We converted RNA to cDNA … and performed quantitative real-time PCR (qPCR)” (Pg. 30, Para. 1). Thus, Thus, Taghiloo, Reading and Ding suggest a method wherein the expression level of the ZNF683 is detected via hybridization-based analysis, polynucleotide sequencing, a real time reverse transcriptase polymerase chain reaction (real time RT-PCR) assay, or a Gene Hybridization Array.
Response to Arguments
Applicant's arguments filed 02/11/2026 do not apply to the new grounds of rejections. Arguments against Reading and Ding on Pg. 7-16 are not persuasive as discussed above. To clarify some instances argued in the response filed 02/11/2026 see responses to each argument made by Applicant below:
Applicants' argument: “Szabo does not make evident that increased expression of ZNF683 (Hobit) allows the identification of a T cell effector/effector memory population associated with effective antitumor immunity, that is predictive of response and is used to identify patients, prior to treatment, who would benefit from PD-1 blockade.” (Pg. 15)
Response: In response to applicant's argument stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Claims 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Taghiloo et al. (“Taghiloo”; (2017). Blimp-1 Expression as an Exhaustion Transcription Factor in Chronic Lymphocytic Leukemia. Research Molecular Medicine, 5 (3): 5-10) in view of Reading et al. (“Reading”; (2018). The function and dysfunction of memory CD 8+ T cells in tumor immunity. Immunological reviews, 283(1), 194-212.) and Ding et al. (“Ding” (2017). Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, The Journal of the American Society of Hematology, 129(26), 3419-3427.) as applied to claim 21 above, and further in view of Sade-Feldman et al. (“Sade-Feldman”; Patent App. No. WO 2018209324 A2, Nov, 15, 2018.).
The teachings of Taghiloo, Reading and Ding are documented above in the rejection of claims 21-26, 33 and 35-39 under 35 U.S.C. 103. Claims 28 and 30 depend on claim 21. Taghiloo, Reading and Ding do not explicitly teach the limitations of claims 28 and 30.
Regarding claim 28, Sade-Feldman teaches method wherein “ZNF683” (Pg. 257, Table 10, CD8_4) in a CD8+ T cell population. Sade-Feldman teaches method wherein “TOX” (Pg. 257, Table 10, CD8_5), “HAVCR2”(Pg. 257, Table 10, CD8_5), “PDCD1”(Pg. 257, Table 10, CD8_5), and “TIGIT”(Pg. 258, Table 10, CD8_5), are in another CD8+ T cell population. Table 10 describes highlighted markers with distinct biological functions. (Para. 571) Thus, Taghiloo, Reading, Ding and Sade-Feldman suggest a method wherein the cytotoxic CD8+ T cell population expressing ZNF683 represents a first CD8+ T cell population, and the sample comprises a second CD8+ T cell population that expresses thymocyte selection associated high mobility group box protein gene (TOX) and one or more exhaustion markers selected from the group consisting of TIGIT, PDCD1, LAG3, and HAVCR2.
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a subject with Richter’s transformation as taught by Taghiloo, Reading and Ding to incorporate the method wherein the ZNF683 is expressed in a first CD8+ T cell population and TOX, TIGIT, PDCD1, and HAVCR2 are expressed in a second CD8+ T cell population as taught by Sade-Feldman and provide a method where the expression of distinct regulators CD8+ immune response can be assessed. Doing so would allow for the evaluation of gene signatures associated immune response in CD8+ T cells to predict if a immunotherapy treatment might yield an immune response in a subject.
Regarding claim 29, Sade-Feldman teaches method wherein “GZMA, GZMB and PRFl (coding for granzyme A, B and perforin 1), had much higher expression in the exhausted clusters CD8 1 to 3 (Table 9) and resembled exhaustion programs previously reported in melanoma” (Para. 571). Thus, Taghiloo, Reading, Ding and Sade-Feldman suggest a method wherein the cytotoxic CD8+ T cell population expressing ZNF683 represents a first CD8+ T cell population, and the sample comprises a second CD8+ T cell population of effector/effector memory (E/EM) CD8+ cells that express GZMB, GZMA, and PRF1.
Response to Arguments
Applicant's arguments filed 02/11/2026 do not apply to the new grounds of rejections. Arguments against Reading and Ding on Pg. 7-19 are not persuasive as discussed above.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Taghiloo et al. (“Taghiloo”; (2017). Blimp-1 Expression as an Exhaustion Transcription Factor in Chronic Lymphocytic Leukemia. Research Molecular Medicine, 5 (3): 5-10) in view of Reading et al. (“Reading”; (2018). The function and dysfunction of memory CD 8+ T cells in tumor immunity. Immunological reviews, 283(1), 194-212.) and Ding et al. (“Ding” (2017). Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, The Journal of the American Society of Hematology, 129(26), 3419-3427.) as applied to claim 21 above, and further in view of Umit et al. (“Umit”; (2018). CD8 expression on clonal b-cll cells and CD8+ lymphocytes in the microenvironment, relations with prognosis and survival. Eastern Journal of Medicine, 23(4), 237.).
The teachings of Taghiloo, Reading and Ding are documented above in the rejection of claims 21-26, 33 and 35-39 under 35 U.S.C. 103. Claim 31 depends on claim 21. Taghiloo, Reading and Ding do not explicitly teach the limitations of claim 31.
Umit discloses”… Richter’s transformation were significantly corelated. CD8+ T lymphocyte richness in the microenvironment was significantly related with survival. Cancer is related with immunodeficiency. With the evolution of tumors, they find ways to elude immune recognition. CD8 expression on B-CLL cells may not be explained with clinical features or prognosis. But the density of CD8 within the infiltrated bone marrow may explain the long term immune escape of CLL cells, with the effort to balance immune regulation by disease control, though resulting with increased autoimmunity” (Abstract).
Regarding claim 31, Umit teaches a method wherein “Richter’s transformation were significantly corelated with CD8 positive microenvironment” (Pg. 239 Col. 2 Para. 2). It would be obvious to the ordinary artisan that “Richter’s transformation were significantly corelated with CD8 positive microenvironment” would be conclusive of a RT patient having a higher percentage of CD8+ cells in comparison to a subject that does not have or have a risk of having RT. Thus, Taghiloo, Reading, Ding and Umit suggest a method wherein the sample from the RT subject comprises a greater percentage of CD8+ cells than the percentage of CD8+ cells in the reference sample.
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a subject with Richter’s transformation as taught by Taghiloo, Reading and Ding to incorporate the method wherein RT subjects is associated with CD8+ T cell microenvironments as taught by Umit and provide a method wherein the sample from the RT subject comprises a greater percentage of CD8+ cells than the percentage of CD8+ cells in the reference sample. Doing so would allow for assessment of CD8+ T cells in patients.
Response to Arguments
Applicant's arguments filed 02/11/2026 do not apply to the new grounds of rejections. Arguments against Reading and Ding on Pg. 7-19 are not persuasive as discussed above. To clarify some instances argued in the response filed 02/11/2026 see responses to each argument made by Applicant below:
Applicants' argument: “Umit does not teach or refer to ZNF683, and does not make evident that increased expression of ZNF683 allows the identification of a T cell effector/effector memory population associated with effective anti-tumor immunity, that is predictive of response and is used to identify patients, prior to treatment, who would benefit from PD-I blockade.” (Pg. 18)
Response: In response to applicant's argument stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Taghiloo et al. (“Taghiloo”; (2017). Blimp-1 Expression as an Exhaustion Transcription Factor in Chronic Lymphocytic Leukemia. Research Molecular Medicine, 5 (3): 5-10) in view of Reading et al. (“Reading”; (2018). The function and dysfunction of memory CD 8+ T cells in tumor immunity. Immunological reviews, 283(1), 194-212.) and Ding et al. (“Ding” (2017). Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, The Journal of the American Society of Hematology, 129(26), 3419-3427.) as applied to claim 21 above, and further in view of Gandhi et al. (“Gandhi”; US Patent App. Pub. No. US 2018/0193342 A1, Jul. 12, 2018).
The teachings of Taghiloo, Reading and Ding are documented above in the rejection of claims 21-26, 33 and 35-39 under 35 U.S.C. 103. Claim 32 depends on claim 21. Taghiloo, Reading and Ding do not explicitly teach the limitations of claim 32.
Regarding claim 32, Ding further teaches a method wherein “confirmed response for RT was defined as a partial response (PR), partial metabolic response (PMR), complete response (CR), or complete metabolic response while receiving single-agent pembrolizumab, using the modified Cheson 2007 lymphoma criteria initially and then updated to the 2014 Lugano lymphoma response criteria” (Pg. 3420, Col. 2, Para. 2). Thus, Ding suggests a method wherein clinical benefit in the subject comprises complete or partial response as defined by Modified Response Criteria for Malignant Lymphoma and Lugano Classification Response criteria.
Taghiloo, Reading and Ding do not explicitly teach the limitation “as defined by response evaluation criteria in solid tumors (RECIST),or stable disease as defined by RECIST, or long-term survival in spite of disease progression or response as defined by irRC criteria.”
Gandhi discloses a method of treating hematological cancers, including Richter's transformation, using checkpoint inhibitors, including PD-1 inhibition (Abstract).
Regarding claim 32, Gandhi teaches a method wherein “ Primary Outcome Measures: The combined incidence of complete response (CR)+ partial response (PR), by investigator assessment of response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ” (Pg. 40, Para. 416). Thus, Ding, Vieira Braga, Oja, Reading and Gandhi teach a method wherein administration provides a clinical benefit in the subject that comprises complete or partial response as defined by response evaluation criteria in solid tumors (RECIST), stable disease as defined by RECIST, or long-term survival in spite of disease progression or response as defined by immune-related response criteria (irRC).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a subject with Richter’s transformation as taught by Taghiloo, Reading and Ding to incorporate the method of evaluating a clinical benefit in the subject that comprises complete or partial response as taught by Gandhi and provide assessment of response by Response Evaluation Criteria in Solid Tumors (RECIST) (Pg. 40, Para. 416). Doing so would be an obvious standard alternative for response evaluation criteria to assess clinical benefit of drug administration to patients.
Response to Arguments
Applicant's arguments filed 02/11/2026 do not apply to the new grounds of rejections. Arguments against Reading and Ding on Pg. 7-19 are not persuasive as discussed above. To clarify some instances argued in the response filed 02/11/2026 see responses to each argument made by Applicant below:
Applicants' argument: “However, Gandhi does not rectify the deficiencies of Ding, …and Reading. Umit does not teach or refer to ZNF683, and does not make evident that increased expression of ZNF683 allows the identification of a T cell effector/effector memory population associated with effective anti-tumor immunity, that is predictive of response and is used to identify patients, prior to treatment, who would benefit from PD-I blockade.” (Pg. 19) Umit is interpreted as Gandhi in this statement.
Response: In response to applicant's argument stated above, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Taghiloo et al. (“Taghiloo”; (2017). Blimp-1 Expression as an Exhaustion Transcription Factor in Chronic Lymphocytic Leukemia. Research Molecular Medicine, 5 (3): 5-10) in view of Reading et al. (“Reading”; (2018). The function and dysfunction of memory CD 8+ T cells in tumor immunity. Immunological reviews, 283(1), 194-212.) and Ding et al. (“Ding” (2017). Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, The Journal of the American Society of Hematology, 129(26), 3419-3427.) as applied to claims 21 and 33 above, and further in view of Khan et al. (“Khan”; (2018). Approach to Richter transformation of chronic lymphocytic leukemia in the era of novel therapies. Annals of Hematology, 97(1), 1-15.).
The teachings of Taghiloo, Reading and Ding are documented above in the rejection of claims 21-26, 33 and 35-39 under 35 U.S.C. 103. Claim 34 depends on claim 33, which depends on claim 21. Taghiloo, Reading and Ding do not explicitly teach the limitations of claim 34.
Khan discloses “Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. About 2–10% of CLL patients develop aggressive histological transformation, most commonly to diffuse large B cell lymphoma (DLBCL), historically called Richter transformation (RT)… Chemoimmunotherapy constitutes the standard treatment for RT, followed by stem cell transplant (SCT) in eligible patients. However, the majority of patients do not proceed to allogeneic SCT, either due to inadequate disease control with initial therapy, poor performance status, or lack of donor availability. Overall outcome is dismal. Some novel agents under investigation, particularly PD-1 inhibitors, are showing clinical activity in Phase I and II trials. An ongoing incidence of RT has been noted in studies of previously treated patients receiving targeted therapies such as ibrutinib and venetoclax; the frequency of RT in patients initially treated with novel agents rather than chemoimmunotherapy will be important to determine with longer follow-up. This review focuses on the development, clinicopathologic features, and treatment of RT in the context of novel therapies.” (Abstract)
Regarding claim 34, Khan teaches a method wherein " Although preliminary, notable findings from this study were that pembrolizumab had selective efficacy in RT; 4/9 patients with RT responded… the study was amended to utilize combination treatment with idelalisib or ibrutinib for patients with RT plus CLL involvement " (Pg. 8, PD-1 antagonist: pembrolizumab, Para. 2). Khan teaches a method wherein “Clinical trials are ongoing in RT with … pembrolizumab with or without either ibrutinib or idelalisib (NCT02332980)”. (Pg. 8, PD-1 antagonist: pembrolizumab, Para. 3). “Pembrolizumab” reads on PD1 inhibitor. Thus, Taghiloo, Reading, Ding and Khan suggest a method wherein the chemotherapeutic agent comprises dacarbazine, temozolomide, nab-paclitaxel, paclitaxel, cisplatin, carboplatin, thalidomide, lenalidomide, ibrutinib, ixazomib, bortezomib, carfilzomib, melphalan, vincristine, cyclophosphamide, doxorubicin, liposomal doxorubicin, or bendamustine.
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a subject with Richter’s transformation as taught by Taghiloo, Reading and Ding to incorporate the method further comprising a chemotherapeutic agent, ibrutinib as taught by Khan and provide a method for treating a subject with Richter’s transformation with a PD1 inhibitor and a chemotherapeutic agent. Doing so would be an obvious be an obvious treatment strategy since it was the strategy prior to the introduction of PD1 inhibitors.
Response to Arguments
Applicant's arguments filed 02/11/2026 do not apply to the new grounds of rejections. Arguments against Reading and Ding on Pg. 7-19 are not persuasive as discussed above.
Conclusion
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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