DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
2. Claims 1-17 are currently pending and under exam herein.
Claims 1-17 are rejected.
Priority
3. This application is a continuation of International Application No. PCT/US22/14670,
which designated the United States and was filed on February 1, 2022. Claimed benefit of domestic priority U.S. Provisional Application No. 63/145,128, filed on 3 February 2021 is acknowledged. In this action, all claims are examined as though they had an effective filing date of 3 February 2021. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Information Disclosure Statement
4. The information disclosure statements (IDSs) submitted on 8 March 2024 is being considered by the examiner.
Drawings
5. The drawing submitted on 23 October 2023 are accepted by the examiner.
Claim Interpretation
6. In claims 1, 4-5 and 7, ‘determining the activity’ of a biomarker(s) is interpreted to include calculating the levels of the biomarker relative to a control condition. In claim 2, ‘obtaining from the classifier the classification” is being interpreted to include performing the classification analysis with the trained classifier.
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 1-17 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.
Claims 1, 10 and 12 recite ‘the step’, which lacks antecedent basis because ‘a step’ has not been introduced previously. Claims 2-9, 11 and 13-17 are similarly rejected by virtue of their dependence on claims 1, 10 and 12 and by their failure to resolve the indefiniteness issue. For the purpose of review and with broadest reasonable interpretation, ‘the step’ will be interpreted to mean ‘a step’.
Claims 13 and 17 recite ‘the methanesufate salt’ and ‘the benzene sulfonate salt’, which lack antecedent basis because ‘a methanesufate salt’ and ‘a benzene sulfonate salt’ have not been introduced previously. For the purpose of review and with broadest reasonable interpretation, ‘the methanesufate salt’ and ‘the benzene sulfonate salt’ will be interpreted to mean ‘a methanesufate salt’ and ‘a benzene sulfonate salt’, respectively.
Claim 10 recites ‘wherein the subject is classified as a fimepinostat responder by the method of claim 1’, which is indefinite because it is unclear if you need to perform the method of claim 1 or if it is a limitation that describes the process by which the subject was previously classified. Claim 13 is similarly rejected by virtue of dependence on claim 10 and for failing to resolve the indefiniteness issue.
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.
7. Claims 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 2A, Prong 1
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1 recites: determining the activity of one or more marker proteins in a tumor sample from the subject
Claim 1 recites: wherein increased or decreased activity of the one or more marker proteins compared to baseline classifies the subject as a fimepinostat responder and an absence of increased or decreased activity of the one or more marker proteins compared to baseline classifies the subject as a fimepinostat non-responder
Claim 2 recites: obtaining from the classifier the classification of the subject as a fimepinostat responder or a fimepinostat non- responder
Claim 2 recites: the trained classifier being trained to differentiate between fimepinostat responders and fimepinostat non-responders
Claim 2 recites: the method of claim 1, wherein the activities of the one or more marker proteins are provided to a trained classifier
Claim 3 recites: the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1, ANGPTL3, YEATS4, IL16, FGD3, ATF7IP, TRIP13, CBX4 and CD37
Claim 4 recites: the method of claim 3, wherein said method comprises the step of determining the activity of two or more marker proteins
Claim 5 recites: the method of claim 4, wherein said method comprises the step of determining the activity of three or more marker proteins
Claim 6 recites: the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1 and ANGPTL3
Claim 7 recites: the method of claim 6, wherein said method comprises the step of determining the activity of PBXIP 1, ETS1 and ANGPTL3
Claim 8 recites: the method of claim 1, wherein the protein activity is determined using the VIPER algorithm
Claim 9 recites: the method of claim 1, wherein the subject is naive to therapy with fimepinostat
The limitations regarding ‘determining the activity of one or more marker proteins’ (compared to baseline), determining the activity of two or more marker proteins, determining the activity of three or more marker proteins’, ‘determining the activity of PBXIP 1, ETS1 and ANGPTL3’, ‘obtaining from the classifier the classification” (which is being interpreted to include performing the classification) and ‘using the VIPER algorithm’ are verbal equivalents that describe a mathematical calculation that is performed as the limitation and are so simple that they could be performed in the human mind or with pen and paper. Therefore, these limitations fall under the "Mathematical concepts" and "Mental processes" groupings of abstract ideas.
The limitations of claim 1 that further limits how the marker protein activities are calculated, the limitations of claims 2-3 and 6, that further limit which biomarkers are evaluated, the limitation of claim2 that limits how the classifier was trained and the limitation of claim 9 directed to which subjects are analyzed, merely further limit the judicial exceptions but do not change their positions as abstract ideas.
The limitation in claim 2 regarding ‘wherein the activities of the one or more marker proteins are provided to a trained classifier’ under broadest reasonable interpretation encompasses copying values into a list of written rules that are used for classification and thus can be performed in the human mind because the human mind is capable of providing values and determining information from other values, thus it falls into the “mental process” grouping of abstract ideas.
As such, claims 1-9 recite an abstract idea (Step 2A, Prong 1: YES).
Step 2A, Prong 2
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite any additional elements. As such, claims 1-9 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not recite any additional elements. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-9 are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
8. Claims 1-2 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
Regarding claim 1, Parker et al. discloses a method of identifying correlations of pretreatment MYC gene signature variations with clinical response to fimepinostat in patients with diffuse large B-cell lymphoma (DLBCL) to identify differences in transcript-level signatures of gene networks in pre-treatment tumor samples associated with future clinical response to fimepinostat. Parker et al. further discloses that Gene Set Enrichment Analysis (GSEA; Subramanian et al., 2005) was used to study changes in transcript expression patterns that correlate with responder (complete/partial response) or non-responder (progressive disease) patient populations. Parker et al. discloses identifying >1500 genes (with FDR <= 0.05) and normalized enrichment scores > 1.3 that were upregulated in the fimepinostat responder population versus a non-responder population. (p. 1, para. 1- p. 2, para. 1; a method of classifying a subject suffering from diffuse large B cell lymphoma as a fimepinostat responder or a fimepinostat non-responder, comprising the step of determining the activity of one or more markers in a tumor sample from the subject, wherein increased or decreased activity of the one or more markers compared to baseline classifies the subject as a fimepinostat responder and an absence of increased or decreased activity of the one or more marker proteins compared to baseline classifies the subject as a fimepinostat non-responder.
Regarding claims 1-2 and 10, Parker et al. is silent to the method wherein the marker is a marker protein (claim 1); the method of claim 1, wherein the activities of the one or more marker proteins are provided to a trained classifier, the trained classifier being trained to differentiate between fimepinostat responders and fimepinostat non-responders (claim 2); and obtaining from the classifier the classification of the subject as a fimepinostat responder or a fimepinostat non-responder and wherein the subject is classified as a fimepinostat responder by the method of any one of claim 1 (claim 10). However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Schweighofer et al.
Regarding claim 1, Schweighofer et al. discloses a method of developing and using biomarkers for stratifying patients with DLBCL into groups based on predicted response to treatment. Schweighofer et al. further discloses that determining the presence, modifications, or expression of the biomarker of interest can be at the protein or nucleotide level and are accomplished using any detection method known to those of skill in the art. Schweighofer et al. further discloses generating biomarkers for selecting treatment to DLBCL in steps including: 1) measuring differential expression between DLBCL patient groups, and 2) using rank-based statistics to determine significance, and 3) further using Kaplan-Meier survival curves of progression-free survival for patients between the two groups (for example low and high BCL-2 gene expression) to validate/confirm biomarkers (abstract; para. 0529, 0111; fig. 1; wherein the marker is a marker protein).
Regarding claim 2, Parker et al. and Schweighofer et al. teach a method of classifying a patient with DLBCL as a fimepinostat responder or non-responder above. Schweighofer et al. further teaches using trained machine learning classifiers for classifying DLBCL patients as responders or non-responders to drugs. In one example, to train a classifier, they first performed DLBCL subtype classification using differential gene expression profiles between drug-responsive and non-responsive patient groups, then developed a model to discriminate the two groups using a linear discriminate analysis (LDA) model/classifier and neural networks with 5-fold cross validation procedure for model selection, and finally selected the best performing model for final classification. In this example, gene expression values are used as features, but Schweighofer et al. discloses that biomarker expression can be measured either at the nucleic acid or protein level (para. 0533, 0499; 0220; the method of claim 1, wherein the activities of the one or more marker proteins are provided to a trained classifier, the trained classifier being trained to differentiate between fimepinostat responders and fimepinostat non-responders; and obtaining from the classifier the classification of the subject as a fimepinostat responder or a fimepinostat non- responder).
Pertaining to claim 10, Schweighofer et al. discloses methods of selecting an individual having a hematological malignancy such as diffuse large B cell lymphoma (DLBCL) for treatment with a TEC inhibitor such as an ITK inhibitor or a BTK inhibitor (e.g. ibrutinib) based on the presence or absence of a one or more biomarkers. Schweighofer et al. further discloses that an individual is administered a therapeutically effective amount of a treatment (TEC inhibitor) if there is an increase in expression level in at least one biomarker gene selected from a list relative to a control. Schweighofer et al. further discloses that the administered treatment can be a pharmaceutically acceptable salt. Schweighofer et al. further discloses that a test for differential expression can classify DLBCL patients as responders or non-responders to Ibrutinib (para. 0191-0193; 0290; 0506; a method of treating diffuse large B-cell lymphoma in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of fimepinostat or a pharmaceutically acceptable salt thereof, wherein the subject is classified as a fimepinostat responder by the method of claim 1).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Schweighofer et al. disclosed that unique mutation patterns underlie DLBCL subtypes which highlights the need for personalized medicine approaches to treating these patients (para. 0534). Schweighofer et al. further discloses that their method includes administering a specific therapeutically effective treatment to a DLBCL patient if there is an increase in expression level in at least one biomarker gene selected from their list relative to a control (para. 0198). Therefore, one of ordinary skill in the art would have been motivated to utilize the method of classifying patients into groups using protein markers and personalizing treatment to DLBCL based on these markers taught by Schweighofer et al. in the method to identify gene biomarkers that are differentially expressed in DLBCL tumors from fimepinostat responders versus non-responders taught by Parker et al. in order to apply personalized/targeted medicine for patients with DLBCL. Furthermore, one of ordinary skill in the art would predict that the biomarker development approach taught by Schweighofer et al. could be readily added to the method of Parker et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for treatment selection. The invention is therefore prima facie obvious.
9. Claims 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over of Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), as applied to claims 1-2 and 10 above, and further in view of Priebe et al. (Cancers, 2020, Vol. 12, p. 1-17; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-2 and 10 were taught by Parker et al. and Schweighofer et al. above.
Pertaining to claims 3 and 6, Parker et al. and Schweighofer et al. are silent to: the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1, ANGPTL3, YEATS4, IL16, FGD3, ATF7IP, TRIP13, CBX4 and CD37 (claim 3) and the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1 and ANGPTL3 (claim 6). However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Priebe et al.
Pertaining to claim 3, Priebe et al. teaches two groups of diffuse large B cell lymphoma (DLBCL) patients, germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, which differ in their response to treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP (rituximab-CHOP) therapies (with ABC type having poorer prognosis). Priebe et al. further discloses overexpression of transcription factor ETS1 in ABC-DLBCL versus GCB-DLBCL, that 97 ETS1-regulated genes are also predominantly expressed in ABC-DLBCL and that ETS1 contributes to the pathogenesis of this lymphoma subtype (abstract; p. 2, para. 1-2; p. 13, para. 2; the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1, ANGPTL3, YEATS4, IL16, FGD3, ATF7IP, TRIP13, CBX4 and CD37).
Pertaining to claim 6, Priebe et al. teaches two groups of diffuse large B cell lymphoma (DLBCL) patients, germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, which differ in their response to treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP (rituximab-CHOP) therapies (with ABC type having poorer prognosis). Priebe et al. further discloses overexpression of transcription factor ETS1 in ABC-DLBCL versus GCB-DLBCL, that 97 ETS1-regulated genes are also predominantly expressed in ABC-DLBCL and that ETS1 contributes to the pathogenesis of this lymphoma subtype (abstract; p. 2, para. 1-2; p. 13, para. 2; the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1 and ANGPTL3).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Priebe et al. disclosed ABC-DLCBL subtype is less responsive to CHOP and R-CHOP than the other subtype and that ETS1 regulates pathways that are fundamental for ABC-DLBCL, indicating that the gene contributes to the pathogenesis of this lymphoma subtype (p. 2, para. 1-2, p. 13, para. 2). Therefore, one of ordinary skill in the art would have been motivated to utilize ETS1 levels as a biomarker in the method of Parker et al. and Schweighofer et al. in developing biomarkers to predict the response to fimepinostat in DLBCL patients because EST1 has a fundamental role contributing to DLBCL pathogenesis in a subset of patients that are less responsive to treatment. Furthermore, one of ordinary skill in the art would predict that the EST1 protein detection taught by Priebe et al. could be readily added to the method of Parker et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to molecular mechanisms and indicators of DLBCL patient subclasses based on response to treatment. The invention is therefore prima facie obvious.
Pertaining to claim 4, the disclosed method of Schweighofer for selecting an individual having diffuse large B cell lymphoma (DLBCL) for treatment with ibrutinib, comprises: (a) determining the presence or absence of a modification in one or more biomarker genes; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of modifications in the one or more biomarker genes. Schweighofer et al. further discloses that the markers can be quantified at the nucleic acid lor protein level (para. 0004, 0220; the method of claim 3, wherein said method comprises the step of determining the activity of two or more marker proteins).
Regarding claim 5, the disclosed method of Schweighofer for selecting an individual having diffuse large B cell lymphoma (DLBCL) for treatment with ibrutinib, comprises: (a) determining the presence or absence of a modification in one or more biomarker genes; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of modifications in the one or more biomarker genes. Schweighofer et al. further discloses that the markers can be quantified at the nucleic acid lor protein level, and discloses several embodiments wherein 3 or more biomarkers can be used together (para. 0004, 0220; the method of claim 4, wherein said method comprises the step of determining the activity of three or more marker proteins).
10. Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over of Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), as applied to claims 1-2 and 10 above, and further in view of Priebe et al. (Cancers, 2020, Vol. 12, p. 1-17; 8 March 2024 IDS) as applied to claims 3-6 above, and further in view of Trotter et al. (US201900040333A1; 8 March 2024 IDS) and Ferretti et al. (Oncoimmuniology, 2018, Vol. 7, p. 1-11). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-2 and 10 are taught by Parker et al. and Schweighofer et al. above.
The limitations of claims 3-6 are taught by Parker et al., Schweighofer et al. and Priebe et al. above.
Regarding claim 7, as indicated above, Parker et al., Schweighofer et al. and Priebe et al. teach using ETS1 as a biomarker to predict responsiveness of DLBCL patients to fimepinostat and to using multiple biomarkers together. The method of claim 6, wherein said method comprises the step of determining the activity of ETS1 and others.
Regarding claim 7, Parker et al., Schweighofer et al. and Priebe et al. are silent to: The method of claim 6, wherein said method comprises the step of determining the activity of PBXIP1. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Trotter et al.
Regarding claim 7, Trotter et al. teaches a method for determining drug efficacy for the treatment of diffuse large b-cell lymphoma (DLBCL) by using protein biomarkers for predicting clinical sensitivity and therapeutic response to certain compounds. Trotter et al. further discloses that these biomarkers include PBXIP1 and activity of biomarkers can be differential activity between two different classes of DLBCL (i.e. GCB and ABC subclasses) (abstract; para. 0364; para. 0150, Fig. 7A-C; the method of claim 6, wherein said method comprises the step of determining the activity of PBXIP1).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Trotter et al. discloses that there exists a significant need for safe and effective methods of treating, preventing and managing cancer, particularly for cancers that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies. Trotter et al. further discloses that their method satisfies these and other needs (para. 0038). Therefore, one of ordinary skill in the art would have been motivated to utilize PBXIP1 levels as a biomarker for response to treatment in DLBCL patients taught by Trotter et al. in the method of Parker et al. and Schweighofer et al. and Priebe et al. for developing biomarkers to predict the response to fimepinostat in DLBCL patients to improve safety and effectiveness in treating DLBCL patients. Furthermore, one of ordinary skill in the art would predict that the PBXIP1 biomarker taught by Trotter et al. could be readily added to the method of Parker et al., Schweighofer et al. and Priebe et al. with a reasonable expectation of success because they both pertain to molecular indicators of predicting DLBCL response to treatment. The invention is therefore prima facie obvious.
Regarding claim 7, Parker et al., Schweighofer et al., Priebe et al. and Trotter et al. are silent to: the method of claim 6, wherein said method comprises the step of determining the activity of ANGPTL3). However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Ferretti et al.
Regarding claim 7, Ferretti et al. teaches investigating the tumor microenvironment of diffuse large B-cell Lymphoma (DLBCL) patients with a focus on IL-25, which was expressed in the tumors. Ferretti et al. teaches that treating with hrIL-25, in DLBCL lymphoma cells increases angiogenesis. Ferretti et al. further disclose characterizing the activity of IL-25 in in vivo mouse models of B-cell non-Hodgkin lymphoma and disclosed that IL-25 exerts anti-tumor activity by dampening expression of pro-angiogentic molecules as VEGF-C, CXCL6 and ANGPT3 (a.k.a ANGPTL3) (abstract; p. 2, col. 1, para. 2; p. 6, col. 1, para. 3 – col. 2, para. 1; p. 3, col. 1, para. 4 – col. 2, para. 5; Fig. 1; Fig. 2; Fig. 4b,c; Table 1; the method of claim 6, wherein said method comprises the step of determining the activity of PBXIP1, ETS1 and ANGPTL3).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Ferretti et al. discloses that IL-25 has intrinsic pro-angiogentic activity in DLBCL and that IL-25 also inhibits neoangiogenesis in two different xenograft models of B-cell non-Hodgkin lymphoma through regulating the levels ANGPTL3, which were observed to change by 5-fold in the presence versus absence of added hrIL-25 (p. 6, col. 1, para. 4; Fig. 4b). Therefore, one of ordinary skill in the art would have been motivated to utilize differential ANGPTL3 levels taught by Ferretti et al. in the method of Parker et al., Schweighofer et al., Priebe et al. and Trotter et al. for developing biomarkers to predict the response to fimepinostat in DLBCL patients because there is evidence of regulation of the levels of ANGPTL3 by IL-25 and mechanistic connection to the level of angiogenesis in DLBCL. Furthermore, one of ordinary skill in the art would predict that differential ANGPTL3 levels taught by Ferretti et al. could be readily added to the method of Parker et al., Schweighofer et al., Priebe et al. and Trotter et al. with a reasonable expectation of success because they both pertain to molecular mechanisms of DLBCL and the detection of varying levels of indicator proteins. The invention is therefore prima facie obvious.
11. Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), as applied to claims 1-2 and 10 above, and further in view of Califano et al. (WO2020198606A1; 8 March 2024 IDS) as evidenced by Califano et al. 2017 (WO2017040311A1 (incorporated into Califano et al. by reference)). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-2 and 10 are taught by Parker et al. and Schweighofer et al. above.
Regarding claim 8, Parker et al. and Schweighofer et al. are silent to: the method of claim 1, wherein the protein activity is determined using the VIPER algorithm. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Califano et al.
Regarding claim 8, Califano et al. disclose a method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject and using the activity values to determine a classification of the subject as a responder or non-responder to a therapy by a compound. Califano et al. further disclose that to identify a biomarker predictive response in MM patients treated with Selinexor, the VIPER algorithm was used to transform gene expression profiles from tumor samples into accurate predictions of protein activity for 6,000 regulatory proteins (abstract; para. 0016; the method of claim 1, wherein the protein activity is determined using the VIPER algorithm).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Califano et al. discloses that VIPER provides protein activity values in terms of normalized enrichment scores, which express activity for all the regulatory proteins in the same scale (para. 0028) enabling utilizing polygenic, multi-protein biomarkers. In addition, as evidenced by Califano et al., 2017, drug sensitivity represents a multifactorial, polygenic (i.e., complex) phenotype, highlighting the need for novel approaches that complement and extend the ‘actionable alteration paradigm’, which is based on single-gene mutations that are poor overall predictors of sensitivity to inhibitors of the corresponding protein (p. 1, line 16 – p. 2, line 4). Therefore, one of ordinary skill in the art would have been motivated to utilization of generation of protein activities using VIPER taught by Califano et al. in the method of Parker et al. and Schweighofer et al. for developing biomarkers to predict the response to fimepinostat in DLBCL patients to improve development of polygenic biomarkers. Furthermore, one of ordinary skill in the art would predict that calculating protein activities using VIPER taught by Califano et al. could be readily added to the method of Parker et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to identifying biomarkers for predicting response to treatment for patients with hematological malignancies. The invention is therefore prima facie obvious.
12. Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), and further in view of Garces (J. Med. Chem, 2019, Vol. 62, p. 4815-4850) The italicized text corresponds to the instant claim limitations.
Parker et al. and Schweighofer et al. teach the limitations of claim 10 above.
Regarding claim 13, Parker et al. and Schweighofer et al. are silent to: the method of claim 10, wherein the fimepinostat is administered as the methanesulfonate salt or the benzenesulfonate salt. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Garces et al.
Pertaining to claim 13, Garces et al. teaches design strategies for phosphatidylinositol 3-kinase (PI3K) inhibitors, a class of medicinally relevant inhibitors of PI3K that are small molecule ATP-competitive inhibitors including fimepinostat (CUDC-907). Garces et al. further teaches synthesizing and testing various PI3K inhibitors and that many compounds suffered solubility issues, but in one case the methanesulfonate salt showed suitable solubility to be progressed in vivo, and this form of the drug effectively slowed tumor growth in a mouse model of glioblastoma (abstract; Table 1; p. 4815, col. 2; p. 4827, col. 2, para. 2; the method of claim 10, wherein the fimepinostat is administered as the methanesulfonate salt or the benzenesulfonate salt).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Garces et al. teaches that the methanesulfonate salt of a PI3K inhibitor compound had better solubility than the non-salt version and had efficacy slowing tumor growth in a mouse model of human glioblastoma (p. 4827, col. 2, para. 2). Therefore, one of ordinary skill in the art would have been motivated to utilize the methanesulfonate salt form of fimepinostat in the method to use biomarkers to select and treat subsets of DLBCL patients with fimepinostat taught by Parker et al. Schweighofer et al. in order to improve the solubility of fimepinostat while retaining anti-tumor activity. Furthermore, one of ordinary skill in the art would predict that the salt form of fimepinostat et al. taught by Garces et al. could be readily added to the method of Parker et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to using PI3K inhibitors to treat cancer. The invention is therefore prima facie obvious.
13. Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS) and Trotter et al. (US20190004033A1; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
Regarding claim 11, Parker et al. and Schweighofer et al. teach the limitation: wherein the subject is classified as a fimepinostat responder by the method of any one of claim 1 as described below:
Regarding claim 1, Parker et al. discloses a method of identifying correlations of pretreatment MYC gene signature variations with clinical response to fimepinostat in patients with diffuse large B-cell lymphoma (DLBCL) to identify differences in transcript-level signatures of gene networks in pre-treatment tumor samples associated with future clinical response to fimepinostat. Parker et al. further discloses that Gene Set Enrichment Analysis (GSEA; Subramanian et al., 2005) was used to study changes in transcript expression patterns that correlate with responder (complete/partial response) or non-responder (progressive disease) patient populations. Parker et al. discloses identifying >1500 genes (with FDR <= 0.05) and normalized enrichment scores > 1.3 that were upregulated in the fimepinostat responder population versus a non-responder population. (p. 1, para. 1- p. 2, para. 1; a method of classifying a subject suffering from diffuse large B cell lymphoma as a fimepinostat responder or a fimepinostat non-responder, comprising the step of determining the activity of one or more markers in a tumor sample from the subject, wherein increased or decreased activity of the one or more markers compared to baseline classifies the subject as a fimepinostat responder and an absence of increased or decreased activity of the one or more marker proteins compared to baseline classifies the subject as a fimepinostat non-responder.
Regarding claim 1, Parker et al. is silent to the method wherein the marker is a marker protein. However, this limitations were known in the art at the time of the effective filing date of the invention as taught by Schweighofer et al.
Regarding claim 1, Schweighofer et al. discloses a method of developing and using biomarkers for stratifying patients with DLBCL into groups based on predicted response to treatment. Schweighofer et al. further discloses that determining the presence, modifications, or expression of the biomarker of interest can be at the protein or nucleotide level and are accomplished using any detection method known to those of skill in the art. Schweighofer et al. further discloses generating biomarkers for selecting treatment to DLBCL in steps including: 1) measuring differential expression between DLBCL patient groups, and 2) using rank-based statistics to determine significance, and 3) further using Kaplan-Meier survival curves of progression-free survival for patients between the two groups (for example low and high BCL-2 gene expression) to validate/confirm biomarkers (abstract; para. 0529, 0111; fig. 1; wherein the marker is a marker protein.
Pertaining to claim 11, Schweighofer et al. discloses methods of selecting an individual having a hematological malignancy such as diffuse large B cell lymphoma (DLBCL) for treatment with a TEC inhibitor such as an ITK inhibitor or a BTK inhibitor (e.g. ibrutinib) based on the presence or absence of a one or more biomarkers. Schweighofer et al. further discloses that an individual is administered a therapeutically effective amount of a treatment (TEC inhibitor) if there is an increase in expression level in at least one biomarker gene selected from a list relative to a control. Schweighofer et al. further discloses that the administered treatment can be a pharmaceutically acceptable salt. Schweighofer et al. further discloses that a test for differential expression can classify DLBCL patients as responders or non-responders to Ibrutinib (para. 0191-0193; 0290; 0506; a method of treating diffuse large B-cell lymphoma in a subject in need thereof, comprising: (a) classifying the subject as a fimepinostat responder or a fimepinostat non-responder by the method of claim 1; and (b) (i) if the subject is classified as a fimepinostat responder, administering to the subject a therapeutically effective amount of fimepinostat or a pharmaceutically acceptable salt thereof).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Schweighofer et al. disclosed that unique mutation patterns underlie DLBCL subtypes which highlights the need for personalized medicine approaches to treating these patients (para. 0534). Schweighofer et al. further discloses that their method includes administering a specific therapeutically effective treatment to a DLBCL patient if there is an increase in expression level in at least one biomarker gene selected from their list relative to a control (para. 0198). Therefore, one of ordinary skill in the art would have been motivated to utilize the method of classifying patients into groups using protein markers and personalizing treatment to DLBCL based on these markers taught by Schweighofer et al. in the method to identify gene biomarkers that are differentially expressed in DLBCL tumors from fimepinostat responders versus non-responders taught by Parker et al. in order to apply personalized/targeted medicine for patients with DLBCL. Furthermore, one of ordinary skill in the art would predict that the biomarker development approach taught by Schweighofer et al. could be readily added to the method of Parker et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for treatment selection. The invention is therefore prima facie obvious.
Regarding claim 11, Parker et al. and Schweighofer et al. are silent to: (ii) if the subject is classified as a fimepinostat non-responder, administering to the subject a therapeutically effective amount of a therapy for diffuse large B-cell lymphoma which is not fimepinostat or a pharmaceutically acceptable salt thereof). However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Trotter et al.
Regarding claim 11, Trotter et al. teaches a method for determining drug efficacy for the treatment of diffuse large B-cell lymphoma (DLBCL) by using analysis of protein biomarkers for predicting clinical sensitivity and therapeutic response to certain compounds. Trotter et al. further discloses that the method of treating a cancer comprises determining whether a compound is immunomodulatory and administering to the subject a therapeutically effective amount of a therapy other than the compound when the compound is indicated as unlikely to be efficacious as an immunomodulatory compound (abstract; para. 0057; (ii) if the subject is classified as a fimepinostat non-responder, administering to the subject a therapeutically effective amount of a therapy for diffuse large B-cell lymphoma which is not fimepinostat or a pharmaceutically acceptable salt thereof).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Trotter et al. discloses that there exists a significant need for safe and effective methods of treating, preventing and managing cancer, particularly for cancers that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies. Trotter et al. further discloses that the present invention satisfies these and other needs (para. 0038). Therefore, one of ordinary skill in the art would have been motivated to utilize the approach to treat with another drug when the drug analyzed is not indicated by the biomarker analysis in the method to determine patient-specific drug efficacy taught by Parker et al. and Schweighofer et al. in order to develop safe and effective treatment methods for cancer. Furthermore, one of ordinary skill in the art would predict that the treatment approach taught by Trotter et al. could be readily added to the method of Parker et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for treatment selection. The invention is therefore prima facie obvious.
14. Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS) in view of Parker et al. (meeting abstract: 2020 ASCO annual meeting; J Clin Oncol Vol. 38, p. 1-3). The italicized text corresponds to the instant claim limitations.
Pertaining to claim 12, Schweighofer et al. discloses a method for selecting an individual having diffuse large B cell lymphoma (DLBCL) for treatment with ibrutinib, comprising: (a) determining the presence or absence of a modification in one or more biomarker genes selected from EP300, MLL2, BCL-2, RB1, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARD11; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of modifications in the one or more biomarker genes selected from EP300, MLL2, BCL-2, RB1, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARD11 (para. 0004; a method of treating DLBCL in a subject in need thereof, comprising the steps of (a) receiving information identifying the subject as a responder; and (b) administering to the subject a therapeutically effective amount of [drug] or a pharmaceutically acceptable salt thereof).
Regarding claim 12, Schweighofer et al. is silent to wherein the subject is a fimepinostat responder, and the drug is an amount of fimepinostat. However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Parker et al.
Pertaining to claim 12, Parker et al. discloses identifying differences in transcript-level signatures of gene networks in pre-treatment tumor samples associated with future clinical response to fimepinostat. Parker et al. further discloses RNA libraries were created and sequenced on the Illumina HiSeq platform. Gene Set Enrichment Analysis was used to study changes in transcript expression patterns that correlate with responder (complete/partial response) or non-responder (progressive disease) pt populations (p. 1, para. 1; wherein the subject is a fimepinostat responder, and the drug is an amount of fimepinostat.
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Parker et al. disclosed that
Fimepinostat, a small molecule dual inhibitor of PI3K α, β, and δ isoforms and Class I and II histone deacetylases (HDACs), is currently under investigation for the treatment of aggressive hematological cancers (p. 1, para. 1). Therefore, one of ordinary skill in the art would have been motivated to utilize the method of detecting gene overexpression in DLBCL patients and its correlation with response to fimepinostat in the method of Parker et al. to develop biomarkers for predicting response of DLBCL to treatment with a BTK inhibitor taught by Schweighofer et al. in order to improve targeted therapeutic options for DLBCL patients with a focus on fimepinostat because fimepinostat is currently under investigation for the treatment of aggressive hematological cancers. Furthermore, one of ordinary skill in the art would predict that the MYC protein detection taught by Parker et al. could be readily added to the method of Schweighofer et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for personalized treatment selection. The invention is therefore prima facie obvious.
15. Claims 1-2 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS) in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
Pertaining to claim 1, Oki et al. discloses a motivation in determining treatments for DLBCL based on the genetic/molecular features of disease to improve efficacy of treatment with a focus on MYC because MYC overexpression confers poorer prognosis and dismal outcomes. Oki et al. discloses analyzing dose escalation and expansion of CUDC-907 (i.e. administering fimepinostat) in relapsed/refractory DLBCL in a clinical trials with DLBCL patients that are either MYC-altered or not. Oki et al. discloses identifying that response rates to CUDC-907 in relapsed/refractory DLBCL patients was better in patients with MYC-altered disease than in those without. Oki et al. further discloses classifying patients as MYC-altered or not based on MYC protein overexpression and gene translocation or amplification in lymphoma cells and that MYC overexpression was defined as MYC protein expression in >=40% of lymphoma cells by immunohistochemistry analysis (and thus if MYC protein expression was in < 40% of lymphoma cells, MYC was not considered to be altered) (p. 1924, col. 1, para. 2 - col. 2, para. 1; p. 1928, col. 2, para. 2; Table 5; p. 1925, col. 1, para. 5; A method of classifying a subject suffering from diffuse large B cell lymphoma as a fimepinostat responder or a fimepinostat non-responder, comprising the step of determining the activity of one or more protein markers in a tumor sample from the subject; and measuring increased or decreased activity of the one or more marker proteins compared to a baseline; and measuring absence of increased or decreased activity of the one or more marker proteins compared to baseline).
Pertaining to claims 1-2 and 10, Oki et al. is silent to wherein increased or decreased activity classifies the subject as a fimepinostat responder and an absence of increased or decreased activity classifies the subject as a fimepinostat non-responder (claim 1); and the method of claim 1, wherein the activities of the one or more marker proteins are provided to a trained classifier, the trained classifier being trained to differentiate between fimepinostat responders and fimepinostat non-responders; and obtaining from the classifier the classification of the subject as a fimepinostat responder or a fimepinostat non- responder) (claim 2); and wherein the subject is classified as a fimepinostat responder by the method of any one of claim 1 (claim 10). However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Schweighofer et al.
Regarding claim 1, Schweighofer et al. discloses a method of developing and using biomarkers for stratifying patients with diffuse large B cell lymphoma (DLBCL) into groups based on predicted response to treatment. Schweighofer et al. further discloses that determining the presence, modifications, or expression of the biomarker of interest can be at the protein or nucleotide level and are accomplished using any detection method known to those of skill in the art. Schweighofer et al. further discloses generating biomarkers for selecting treatment to DLBCL in steps including: 1) measuring differential expression between DLBCL patient groups, and 2) using rank-based statistics to determine significance, and 3) further using Kaplan-Meier survival curves of progression-free survival for patients between the two groups to validate/confirm biomarkers. Schweighofer et al. further discloses developing a test (i.e. a classification algorithm) for differential expression of genes between DLBCL responders and non-responders to Ibrutinib and using the test to classify subtypes of DLBCL (abstract; para. 0523; 0529, 0111; fig. 1; wherein increased or decreased activity classifies the subject as a [drug] responder and an absence of increased or decreased activity classifies the subject as a [drug] non-responder).
Regarding claim 2, Oki et al. and Schweighofer et al. teach a method of classifying a patient with DLBCL as a fimepinostat responder or non-responder above. Schweighofer et al. further teaches using trained machine learning classifiers for classifying DLBCL patients as responders or non-responders to drugs. In one example, to train a classifier, they first performed DLBCL subtype classification using differential gene expression profiles between drug-responsive and non-responsive patient groups, then developed a model to discriminate the two groups using a linear discriminate analysis (LDA) model/classifier and neural networks with 5-fold cross validation procedure for model selection, and finally selected the best performing model for final classification. In this example, gene expression values are used as features, but Schweighofer et al. discloses that biomarker expression can be measured either at the nucleic acid or protein level (para. 0533, 0499; 0220; the method of claim 1, wherein the activities of the one or more marker proteins are provided to a trained classifier, the trained classifier being trained to differentiate between fimepinostat responders and fimepinostat non-responders; and obtaining from the classifier the classification of the subject as a fimepinostat responder or a fimepinostat non- responder).
Pertaining to claim 10, Schweighofer et al. discloses methods of selecting an individual having a hematological malignancy such as diffuse large B cell lymphoma (DLBCL) for treatment with a TEC inhibitor such as an ITK inhibitor or a BTK inhibitor (e.g. ibrutinib) based on the presence or absence of a one or more biomarkers. Schweighofer et al. further discloses that an individual is administered a therapeutically effective amount of a treatment (TEC inhibitor) if there is an increase in expression level in at least one biomarker gene selected from a list relative to a control. Schweighofer et al. further discloses that the administered treatment can be a pharmaceutically acceptable salt. Schweighofer et al. further discloses that a test for differential expression can classify DLBCL patients as responders or non-responders to Ibrutinib (para. 0191-0193; 0290; 0506; a method of treating diffuse large B-cell lymphoma in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of fimepinostat or a pharmaceutically acceptable salt thereof, wherein the subject is classified as a fimepinostat responder by the method of claim 1).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Schweighofer et al. disclosed that unique mutation patterns underlie DLBCL subtypes which highlights the need for personalized medicine approaches to treating these patients (para. 0534). Therefore, one of ordinary skill in the art would have been motivated to utilize the comparing levels of multiple protein biomarkers versus control for classifying DLBCL patients based on treatment taught by Schweighofer et al. in the method to identify MYC as a protein marker of differential abundance between fimepinostat responders or non-responders taught by Oki et al. in order to develop personalized medicine for patients with DLBCL because it is a heterogeneous disease. Furthermore, one of ordinary skill in the art would predict that the biomarker development approach taught by Schweighofer et al. could be readily added to the method of Oki et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for treatment selection. The invention is therefore prima facie obvious.
Regarding claim 9, Oki et al. disclose that at the time of their study, CUDC-907 (fimepinostat) was a first-in-class drug that targets both HDAC and PI3K and that in their study, it was administered to patients with and without MYC alterations. Oki et al discloses all previous treatments of patients enrolled in the study and although two patients (5%) were previously treated with a drug inhibiting HDAC or PI3K, none were previously treated with a drug that was an HDAC and PI3K inhibitor. Therefore, none of the patients in the study disclosed by Oki et al. were previously treated with fimepinostat before the study (Oki et al., Table 1; p. 1924, col. 1, para. 6; the method claim 1, wherein the subject is naive to therapy with fimepinostat).
16. Claims 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS) in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), as applied to claims 1, 2 and 9 above, and further in view of Priebe et al. (Cancers, 2020, Vol. 12, p. 1-17; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-2 and 9-10 were taught by Oki et al. and Schweighofer et al. above.
Pertaining to claims 3 and 6, Oki et al. and Schweighofer et al. are silent to: the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1, ANGPTL3, YEATS4, IL16, FGD3, ATF7IP, TRIP13, CBX4 and CD37 (claim 3) and the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1 and ANGPTL3 (claim 6). However, these limitations were known in the art at the time of the effective filing date of the invention as taught by Priebe et al.
Pertaining to claim 3, Priebe et al. teaches two groups of diffuse large B cell lymphoma (DLBCL) patients, germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, which differ in their response to treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP (rituximab-CHOP) therapies (with ABC type having poorer prognosis). Priebe et al. further discloses overexpression of transcription factor ETS1 in ABC-DLBCL versus GCB-DLBCL, that 97 ETS1-regulated genes are also predominantly expressed in ABC-DLBCL and that ETS1 contributes to the pathogenesis of this lymphoma subtype (abstract; p. 2, para. 1-2; p. 13, para. 2; the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1, ANGPTL3, YEATS4, IL16, FGD3, ATF7IP, TRIP13, CBX4 and CD37).
Pertaining to claim 6, Priebe et al. teaches two groups of diffuse large B cell lymphoma (DLBCL) patients, germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, which differ in their response to treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP (rituximab-CHOP) therapies (with ABC type having poorer prognosis). Priebe et al. further discloses overexpression of transcription factor ETS1 in ABC-DLBCL versus GCB-DLBCL, that 97 ETS1-regulated genes are also predominantly expressed in ABC-DLBCL and that ETS1 contributes to the pathogenesis of this lymphoma subtype (abstract; p. 2, para. 1-2; p. 13, para. 2; the method of claim 1, wherein the one or more marker proteins are selected from the group consisting of PBXIP1, ETS1 and ANGPTL3).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Priebe et al. disclosed ABC-DLCBL subtype is less responsive to CHOP and R-CHOP than the other subtype and that ETS1 regulates pathways that are fundamental for ABC-DLBCL, indicating that the gene contributes to the pathogenesis of this lymphoma subtype (p. 2, para. 1-2, p. 13, para. 2). Therefore, one of ordinary skill in the art would have been motivated to utilize ETS1 levels as a biomarker taught by Priebe et al. in the method of Oki et al. and Schweighofer et al. in developing biomarkers to predict the response to fimepinostat in DLBCL patients because EST1 has a fundamental role contributing to DLBCL pathogenesis in a subset of patients that are less responsive to treatment. Furthermore, one of ordinary skill in the art would predict that the EST1 protein detection taught by Priebe et al. could be readily added to the method of Oki et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to molecular mechanisms and indicators of DLBCL patient subclasses based on response to treatment. The invention is therefore prima facie obvious.
Pertaining to claim 4, the disclosed method of Schweighofer for selecting an individual having diffuse large B cell lymphoma (DLBCL) for treatment with ibrutinib, comprises: (a) determining the presence or absence of a modification in one or more biomarker genes; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of modifications in the one or more biomarker genes. Schweighofer et al. further discloses that the markers can be quantified at the nucleic acid lor protein level (para. 0004, 0220; the method of claim 3, wherein said method comprises the step of determining the activity of two or more marker proteins).
Regarding claim 5, the disclosed method of Schweighofer for selecting an individual having diffuse large B cell lymphoma (DLBCL) for treatment with ibrutinib, comprises: (a) determining the presence or absence of a modification in one or more biomarker genes; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of modifications in the one or more biomarker genes. Schweighofer et al. further discloses that the markers can be quantified at the nucleic acid lor protein level, and discloses several embodiments wherein 3 or more biomarkers can be used together (para. 0004, 0220; the method of claim 4, wherein said method comprises the step of determining the activity of three or more marker proteins).
17. Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS) in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), as applied to claims 1, 2 and 9 above, and further in view of Priebe et al. (Cancers, 2020, Vol. 12, p. 1-17; 8 March 2024 IDS) as applied to claims 3-6 above, and further in view of Trotter et al. (US201900040333A1; 8 March 2024 IDS) and Ferretti et al. (Oncoimmuniology, 2018, Vol. 7, p. 1-11). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-2 and 9-10 are taught by Oki et al. and Schweighofer et al. above.
The limitations of claims 3-6 are taught by Oki et al., Schweighofer et al. and Priebe et al. above.
Regarding claim 7, as indicated above, Oki et al., Schweighofer et al. and Priebe et al. teach using ETS1 as a biomarker to predict responsiveness of DLBCL patients to fimepinostat and to using multiple biomarkers together, which teaches the limitation: the method of claim 6, wherein said method comprises the step of determining the activity of ETS1 and others. Oki et al., Schweighofer et al. and Priebe et al. are silent to: The method of claim 6, wherein said method comprises the step of determining the activity of PBXIP1. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Trotter et al.
Regarding claim 7, Trotter et al. teaches a method for determining drug efficacy for the treatment of diffuse large b-cell lymphoma (DLBCL) by using protein biomarkers for predicting clinical sensitivity and therapeutic response to certain compounds. Trotter et al. further discloses that these biomarkers include PBXIP1 and activity of biomarkers can be differential activity between two different classes of DLBCL (i.e. GCB and ABC subclasses) (abstract; para. 0364; para. 0150, Fig. 7A-C; the method of claim 6, wherein said method comprises the step of determining the activity of PBXIP1).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Trotter et al. discloses that there exists a significant need for safe and effective methods of treating, preventing and managing cancer, particularly for cancers that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies. Trotter et al. further discloses that their method satisfies these and other needs (para. 0038). Therefore, one of ordinary skill in the art would have been motivated to utilize PBXIP1 levels as a biomarker for response to treatment in DLBCL patients taught by Trotter et al. in the method of Oki et al. and Schweighofer et al. and Priebe et al. for developing biomarkers to predict the response to fimepinostat in DLBCL patients to improve safety and effectiveness in treating DLBCL patients. Furthermore, one of ordinary skill in the art would predict that the PBXIP1 biomarker taught by Trotter et al. could be readily added to the method of Oki et al., Schweighofer et al. and Priebe et al. with a reasonable expectation of success because they both pertain to molecular indicators of predicting DLBCL response to treatment. The invention is therefore prima facie obvious.
Regarding claim 7, Oki et al., Schweighofer et al., Priebe et al. and Trotter et al. are silent to: the method of claim 6, wherein said method comprises the step of determining the activity of ANGPTL3). However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Ferretti et al.
Regarding claim 7, Ferretti et al. teaches investigating the tumor microenvironment of diffuse large B-cell Lymphoma (DLBCL) patients with a focus on IL-25, which was expressed in the tumors. Ferretti et al. teaches that treating with hrIL-25, in DLBCL lymphoma cells increases angiogenesis. Ferretti et al. further disclose characterizing the activity of IL-25 in in vivo mouse models of B-cell non-Hodgkin lymphoma and disclosed that IL-25 exerts anti-tumor activity by dampening expression of pro-angiogentic molecules as VEGF-C, CXCL6 and ANGPT3 (a.k.a ANGPTL3) (abstract; p. 2, col. 1, para. 2; p. 6, col. 1, para. 3 – col. 2, para. 1; p. 3, col. 1, para. 4 – col. 2, para. 5; Fig. 1; Fig. 2; Fig. 4b,c; Table 1; the method of claim 6, wherein said method comprises the step of determining the activity of PBXIP1, ETS1 and ANGPTL3).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Ferretti et al. discloses that IL-25 has intrinsic pro-angiogentic activity in DLBCL and that IL-25 also inhibits neoangiogenesis in two different xenograft models of B-cell non-Hodgkin lymphoma through regulating the levels ANGPTL3, which were observed to change by 5-fold in the presence versus absence of added hrIL-25(p. 6, col. 1, para. 4; Fig. 4b). Therefore, one of ordinary skill in the art would have been motivated to utilize differential ANGPTL3 levels taught by Ferretti et al. in the method of Oki et al. and Schweighofer et al., Priebe et al. and Trotter et al. for developing biomarkers to predict the response to fimepinostat in DLBCL patients because there is evidence of regulation of the levels of ANGPTL3 by IL-25 and mechanistic connection to the level of angiogenesis in DLBCL. Furthermore, one of ordinary skill in the art would predict that differential ANGPTL3 levels taught by Ferretti et al. could be readily added to the method of Oki et al., Schweighofer et al., Priebe et al. and Trotter et al. with a reasonable expectation of success because they both pertain to molecular mechanisms of DLBCL and the detection of varying levels of indicator proteins. The invention is therefore prima facie obvious.
18. Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS) in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), as applied to claims 1, 2 and 9 above, and further in view of Califano et al. (WO2020198606A1; 8 March 2024 IDS) as evidenced by Califano et al. 2017 (WO2017040311A1 (incorporated into Califano et al. by reference)). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-2 and 9-10 are taught by Oki et al. and Schweighofer et al. above.
Regarding claim 8, Oki et al. and Schweighofer et al. are silent to: the method of claim 1, wherein the protein activity is determined using the VIPER algorithm. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Califano et al.
Regarding claim 8, Califano et al. disclose a method of treating a patient suffering from multiple myeloma, comprising determining a plurality of protein activity values in a subject suffering from multiple myeloma (MM), each protein activity value corresponding to one of a set of proteins in the subject and using the activity values to determine a classification of the subject as a responder or non-responder to a therapy by a compound. Califano et al. further disclose that to identify a biomarker predictive response in MM patients treated with Selinexor, the VIPER algorithm was used to transform gene expression profiles from tumor samples into accurate predictions of protein activity for 6,000 regulatory proteins (abstract; para. 0016; the method of claim 1, wherein the protein activity is determined using the VIPER algorithm).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Califano et al. discloses that VIPER provides protein activity values in terms of normalized enrichment scores, which express activity for all the regulatory proteins in the same scale (para. 0028) enabling utilizing polygenic, multi-protein biomarkers. In addition, as evidenced by Califano et al., 2017, drug sensitivity represents a multifactorial, polygenic (i.e., complex) phenotype, highlighting the need for novel approaches that complement and extend the ‘actionable alteration paradigm’, which is based on single-gene mutations that are poor overall predictors of sensitivity to inhibitors of the corresponding protein (p. 1, line 16 – p. 2, line 4). Therefore, one of ordinary skill in the art would have been motivated to utilization of generation of protein activities using VIPER taught by Califano et al. in the method of Oki et al. and Schweighofer et al. for developing biomarkers to predict the response to fimepinostat in DLBCL patients to improve development of polygenic biomarkers. Furthermore, one of ordinary skill in the art would predict that calculating protein activities using VIPER taught by Califano et al. could be readily added to the method of Oki et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to identifying biomarkers for predicting response to treatment for patients with hematological malignancies. The invention is therefore prima facie obvious.
19. Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS) in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), and further in view of Garces (J. Med. Chem, 2019, Vol. 62, p. 4815-4850) The italicized text corresponds to the instant claim limitations.
Oki et al. and Schweighofer et al. teach the limitations of claims 1-2 and 9-10 above.
Regarding claim 13, Oki et al. and Schweighofer et al. are silent to: the method of claim 10, wherein the fimepinostat is administered as the methanesulfonate salt or the benzenesulfonate salt. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Garces et al.
Pertaining to claim 13, Garces et al. teaches design strategies for phosphatidylinositol 3-kinase (PI3K) inhibitors, a class of medicinally relevant inhibitors of PI3K that are small molecule ATP-competitive inhibitors including fimepinostat (CUDC-907). Garces et al. further teaches synthesizing and testing various PI3K inhibitors and that many compounds suffered solubility issues, but in one case the methanesulfonate salt showed suitable solubility to be progressed in vivo, and this form of the drug effectively slowed tumor growth in a mouse model of glioblastoma (abstract; Table 1; p. 4815, col. 2; p. 4827, col. 2, para. 2; the method of claim 10, wherein the fimepinostat is administered as the methanesulfonate salt or the benzenesulfonate salt).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Garces et al. teaches that the methanesulfonate salt of a PI3K inhibitor compound had better solubility than the non-salt version and had efficacy slowing tumor growth in a mouse model of human glioblastoma (p. 4827, col. 2, para. 2). Therefore, one of ordinary skill in the art would have been motivated to utilize the methanesulfonate salt form of fimepinostat taught by Garces et al. in the method to use biomarkers to select and treat subsets of DLBCL patients with fimepinostat taught by Oki et al. Schweighofer et al. in order to improve the solubility of fimepinostat while retaining anti-tumor activity. Furthermore, one of ordinary skill in the art would predict that the salt form of fimepinostat et al. could be readily added to the method of Oki et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to using PI3K inhibitors to treat cancer. The invention is therefore prima facie obvious.
20. Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS), in view of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS) and Trotter et al. (US20190004033A1; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
Regarding claim 11, Oki et al. and Schweighofer et al. teach the limitation: classifying the subject as a fimepinostat responder or a fimepinostat non-responder by the method of claim 1 as described below:
Pertaining to claim 1, Oki et al. discloses a motivation in determining treatments for DLBCL based on the genetic/molecular features of disease to improve efficacy of treatment with a focus on MYC because MYC overexpression confers poorer prognosis and dismal outcomes. Oki et al. discloses analyzing dose escalation and expansion of CUDC-907 (fimepinostat) in relapsed/refractory DLBCL in a clinical trials with DLBCL patients that are either MYC-altered or not. Oki et al. discloses identifying that response rates to CUDC-907 in relapsed/refractory DLBCL patients was better in patients with MYC-altered disease than in those without. Oki et al. further discloses classifying patients as MYC-altered or not based on MYC protein overexpression and gene translocation or amplification in lymphoma cells and that MYC overexpression was defined as MYC protein expression in >=40% of lymphoma cells by immunohistochemistry analysis (and thus if MYC protein expression was in < 40% of lymphoma cells, MYC was not considered to be altered) (p. 1924, col. 1, para. 2 - col. 2, para. 1; p. 1928, col. 2, para. 2; Table 5; p. 1925, col. 1, para. 5; A method of classifying a subject suffering from diffuse large B cell lymphoma as a fimepinostat responder or a fimepinostat non-responder, comprising the step of determining the activity of one or more protein markers in a tumor sample from the subject; and measuring increased or decreased activity of the one or more marker proteins compared to a baseline; and measuring absence of increased or decreased activity of the one or more marker proteins compared to baseline.
Pertaining to claim 1, Oki et al. is silent to wherein increased or decreased activity classifies the subject as a fimepinostat responder and an absence of increased or decreased activity classifies the subject as a fimepinostat non-responder. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Schweighofer et al.
Regarding claim 1, Schweighofer et al. discloses a method of developing and using biomarkers for stratifying patients with diffuse large B cell lymphoma (DLBCL) into groups based on predicted response to treatment. Schweighofer et al. further discloses that determining the presence, modifications, or expression of the biomarker of interest can be at the protein or nucleotide level and are accomplished using any detection method known to those of skill in the art. Schweighofer et al. further discloses generating biomarkers for selecting treatment to DLBCL in steps including: 1) measuring differential expression between DLBCL patient groups, and 2) using rank-based statistics to determine significance, and 3) further using Kaplan-Meier survival curves of progression-free survival for patients between the two groups to validate/confirm biomarkers. Schweighofer et al. further discloses developing a test (i.e. a classification algorithm) for differential expression of genes between DLBCL responders and non-responders to Ibrutinib and using the test to classify subtypes of DLBCL (abstract; para. 0523; 0529, 0111; Fig. 1; wherein increased or decreased activity classifies the subject as a [drug] responder and an absence of increased or decreased activity classifies the subject as a [drug] non-responder).
Pertaining to claim 11, Oki et al. is silent to: a method of treating diffuse large B-cell lymphoma in a subject in need thereof, comprising: (b) (i) if the subject is classified as a fimepinostat responder, administering to the subject a therapeutically effective amount of fimepinostat or a pharmaceutically acceptable salt thereof). However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Schweighofer et al.
Pertaining to claim 11, Schweighofer et al. discloses methods of selecting an individual having a hematological malignancy such as diffuse large B cell lymphoma (DLBCL) for treatment with a TEC inhibitor such as an ITK inhibitor or a BTK inhibitor (e.g. ibrutinib) based on the presence or absence of a one or more biomarkers. Schweighofer et al. further discloses that an individual is administered a therapeutically effective amount of a treatment (TEC inhibitor) if there is an increase in expression level in at least one biomarker gene selected from a list relative to a control. Schweighofer et al. further discloses that the administered treatment can be a pharmaceutically acceptable salt. Schweighofer et al. further discloses that a test for differential expression can classify DLBCL patients as responders or non-responders to Ibrutinib (para. 0191-0193; 0290; 0506; a method of treating diffuse large B-cell lymphoma in a subject in need thereof, comprising: (b) (i) if the subject is classified as a fimepinostat responder, administering to the subject a therapeutically effective amount of fimepinostat or a pharmaceutically acceptable salt thereof).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Schweighofer et al. disclosed that unique mutation patterns underlie DLBCL subtypes which highlights the need for personalized medicine approaches to treating these patients (para. 0534). Therefore, one of ordinary skill in the art would have been motivated to utilize the comparing levels of multiple protein biomarkers versus control for classifying DLBCL patients based on treatment taught by Schweighofer et al. in the method to identify MYC as a protein marker of differential abundance between fimepinostat responders or non-responders taught by Oki et al. in order to develop personalized medicine for patients with DLBCL because it is a heterogeneous disease. Furthermore, one of ordinary skill in the art would predict that the biomarker development approach taught by Schweighofer et al. could be readily added to the method of Oki et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for treatment selection. The invention is therefore prima facie obvious.
Regarding claim 11, Oki et al. and Schweighofer et al. are silent to: (ii) if the subject is classified as a fimepinostat non-responder, administering to the subject a therapeutically effective amount of a therapy for diffuse large B-cell lymphoma which is not fimepinostat or a pharmaceutically acceptable salt thereof). However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Trotter et al.
Regarding claim 11, Trotter et al. teaches a method for determining drug efficacy for the treatment of diffuse large B-cell lymphoma (DLBCL) by using analysis of protein biomarkers for predicting clinical sensitivity and therapeutic response to certain compounds. Trotter et al. further discloses that the method of treating a cancer comprises determining whether a compound is immunomodulatory and administering to the subject a therapeutically effective amount of a therapy other than the compound when the compound is indicated as unlikely to be efficacious as an immunomodulatory compound (abstract; para. 0057; (ii) if the subject is classified as a fimepinostat non-responder, administering to the subject a therapeutically effective amount of a therapy for diffuse large B-cell lymphoma which is not fimepinostat or a pharmaceutically acceptable salt thereof).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Trotter et al. discloses that there exists a significant need for safe and effective methods of treating, preventing and managing cancer, particularly for cancers that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies. Trotter et al. further discloses that the present invention satisfies these and other needs (para. 0038). Therefore, one of ordinary skill in the art would have been motivated to utilize the approach to treat with another drug when the drug analyzed is not indicated by the biomarker analysis taught by Trotter et al. in the method to determine patient-specific drug efficacy taught by Oki et al. and Schweighofer et al. in order to develop safe and effective treatment methods for cancer. Furthermore, one of ordinary skill in the art would predict that the treatment approach taught by Trotter et al. could be readily added to the method of Oki et al. and Schweighofer et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for treatment selection. The invention is therefore prima facie obvious.
21. Claims 12 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over of Schweighofer et al. (US20160032404A1; 8 March 2024 IDS) in view of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS). The italicized text corresponds to the instant claim limitations.
Pertaining to claim 12, Schweighofer et al. discloses a method for selecting an individual having diffuse large B cell lymphoma (DLBCL) for treatment with ibrutinib, comprising: (a) determining the presence or absence of a modification in one or more biomarker genes selected from EP300, MLL2, BCL-2, RB1, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARD11; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of modifications in the one or more biomarker genes selected from EP300, MLL2, BCL-2, RB1, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARD11 (para. 0004; a method of treating DLBCL in a subject in need thereof, comprising the steps of (a) receiving information identifying the subject as a responder; and (b) administering to the subject a therapeutically effective amount of [drug] or a pharmaceutically acceptable salt thereof).
Schweighofer et al. is silent to wherein the subject is a fimepinostat responder, and the drug is an amount of fimepinostat (claim 12); the method of claim 12, wherein the fimepinostat or pharmaceutically acceptable salt thereof is orally administered (claim 14); the method of claim 14, wherein the fimepinostat or pharmaceutically acceptable salt thereof is administered at a daily dose of 60 mg free base equivalent) (claim 15) and the method of claim 14, wherein the fimepinostat or pharmaceutically salt thereof is administered at a dose of 60 mg free base equivalent for five days, followed by no fimepinostat or pharmaceutically acceptable salt thereof for two days) (claim 16). However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Oki et al.
Pertaining to claim 12, Oki et al. discloses a motivation in determining treatments for DLBCL based on the genetic/molecular features of disease to improve efficacy of treatment with a focus on MYC because MYC overexpression confers poorer prognosis and dismal outcomes. Oki et al. discloses analyzing dose escalation and expansion of CUDC-907 (i.e. administering fimepinostat) in relapsed/refractory DLBCL in a clinical trials with DLBCL patients that are either MYC-altered or not. Oki et al. discloses identifying that response rates to CUDC-907 in relapsed/refractory DLBCL patients was better in patients with MYC-altered disease than in those without. Oki et al. further discloses classifying patients as MYC-altered or not based on MYC protein overexpression and gene translocation or amplification in lymphoma cells and that MYC overexpression was defined as MYC protein expression in >=40% of lymphoma cells by immunohistochemistry analysis (and thus if MYC protein expression was in < 40% of lymphoma cells, MYC was not considered to be altered) (p. 1924, col. 1, para. 2 - col. 2, para. 1; p. 1928, col. 2, para. 2; Table 5; p. 1925, col. 1, para. 5; wherein the subject is a fimepinostat responder, and the drug is an amount of fimepinostat.
Pertaining to claim 14, Oki et al. discloses that in their study to identify effects of MYC overexpression on response to fimepinostat, patients received CUDC-907 capsules (Pharmatek Laboratories Inc., San Diego, CA, USA) orally, within 30 minutes of a meal, in 21-day cycles until disease progression or other criteria for treatment discontinuation were met. (p. 1925, col. 1, para. 2; the method of claim 12, wherein the fimepinostat or pharmaceutically acceptable salt thereof is orally administered).
Pertaining to claim 15, Oki et al. disclose that in treating relapsed/refactory DLBCL patients with CUDC-907 (fimepinostat), in dose expansion, the CUDC-907 recommended phase II dose (RP2D) of 60 mg for 5 days on/2 days off (5/2) was used as a monotherapy (p. 1924, col. 2, para. 2; The method of claim 14, wherein the fimepinostat or pharmaceutically acceptable salt thereof is administered at a daily dose of 60 mg free base equivalent).
Pertaining to claim 16, Oki et al. disclose that in treating relapsed/refactory DLBCL patients with CUDC-907 (fimepinostat), in dose expansion, the CUDC-907 recommended phase II dose (RP2D) of 60 mg for 5 days on/2 days off (5/2) was used as a monotherapy (p. 1924, col. 2, para. 2; the method of claim 14, wherein the fimepinostat or pharmaceutically salt thereof is administered at a dose of 60 mg free base equivalent for five days, followed by no fimepinostat or pharmaceutically acceptable salt thereof for two days).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Oki et al. disclosed that given the heterogeneity of DLBCL and the need for new therapeutic options, there is increasing interest in
determining treatments based on the genetic/molecular features of the disease. Oki et al. further disclose the importance of high MYC protein overexpression in a subset of DLBCL patients, suggesting it is a defining feature of DLBCL (p. 1924, col. 1, para. 2-3). Therefore, one of ordinary skill in the art would have been motivated to utilize the method of detecting MYC protein overexpression in DLBCL patients and its correlation with response to fimepinostat taught by Oki et al. in the method to develop biomarkers for predicting response of DLBCL to treatment with a BTK inhibitor taught by Schweighofer et al. in order to improve targeted therapeutic options for DLBCL patients with a focus on MYC, which has emerged as a defining feature of DLBCL. Furthermore, one of ordinary skill in the art would predict that the MYC protein detection taught by Oki et al. could be readily added to the method of Schweighofer et al. with a reasonable expectation of success because they both pertain to DLBCL patient stratification for personalized treatment selection. The invention is therefore prima facie obvious.
22. Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Schweighofer et al. (US20160032404A1; 8 March 2024 IDS), in view of Oki et al. (Non-Hodgkin lymphoma, 2017, Vol. 102, p. 1923-1930; 8 March 2024 IDS), as applied to claims 12 and 14-16 above, and further in view of Garces (J. Med. Chem, 2019, Vol. 62, p. 4815-4850). The italicized text corresponds to the instant claim limitations.
The limitations of claims 12 and 14-16 were taught by Schweighofer et al. and Oki et al.
Regarding claim 17, Oki et al. and Schweighofer et al. are silent to: the method of claim 15, wherein the fimepinostat is administered as the methanesulfonate salt. However, this limitation was known in the art at the time of the effective filing date of the invention as taught by Garces et al.
Pertaining to claim 17, Garces et al. teaches design strategies for phosphatidylinositol 3-kinase (PI3K) inhibitors, a class of medicinally relevant inhibitors of PI3K that are small molecule ATP-competitive inhibitors including fimepinostat (CUDC-907). Garces et al. further teaches synthesizing and testing various PI3K inhibitors and that many compounds suffered solubility issues, but in one case the methanesulfonate salt showed suitable solubility to be progressed in vivo, and this form of the drug effectively slowed tumor growth in a mouse model of glioblastoma (abstract; Table 1; p. 4815, col. 2; p. 4827, col. 2, para. 2; the method of claim 15, wherein the fimepinostat is administered as the methanesulfonate salt).
An invention would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Garces et al. teaches that the methanesulfonate salt of a PI3K inhibitor compound had better solubility than the non-salt version and had efficacy slowing tumor growth in a mouse model of human glioblastoma (p. 4827, col. 2, para. 2). Therefore, one of ordinary skill in the art would have been motivated to utilize the methanesulfonate salt form of fimepinostat taught by Garces et al. in the method to use biomarkers to select and treat subsets of DLBCL patients with fimepinostat taught by Schweighofer et al. and Oki et al. in order to improve the solubility of fimepinostat while retaining anti-tumor activity. Furthermore, one of ordinary skill in the art would predict that the salt form of fimepinostat et al. could be readily added to the method of Schweighofer et al. and Oki et al. with a reasonable expectation of success because they both pertain to using PI3K inhibitors to treat cancer. The invention is therefore prima facie obvious.
Conclusion
23. No claims are allowed.
Claims 10-11 and 13 were examined for patent eligibility under U.S.C. 101 and were found to be patent eligible at Step 2A, prong 1 because although they recite ‘determining the activity of one or more marker proteins’, which is a judicial exception that fall into the ‘abstract idea’ category, the abstract idea is integrated into the practical application of administering to a subject with non-baseline activity, the treatment of fimepinostat for large B-cell lymphoma.
Claims 12 and 14-17 were examined for patent eligibility under U.S.C. 101 and were found to be patent eligible at Step 2A, prong 1 because they do not contain any judicial exceptions.
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/J.J.S./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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