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 .
In view of the appeal brief filed on 06/17/2026, PROSECUTION IS HEREBY REOPENED. New grounds of rejection are set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below:
/WU CHENG W SHEN/ Supervisory Patent Examiner, Art Unit 1682
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10, drawn to a method of predicting a response of a prostate cancer subject to radiotherapy and specie: the group of the first 8 listed genes: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, and EZR, in the reply filed on 08/21/2025 is acknowledged.
Claims 11-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, claims 11-15, drawn to an apparatus, and Group III, claims 16-17, drawn to a method of receiving a biological sample and use of a kit, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/21/2025.
Claims Status
Claims 1-2 and 4-17 are pending.
Claims 11-17 are withdrawn.
Claims 1-2 and 4-10 are currently under examination
Priority
This application is the U.S. National Phase application under 35 U.S.C. §371 of International Application No. PCT/EP2021/055450, filed on March 4, 2021, which claims the benefit of European Application 20161181.1, filed March 5, 2020.
Acknowledgment is made of applicant' s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of EP20161181.1 has been submitted on Aug. 31, 2022. Accordingly, the priority date of instant claims is determined to be March 5, 2020, the filing date of EP20161181.1.
Claim Objections
Claim 2 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Note: Objections are not appealable to the board. (See MPEP 706.01)
Response to Arguments
Applicant's arguments filed 06/17/2026 (Pg. 10) with respect to claims 1-2 have been fully considered but are not persuasive. To clarify some instances argued in the response filed 06/17/2026 see responses to each argument made by Applicant below:
Applicant’s argument: “Applicant asserts that there is indeed a difference in scope between claims 1 and 2” (Pg. 10)
Response: “determining a gene expression profile” is an implicit method of “receiving the result of a determination of a gene expression profile”, thus without a more detailed difference in the limitations, claim 2 remains a substantial duplicate of claim 1. The scope of claim 1 is data gathering of expression values, and scope of claim 2 is data gathering of expression values, without additional claimed limitations the scopes are interpreted as the same. Also, just applying a processor is not considered to distinctively change the scope, without further limitations to distinguish the claim limitations.
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.
Claim 1-2 and 4-10 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 1 is indefinite over the limitations “optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject” (ln 10-11), “determining the prediction of the radiotherapy response based on the gene expression profiles” (ln 8-9). It is unclear as to what the metes and bounds of the assessment comprise.
Furthermore, it unclear if the prediction or a therapy recommendation is provided, if the step remains optional, or whether determining the prediction or a therapy response makes providing the prediction or a therapy recommendation to a medical caregiver or the subject optional.
Claims 4-10 depend on claim 1.
Claim 2 is indefinite over the limitations “optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject” (ln 10-11), “determining, by a processor, the prediction of the radiotherapy response based on the gene expression profiles” (ln 8-9). It is unclear as to what the metes and bounds of the assessment comprise. Furthermore, it’s unclear if the prediction or a therapy recommendation is provided, if the step remains optional, or whether determining, by a processor, the prediction or a therapy response makes providing the prediction or a therapy recommendation to a medical caregiver or the subject optional.
Claim 6 is indefinite because a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the narrow recitation “preferably, all of the T-Cell receptor signaling genes”, and the claim also recites “fifteen or more” which is the broader statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 7 is indefinite because a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites the broad recitation “eight or more” which encompasses any number higher than 8, and the claim also recites “for example, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 7, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 10, the phrase "such as" recited in line 5 of claim 10 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2 and 4-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards abstract ideas related to mental processes and routine and conventional steps of determining a gene expression profile and determining the prediction of response, without significantly more. The claim(s) recite(s) abstract ideas. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 1 is directed towards: A method of predicting a response of a prostate cancer subject to radiotherapy, comprising: determining a gene expression profile for each of eight or moredetermining the prediction of the radiotherapy response based on the gene expression profiles for the eight or more T-Cell receptor signaling genes, and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject.
The “determining a gene expression profile…, said gene expression profiles being determined in a biological sample obtained from the subject”, “determining the prediction of the radiotherapy response based on the gene expression profiles” and “providing the prediction or a therapy recommendation based on the prediction” are considered abstract ideas (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and are considered to be routine and conventional steps as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about the T-Cell receptor signaling genes, determining of the prediction of the radiotherapy response, biological sample, and radiotherapy.
Furthermore, the instant claim 7 is directed towards, “The method as defined in claim 1, wherein the determining of the prediction of the radiotherapy response comprises combining the gene expression profiles for eight or more, for example, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all, of the T-Cell receptor signaling genes with a regression function that had been derived from a population of prostate cancer subjects.”
The “combining the gene expression profiles … with a regression function” is considered an abstract idea related to a mathematical relationship or formula.
The instant claim 2 is directed towards: A method of predicting a response of a prostate cancer subject to radiotherapy, comprising: receiving the result of a determination of a gene expression profile for each of eight or more T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR, FYN, LAT, LCK, PAG1, PDE4D, PRKACA, PRKACB, PTPRC, and ZAP70, said gene expression profiles being determined in a biological sample obtained from the subject, determining, by a processor, the prediction of the radiotherapy response based on the gene expression profiles for the eight or more T-Cell receptor signaling genes; and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject.
The “receiving the result of a determination of gene expression profile…, said gene expression profiles being determined in a biological sample obtained from the subject”, “determining, by a processor, the prediction of the radiotherapy response based on the gene expression profiles” and “providing the prediction or a therapy recommendation based on the prediction” are considered abstract ideas (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and are considered to be active steps requiring the analysis of a sample. The processor is considered a simple application to a mental process that can be performed mentally or is analogous to human mental work.
The active step is routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract ideas.
With regard to claim 1, the claim recites “A method of predicting a response of a prostate cancer subject to radiotherapy, comprising: determining a gene expression profile for each of eight or moredetermining the prediction of the radiotherapy response based on the gene expression profiles for the eight or more T-Cell receptor signaling genes, and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject.” The “determining a gene expression profile…said gene expression profiles being determined in a biological sample obtained from the subject”, “determining the prediction of the radiotherapy response based on the gene expression profiles” and “providing the prediction or a therapy recommendation based on the prediction” are considered abstract ideas (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and are considered to be active steps requiring the analysis of a sample.
With regard to claim 2, “A method of predicting a response of a prostate cancer subject to radiotherapy, comprising: receiving the result of a determination of a gene expression profile for each of eight or more T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR, FYN, LAT, LCK, PAG1, PDE4D, PRKACA, PRKACB, PTPRC, and ZAP70, said gene expression profiles being determined in a biological sample obtained from the subject, determining, by a processor, the prediction of the radiotherapy response based on the gene expression profiles for the eight or more T-Cell receptor signaling genes; and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject.” The “determining a gene expression profile…said gene expression profiles being determined in a biological sample obtained from the subject”, “determining, by a processor, the prediction of the radiotherapy response based on the gene expression profiles” and “providing the prediction or a therapy recommendation based on the prediction” are considered abstract ideas (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and are considered to be active steps requiring the analysis of a sample. The processor is considered a simple application of a processor to a mental process that can be performed mentally or is analogous to human mental work.
With regard to claim 7, the method as defined in claim 1, wherein the determining of the prediction of the radiotherapy response comprises combining the gene expression profiles for eight or more, for example, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all, of the T-Cell receptor signaling genes with a regression function that had been derived from a population of prostate cancer subjects.” The “combining the gene expression profiles … with a regression function” is considered an abstract idea related to a mathematical relationship or formula.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claims 1 and 2, the claim requires the routine and conventional active steps of determining or receiving the result of a determination of a gene expression profile, and determining the prediction of the radiotherapy response similar to that of Davicioni et al. (“Davicioni”; Patent App. Pub. WO 2019028285 A2, Feb. 07, 2019, Filed on Aug. 02, 2018, as cited in IDS).
Davicioni discloses “Methods, systems, and kits for the diagnosis, prognosis and the determination of cancer progression of prostate cancer in a subject are disclosed. In particular, the disclosure relates to the use of immune cell-specific gene expression in determining prognosis and identifying individuals in need of treatment for prostate cancer who will be responsive to radiation therapy.” (Abstract).
Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require further limitations about the T-Cell receptor signaling genes, determining of the prediction of the radiotherapy response, biological sample, and radiotherapy. which are all routine and conventional based on Davicioni et al. (“Davicioni”; Patent App. Pub. WO 2019028285 A2, Feb. 07, 2019, Filed on Aug. 02, 2018, as cited in IDS) in view of Bou-Dargham et al. (“Bou-Dargham”; (2019). Cancer Immune Evasion Mechanisms and the Role of Granzyme B in Tumor Progression (Doctoral dissertation, The Florida State University), Valdman, et al. (“Valdman”; (2005). Ezrin expression in prostate cancer and benign prostatic tissue. European urology, 48(5), 852–857.), and Mosenden et al. (“Mosenden”; (2011). Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells. Cellular signalling, 23(6), 1009–1016.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2 and 4-10 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Davicioni et al. (“Davicioni”; Patent App. Pub. WO 2019028285 A2, Feb. 07, 2019, Filed on Aug. 02, 2018, as cited in IDS) in view of Bou-Dargham et al. (“Bou-Dargham”; (2019). Cancer Immune Evasion Mechanisms and the Role of Granzyme B in Tumor Progression (Doctoral dissertation, The Florida State University), Valdman, et al. (“Valdman”; (2005). Ezrin expression in prostate cancer and benign prostatic tissue. European urology, 48(5), 852–857.), and Mosenden et al. (“Mosenden”; (2011). Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells. Cellular signalling, 23(6), 1009–1016.
Davicioni discloses “Methods, systems, and kits for the diagnosis, prognosis and the determination of cancer progression of prostate cancer in a subject are disclosed. In particular, the disclosure relates to the use of immune cell-specific gene expression in determining prognosis and identifying individuals in need of treatment for prostate cancer who will be responsive to radiation therapy.” (Abstract).
Regarding claim 1, Davicioni teaches a method wherein “a) obtaining a biological sample comprising cancer cells from the patient; b) measuring levels of immune cell-specific gene expression in the biological sample; c) calculating levels of one or more immune cell types in the biological sample based on the levels of immune cell-specific gene expression; d) determining the prognosis of the patient based on the levels of the one or more immune cell types in the biological sample; and e) administering a treatment to the subject based on the prognosis. In some embodiments, the cancer is prostate cancer” (Para. 10). Davicioni teaches use of immune cell-specific gene expression in determining prognosis and identifying individuals in need of treatment for prostate cancer who will be responsive to radiation therapy” (Para. 9). Davicioni teaches “the immune cell-specific gene is one or more genes selected from Table 2. In some embodiments, the immune cell-specific gene comprises or consists of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, or 250 genes selected from Table 2” (Para. 10). Davicioni teaches Table 2 comprising CD2, CD3E, and CD3G (Table 2) and suggests expression CD4 as “CD4+ T-cells” is taught (Para. 205). Moreover, Davicioni teaches a method comprising “Human Exon 1.0 ST microarray (Thermo-Fisher, Carlsbad, CA)” (Para. 192). Davicioni teaches “The models and/or algorithms can be provided in machine readable format and may be used to correlate expression levels or an expression profile with a disease state, and/or to designate a treatment modality for a patient or class of patients. Array data can be managed, classified, and analyzed using techniques known in the art.” (Para. 133-134) and “machine learning algorithm may comprise Data Pre-processing” (Para. 137). “Human Exon 1.0 ST microarray” reads on the genes CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR in the human genome. “machine readable format” reads on being read by a processor. Thus, Davicioni suggests a method comprising determining a gene expression profile for each of eight or more, T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR, said gene expression profiles being determined in a biological sample obtained from the subject, determining the prediction of the radiotherapy response based on the gene expression profiles for eight or more T-Cell receptor signaling genes, and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject; and receiving the result of a determination of a gene expression profile for each of eight or more T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR said gene expression profiles being determined in a biological sample obtained from the subject, determining, by a processor, the prediction of the radiotherapy response based on the gene expression profiles for eight or more T-Cell receptor signaling genes; and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject.
Although Davicioni does suggest determining and receiving the result of a determination of a gene expression profile gene expression of the elected species CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR as indicated by use of Human Exon 1.0 ST microarray (see attachment confirming the presence of probes for each of these genes), Davicioni does not explicitly teach a method comprising determining the prediction of the radiotherapy response based on the gene expression profiles for the eight or more T-Cell receptor signaling genes.
Bou-Dargham discloses “Major hallmarks of cancer include metastasis and evading the immune system. Despite cutting edge treatments developed in an era of extensive cancer research, immunotherapy has not been proven efficient enough in solid tumors, and metastasis still accounts for the majority of cancer deaths. The overall unsatisfactory response rates to immunotherapy are mainly due to the lack of biomarkers that can predict a patient’s response and the lack of a good understanding of the different immune cell infiltration trends observed in tumors. To address these gaps in breast and prostate cancer, RNA sequenced data for breast and prostate cancer samples were obtained from The Cancer Genome Atlas (TCGA) and analyzed to identify immune evasion mechanisms and understand immune cell infiltration. Breast and prostate cancer populations were each clustered into different immune evasion groups. Then biomarkers predictive of the identified clusters were identified and could be used as predictors of immune evasion and the corresponding immunotherapy options.” (Abstract).
Regarding claims 1-2, Bou-Dargham teaches a method comprising “We collected a list of 2,000 immune genes from previous publications and gene sets from the Molecular Signatures Database (MSigDB) (Appendix C). This expression data for this list was obtained from TCGA for prostate cancer samples” (Pg. 13, 2.2 Immune Gene Sets for Prostate Cancer). Bou-Dargham teaches a method comprising “data from TCGA were checked for the expression of 2,000 immune-related genes identified in previously published gene sets and the Molecular Signatures Database (MSigDB) (Appendix C). The patients were then clustered sequentially, using our sequential biclustering method to categorize patients based on their immune gene expression.” (Pg. 48-49). Accordingly, Bou-Dargham teaches a method comprising Appendix C which lists CD2, CD247, CD28, CD3E, CD3G, CD4, and CSK. (Pg. 78-79, Appendix C, IMMUNE GENE SETS USED FOR PROSTATE CANCER BICLUSTERING). Thus, Davicioni and Bou-Dargham suggest a method comprising determining and receiving a result of a determination of a gene expression profile for each of eight or more, T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK,EZR determining the prediction of the radiotherapy response based on the gene expression profiles for the T-Cell receptor signaling genes, optionally by a processor.
However, Davicioni and Bou-Dargham do not explicitly suggest determining the prediction of the radiotherapy response based on the gene expression profiles for the T-Cell receptor signaling gene EZR.
Valdman discloses “…Conclusion: Ezrin was expressed in the majority of prostate cancers and correlated with adverse prognostic factors.” (Abstract)
Regarding claims 1-2, Valdman teaches a method comprising “Ezrin expression was assessed” (Pg. 853, Materials and Methods- Immunohistochemistry). Valdman teaches that this is “the first report of ezrin protein expression in a consecutive series of clinical prostate cancer specimens. We have previously demonstrated an increased expression in prostate cancer and high-grade PIN in comparison with normal prostatic epithelium in a limited number of specimens. The aims of this study were to assess staining patterns in benign prostatic tissue and to investigate possible correlations between ezrin expression in prostate cancer and histopathological and prognostic data” (Pg. 855, Discussion, Para. 1) and “our results are in accordance with previous studies showing gradual increase in ezrin expression following tumor progression and loss of differentiation” (Pg. 855, Discussion, Para. 2). Furthermore, the editorial comment by Jack Schalken notes that “Evidence for the close interplay between cell-adhesion and -signaling was first found for the E-cadherin complex associated β-catenin. β-catenin can both act in the complex linking E-cadherin to the cortical cytoskeleton, but can as well function in a transcription initiation complex through interaction with T-cell transcription factors. Thus, the pathway it is involved in, also termed the wingless pathway has now gained tremendous interest as target for cancer therapy. More recently a member of the ezrin radixin moezin complex (ERM) the protein is also involved to link membrane proteins to the cortical cytoskeleton was found to be involved in signal transduction. Through a direct effect on the P3 kinase AHT pathway, it promotes survival of epithelial cells.
Furthermore, Mosenden discloses “type I PKA is anchored close to the T cell receptor (TCR) in lipid rafts by the Ezrin–ERM-binding phosphoprotein of 50 kDa (EBP50)-phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) scaffold complex. The most TCR-proximal target for type I PKA is C-terminal Src kinase (Csk), which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis. Recently, induction of cAMP levels in responder T cells has emerged as one of the mechanisms by which regulatory T (TR) cells execute their suppressive action. Thus, the cAMP-type I PKA–Csk pathway emerges as a putative target for therapeutic intervention in autoimmune disorders as well as in cancer, where TR cell-mediated suppression contributes to suboptimal local immune responses” (Abstract)
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Regarding claims 1-2, Mosenden teaches “a TCR-proximal pathway for regulation of T cell immune function by cAMP has been unraveled”, “Type I PKA colocalizes with the TCR complex”, “We have identified Ezrin as the functionally important AKAP for type I PKA in T cell lipid rafts” (Pg. 1013, 4.2 The cAMP-type I PKA-C-terminal Src kinase (Csk) pathway in T cell lipid rafts). Mosenden teaches “Our recent mapping of PGE2-dependent phosphorylation networks in T cells identified PKA as a central signaling node. PKA regulates T cell immune function at multiple levels as illustrated in Fig. 4” (Pg. 1011, 4.1. Mechanisms for PKA-mediated modulation of T cell immune function). Mosenden teaches Fig. 4 which illustrates some of the T-Cell receptor signaling proteins involved in the regulation of T-cell activation such as Ezrin (EZR), Csk, CD4, CD3 protein complex (CD3E, CD3G, CD3D, CD3Z (CD247)), LAT, LCK, PAG, ZAP70, etc. (See Fig. 4 below). Mosenden also teaches Fig. 5 which illustrates some of the proteins and cofactors involved in suppression of T-Cell receptor signaling involved in the regulation of T-cell activation such as Ezrin, Csk, CD3 protein complex (CD3E, CD3G, CD3D, CD3Z (CD247)), LCK, PAG, PDEs, etc. Moreover, Mosenden teaches that “Tumor-derived PGE2 contributes to cancer progression among others by promoting the conversion of adaptive TR cells into the regulatory phenotype. TR cells induced in the periphery have been shown to accumulate at tumor sites, where they may impair the development of effective antitumor immune responses…In patients with … malignancies the percentage of TR cells in peripheral blood correlates inversely with disease prognosis” (Pg. 1014. 4.3 Induction of cAMP levels in responder T cells as a mechanism of TR cell action). Hence, Valdman and Mosenden suggest determining the prediction of a treatment response in a prostate cancer sample based on T-cell receptor signaling gene EZR.
Thus, Davicioni, Bou-Dargham, Valdman and Mosenden suggest a method of predicting a response of a prostate cancer subject to radiotherapy, comprising: determining and or receiving a result of a determination of a gene expression profile for each of eight or more T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR (elected species), said gene expression profiles being determined in a biological sample obtained from the subject, determining, the prediction of the radiotherapy response based on the gene expression profiles for the eight or more T-Cell receptor signaling genes ,optionally by a processor, and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject.
Davicioni, Bou-Dargham, Valdman and Mosenden are considered to be analogous to the claimed invention because they are in the same field of Immuno-regulatory gene expression related to cancer diagnosis and prognosis. Davicioni notes that the impact of immune content and specific immune cell types on prostate cancer biology is highly complex and suggests that while some embodiments of the disclosure have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the disclosure (Para. 7; Para. 210). Thus, one of skill in the art would be motivated to modify the prior art to further investigate to further investigate the complexities of immune content and specific immune cell types on prostate 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 comprising: determining and/or receiving a result of a determination of a gene expression profile for each of eight or more T-Cell receptor signaling genes selected from the group comprising: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR (elected species); determining a prediction of the radiotherapy response based on the gene expression profiles of eight or more T-Cell receptor signaling genes, optionally by a processor, and optionally, providing the prediction or a therapy recommendation based on the prediction to a medical caregiver or the subject as suggested by Davicioni to incorporate the method comprising determining the prediction of treatment response based on the expression profile of T-Cell receptor signaling genes comprising CD2, CD247, CD28, CD3E, CD3G, CD4, CSK from expression data obtained from a prostate cancer sample as suggested by Bou-Dargham; incorporate determining the expression of EZR in prostate cancer sample as suggested by Valdman; and incorporate determining the prediction of a treatment response in a prostate cancer sample based on T-cell receptor signaling regulator EZR as suggested by Mosenden and together provide a method of predicting a response of a prostate cancer subject to radiotherapy according to the limitations of claims 1-2. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1-2. Doing so would provide an assessment of specific genes involved in regulating T-cell activation or suppression to predict the anticancer immune response of a prostate cancer subject to radiotherapy.
The teachings of Davicioni, Bou-Dargham, Valdman and Mosenden are documented above in the rejection of claims 1-2 under 35 U.S.C. 103. Claims 4-10 depend on claim 1. Claim 2 is independent of claim 1.
Regarding claims 4-6, Davicioni teaches “In some embodiments, the immune cell-specific gene comprises or consists of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, or 250 genes” (Para. 10). Davicioni teaches “obtaining an expression level of one or more immune cell-specific genes in a sample” (Para. 36). Furthermore, Bou-Dargham teaches Appendix C “IMMUNE GENE SETS USED FOR PROSTATE CANCER BICLUSTERING (2000 GENES)” which lists CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, FYN, LAT, LCK, PAG1, PRKACA, PRKACB, PTPRC, and ZAP70. (Pg. 78-79 and 81-82).
Additionally, Mosenden highlights CD3 TCR subunits (CD3E, CD3G, CD247), CD4, CSK, EZR, LCK, PAG, and ZAP70 in Fig. 4 illustration of PKA modulates T cell immune function at multiple levels. Mosenden highlights PDE, CSK, EZR, LCK, PAG in Fig. 5 illustration of inhibitory cAMP-type I PKA–Csk pathway in T cell lipid rafts and that the “PDE4 family…seems to account for the majority of the cAMP-hydrolyzing activity in T cells” (Pg.1010, Introduction; Fig. 5). “PDE” reads on PDE4. Mosenden highlights CD28 in the Fig. illustration of Overview of T cell activation. (Fig. 3). Mosenden also teaches “Specificity in PKA signaling is ensured by the differential expression of distinct isoforms and splice variants of… the C subunit in various tissues and cell types... three different C subunit isoforms, Cα, Cβ and PrKX/PKARE are expressed in humans and mice” “Cα, Cβ” read on PRKACA and PRKACB. Mosenden teaches “Upon TCR activation, PAG is rapidly dephosphorylated by a mechanism that appears to involve the activity of the phosphatase CD45”(Pg. 1013, 4.2, The cAMP-type I PKA-C-terminal Src kinase (Csk) pathway in T cell lipid rafts) “CD45” reads on PTPRC. CD28
Mosenden teaches that T-cell “Activation is accompanied with formation of the immunological synapse, coalescence of lipid rafts in the T cell membrane and activation of Lck and Fyn, which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 subunits of the TCR complex… Subsequently, Zap-70 phosphorylates linker for activation of T cells (LAT).” (Pg. 1011, T cell activation)
Thus, Davicioni, Bou-Dargham, Valdman and Mosenden suggest a method wherein the eight or more T- Cell receptor signaling genes comprise nine or more of the T-Cell receptor signaling genes; wherein the eight or more T- Cell receptor signaling genes comprise twelve or more of the T-Cell receptor signaling genes; and wherein eight or more T- Cell receptor signaling genes comprise fifteen or more, preferably, all of the T-Cell receptor signaling genes.
Regarding claim 7, Davicioni teaches a method wherein “Feature selection can be performed by regularized logistic regression” (Para. 81) and “assaying the expression level for a plurality of targets may comprise the use of a machine learning algorithm. The machine learning algorithm may comprise a supervised learning algorithm…regression… Supervised learning may comprise ordinal classification such as regression analysis” (Para. 135). Thus, Davicioni, Bou-Dargham, Valdman and Mosenden suggest a method wherein the determining of the prediction of the radiotherapy response comprises combining the gene expression profiles for eight or more, for example, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all, of the T-Cell receptor signaling genes with a regression function that had been derived from a population of prostate cancer subjects.
Regarding claim 8, Davicioni teaches a method wherein treatment in step e is carried out after sample collection in step (a) and prognosis in step (d) “a) obtaining a biological sample comprising prostate cancer cells from the patient; … d) determining the prognosis of the patient based on the levels of the one or more immune cell types in the biological sample; and e) administering a treatment to the subject based on the prognosis, wherein the treatment is selected from the group consisting of.., radiation therapy” (Para. 11). Davicioni teaches a method wherein “the method is performed before treatment of the patient with radiation therapy” (Para. 27). Thus, Davicioni, Bou-Dargham, Valdman and Mosenden suggest a method wherein the biological sample is obtained from the subject before the start of the radiotherapy.
Regarding claim 9, Davicioni teaches a method wherein “For patients with intermediate test scores consistent with biochemical recurrence only (BCR-only or elevated PSA that does not rapidly become manifested as systemic disease only localized adjuvant therapy (e.g., radiation therapy of the prostate bed)” (Para.183; Para.188). Thus, Davicioni, Bou-Dargham, Valdman and Mosenden suggest a method wherein the radiotherapy is radical radiotherapy or salvage radiotherapy.
Regarding claim 10, Davicioni teaches a method wherein “The significance of the levels of immune cell-specific gene expression may be evaluated using, for example … positive predictive value (PPV), negative predictive value (NPV),” (Para. 30). Davicioni teaches “In addition, diagnosing, predicting, or monitoring a status or outcome of a cancer may comprise identifying or predicting responders or non-responders to an anticancer therapy (e.g., radiation therapy). In some instances, diagnosing, predicting, or monitoring may comprise determining a therapeutic regimen. Determining a therapeutic regimen may comprise administering an anti-cancer therapy. In some embodiments, determining a therapeutic regimen may comprise modifying, recommending, continuing or discontinuing an anti-cancer regimen… In some instances, if the sample expression patterns are consistent with the expression pattern for a known disease or disease outcome, the expression patterns can be used to designate one or more treatment modalities (e.g., therapeutic regimens, anti-cancer regimen). An anti-cancer regimen may comprise one or more anti -cancer therapies. Examples of anticancer therapies include surgery, chemotherapy, radiation therapy, immunotherapy/biological therapy, and photodynamic therapy” (Para. 139). Davicioni also teaches a method wherein “For patients with high test scores consistent with systemic disease outcome after prostatectomy, additional treatment modalities such as adjuvant chemotherapy (e.g., docetaxel, mitoxantrone and prednisone), systemic radiation therapy (e.g., samarium or strontium) and/or anti-androgen therapy (e.g., surgical castration, finasteride, dutasteride) can be designated.” (Para. 182). “determining a therapeutic regimen” and “modifying …regimen” read on radiotherapy provided earlier than is standard and increased radiation dosage. Thus, Davicioni, Bou-Dargham, Valdman and Mosenden suggest a method wherein the prediction of the radiotherapy response is negative or positive for the effectiveness of the radiotherapy, wherein a therapy is recommended based on the prediction and, if the prediction is negative, the recommended therapy comprises one or more of: (i) radiotherapy provided earlier than is the standard; (ii) radiotherapy with an increased radiation dose; (iii) an adjuvant therapy, such as androgen deprivation therapy; and iv) an alternative therapy that is not a radiation therapy.
Response to Arguments
Applicant's arguments filed 06/17/2026 (Pg. 12-24) with respect to claims 1-2 and 4-10 have been fully considered but do not apply to the new grounds of rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-2 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/023,598 in view of Davicioni et al. (“Davicioni”; Patent App. Pub. WO 2019028285 A2, Feb. 07, 2019, Filed on Aug. 02, 2018, as cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of copending Application No. 18/023,598.
The claims of copending Application No. 18/023,598 are drawn to:
“1. (Currently Amended) A method of treating human prostate cancer subject, comprising:(A) receiving a prediction of a response of the prostate cancer subject to a therapy or a personalization of the therapy, wherein the prediction or personalization is based on: (a)obtaining a first gene expression profile for each of one or more immune defense response genes selected from the group consisting of:AIM2, APOBEC3A, CIAO1, DDX58, DHX9, IFI16, IFIH1, IFIT1,IFIT3, LRRFIP1,MYD88, OAS1, TLR8, and ZBP1, said first gene expression profile(s) being determined in a biological sample obtained from the subject; (b) obtaining a second gene expression profile for each of one or more T-Cell receptor signaling genes selected from the group consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR, FYN, LAT, LCK, PAG1, PDE4D, PRKACA, PRKACB, PTPRC, and ZAP70, said second gene expression profile(s) being determined in a biological sample obtained from the subject; (c) obtaining a third gene expression profile for each of one or more PDE4D7 correlated genes selected from the group consisting of: ABCC5, CUX2, KIAA1549, PDE4D, RAP1GAP2, SLC39Al 1, TDRD1, and VWA2, said third gene expression profile(s) being determined in a biological sample obtained from the subject; wherein the biological sample comprises prostate tissue or blood, (B) treating the subject with a therapy based on the received prediction or personalization, wherein, when a positive response to the therapy is predicted, the therapy administered to the subject is radical radiotherapy, salvage radiotherapy, salvage androgen deprivation therapy, or cytotoxic chemotherapy, and wherein, when a negative response to the therapy is predicted, the therapy administered to the subject comprises one or more of: (i) radiotherapy provided earlier than is standard; (ii) radiotherapy with an increased radiation dose; (iii) an adjuvant therapy comprising androgen deprivation therapy; and (iv) an alternative therapy that is not a radiation therapy..”
The teachings of Davicioni are documented above in the rejection of claims 1-2 and 4-10 under 35 U.S.C. 103.
Therefore, the invention as recited in claims 1-2 are prima facie obvious over the copending Application No. 18/023,598 in view of Davicioni. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to use a method of predicting a response of a prostate cancer subject to radiotherapy according to the limitations recited in claims 1-2 of the instant application based on claim 1 of copending Application No. 18/023,598 in view of Davicioni et al. (Patent App. No. WO 2019028285 A2).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 8-9 of copending Application No. 18/029,748 in view of Davicioni et al. (“Davicioni”; Patent App. Pub. WO 2019028285 A2, Feb. 07, 2019, Filed on Aug. 02, 2018, as cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of copending Application No. 18/029,748.
The claims of copending Application No. 18/029,748 are drawn to:
“1. A method comprising: determining or receiving the result of a determination of consisting of: CD2, CD247, CD28, CD3E, CD3G, CD4, CSK, EZR, FYN, LAT, LCK, PAG1, PDE4D, PRKACA, PRKACB, PTPRC, and ZAP70, or PDE4D7 correlated genes selected from the group consisting of: ABCC5, CUX2, KIAA1549, PDE4D, RAP1GAP2, SLC39A11, TDRD1, and VWA2, or wherein said three or more genes comprise at least one or more gene(s) selected from each of the immune defense response genes, T-Cell receptor signaling genes and PDE4D7 correlated genes, wherein the gene expression profiles of the three or more genes are determined via a biological sample obtained from the subject; and determining a prediction of the outcome based on the gene expression profiles of the three or more genes.
8. The method as defined in claim 1, wherein the outcome is a prediction of therapy response and wherein the biological sample is obtained from the subject before the start of the therapy.
9. The method as defined in claim 1, wherein the therapy is surgery, radiotherapy, cytotoxic chemotherapy (CTX), or immunotherapy.”
The teachings of Davicioni are documented above in the rejection of claims 1-2 and 4-10 under 35 U.S.C. 103.
Therefore, the invention as recited in claims 1-2 are prima facie obvious over the copending Application No. 18/029,748 in view of Davicioni. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to use a method of predicting a response of a prostate cancer subject to radiotherapy according to the limitations recited in claims 1-2 of the instant application based on claims 1 and 8-9 of copending Application No. 18/029,748 in view of Davicioni et al. (Patent App. No. WO 2019028285 A2).
This is a provisional nonstatutory double patenting rejection.
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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