DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1, 5, 9, 27, and 45 are amended.
Claims 3-4, 38-39, 44, and 46 are cancelled.
Claims 1-2, 5-9, 12, 27, 40-43, and 45 are pending and are examined on the merits.
Objections Withdrawn
All objections to the claims with regard to drawings and specification are withdrawn in view of Applicant’s amendments.
Rejections Withdrawn
Claims 3-4, 38-39, 44, and 46 are cancelled, rendering all previous rejections moot.
Rejection of claims 1-2, 5-9, 12, 27, and 40-43 under 35 U.S.C. §101 are withdrawn with Applicant amendment of the claims.
Rejection of claim 27 under 35 U.S.C. §103 are withdrawn with Applicant amendment of claims necessitating new rejections.
Claim Interpretation
In the response on 7/2/2026 Applicant did not contest to the interpretation of instant claim 12 to invoke 35 U.S.C. §112(f) as a means plus function limitation. Therefore, the interpretation of instant claim 12 under 35 U.S.C. §112(f) as set forth in the previous office action is maintained.
Rejections Maintained
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.
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.
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.
Claims 1-2, 9, 12, 40-42, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Shaughnessy et al (US Patent No. 9,650,677 B2, hereinafter Shaughnessy) and further in view of Schäfer et al (Differentiation, 1996, 60:99-108, hereinafter Schäfer), Moreau et al (Blood, 2011, 118(22):5752-5758; hereinafter Moreau).
Regarding instant claims 1-2, 9, 12, 40-42, and 45, Shaughnessy teaches a method of determining the prognosis of a multiple myeloma patient, comprising obtaining malignant plasma cells from the bone marrow (page 29, lines 46-49) that comprise plasma cells with and without t(4;14) translocation from the patient (page 30, section 11, lines 11-28), determining the gene expression of desmoglein 2 (DSG2), comparing the expression level of DSG2 with the gene expression level of a control individual wherein overexpression of DSG2 indicates that the patient would have poor prognosis (claim 6; page 25, section 1, lines 35-39; page 27, section 6, lines 9-58), and treating an individual having high-risk multiple myeloma comprising high dose chemotherapy comprising bortezomib (proteasome inhibitor), thalidomide (immunomodulatory drug), or a combination thereof (claim 3). Shaughnessy also teaches that the microarrays were processed using a computer processor means to determine gene expression levels of genes, e.g. DSG2 (page 29, section 10, lines 18-50). Shaughnessy further teaches that the level of DSG2 along with other genes were also measured at the RNA level (claim 7; page 26, section 4, lines 4-9). Finally, Shaughnessy teaches determining the level of gene expression using CD138-enriched plasma cells isolated from patients (page 29, section 9, lines 46-49).
Shaughnessy, however, does not teach the localization of DSG2 in the cell. Additionally, Shaughnessy does not explicitly teach using an antibody to determine the level of expression of DSG2. Furthermore, Shaughnessy does not teach that a corticosteroid is used in combination with a proteasome inhibitor and/or an immunomodulatory drug when treating myeloma in patients with poor or intermediate prognosis myeloma.
The deficiency is resolved by Schäfer et al and Moreau et al.
Schäfer teaches that DSG2 is a transmembrane glycoprotein and is the only Dsg isoform that is found in diverse kinds of tissues, tumors, and cultured cell lines (page 99, abstract). Schäfer further teaches using an antibody specific for the Dsg2 isoform wherein the antibody binds to the cell surface-exposed desmoglein, allowing visualization of distinguished DSG2 expression in vitro as well as in immunohistochemistry of tissues and assessing the expression of non-desmosome-bound Dsg2 in epithelial cells, including diffusely growing or suspended tumor cells found in bone marrow (page 104, right column, paragraph 3- page 105, left column, paragraph 1).
Moreau teaches a clinical study wherein: 1) the patients were categorized according to cytogenetic risk (chromosomal abnormalities) and the international staging system (page 5755, Table 1), and 2) the treatments comprised of either VD (bortezomib plus dexamethasone) or vtD (bortezomib and thalidomide plus dexamethasone) (page 5753, abstract; page 5753, right column, Study design). Moreau discloses that the impact of both genetic risk and clinical risk (based on the international staging system), overall, did not significantly change the ability to achieve a deep response to the VD or vtD induction therapy (page 5756, Table 3), both high- and standard-risk patients ultimately experienced similar long-term outcomes under the treatment protocols (page 5757, Figure 2), and the vtD arm compared to the VD arm showed a superior induction regimen, suggesting that vtD can be considered as a new effective triplet combination to treat patients with multiple myeloma (page 5757, left column, paragraph 2).
Regarding instant claims 1-2, 9, 12, 40-41, and 45, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) obtaining malignant plasma cells, wherein the plasma cells are CD138+, from the bone marrow that comprise plasma cells with and without t(4;14) translocation from the patient, 2) determining the gene expression of desmoglein 2 (DSG2) and other genes using microarray analysis that are processed using a computer processor means, and 3) comparing the expression level of DSG2 with the gene expression level of a control individual wherein overexpression of DSG2 indicates that the patient would have poor prognosis, as taught by Shaughnessy, and modify the method to comprise a treatment step wherein subjects determined to have DSG2-high plasma cells are treated with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells are treated with treatments for intermediate genetic risk myeloma, wherein the treatment comprises administration to a subject a proteasome inhibitor (bortezomib), an immunomodulatory drug (thalidomide), and a corticosteroid (dexamethasone), e.g. the vtD treatment, as taught by Moreau. This is obvious, because Shaughnessy teaches a method of determining the prognosis of a multiple myeloma patient wherein the method comprises: 1) obtaining malignant plasma cells, wherein the plasma cells are CD138+, from the bone marrow that comprise plasma cells with and without t(4;14) translocation from the patient, 2) determining the gene expression of DSG2 using microarray analysis that are processed using a computer processor means, and 3) comparing the expression level of DSG2 with the gene expression level of a control individual wherein the increased level of DSG2 indicates poor prognosis for the patient, and Moreau teaches a clinical study wherein patients who were categorized by cytogenic and clinical risk displayed superior induction treatment to the vtD triplet regimen compared to the VD regimen. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) obtaining malignant plasma cells, wherein the plasma cells are CD138+, from the bone marrow that comprise plasma cells with and without t(4;14) translocation from the patient, 2) determining the gene expression of DSG2 and other genes using microarray analysis that are processed using a computer processor means, and 3) comparing the expression level of DSG2 with the gene expression level of a control individual wherein overexpression of DSG2 indicates that the patient would have poor prognosis as taught by Shaughnessy and modify the method to comprise a treatment step wherein subjects determined to have DSG2-high plasma cells are treated with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells are treated with treatments for intermediate genetic risk myeloma, wherein the treatment comprises administration to a subject a proteasome inhibitor (bortezomib), an immunomodulatory drug (thalidomide), and a corticosteroid (dexamethasone), e.g. the vtD treatment, as taught by Moreau to form the instant method of treating a subject suffering from multiple myeloma, the instant method comprising: 1) obtaining malignant CD138+ plasma cells from the bone marrow that comprise plasma cells with and without t(4;14) translocation, 2) determining the instant gene expression of DSG2 and other genes using microarray analysis that are processed using computer processor means described in instant application, 3) comparing the instant expression level of DSG2 with the gene expression level of a control individual wherein overexpression of DSG2 indicates that the patient would have poor prognosis, and 4) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, wherein the instant treatment comprises administration to a subject a proteasome inhibitor (bortezomib), an immunomodulatory drug (thalidomide), and a corticosteroid (dexamethasone).
Regarding instant claim 42, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the gene expression level of DSG2 in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, as taught by the combined teachings of Shaughnessy and Moreau above, and modify the method to use an antibody specific for Dsg2 on the cell surface to determine the level of DSG2 in malignant plasma cells as taught by Schäfer. This is obvious, because the combined teachings of Shaughnessy and Moreau teach a method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the gene expression level of DSG2 in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, and Schäfer discloses an antibody that targets DSG2 at the cell surface, allowing for the visualization of non-desmosome bound DSG2 proteins in epithelial cells including tumor cells in the bone marrow. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the gene expression level of DSG2 in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, as taught by the combined teachings of Shaughnessy and Moreau above, and modify the method to include determining the level of DSG2 using an antibody that targets Dsg2 at the cell surface as taught by Schäfer to form the instant method of treating a subject suffering from multiple myeloma, the instant method comprising: 1) determining the expression level of DSG2 in malignant plasma cells from the patient wherein the instant method to measure DSG2 level comprises using an antibody that binds to DSG2 at the cell surface, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma.
Regarding instant claim 27, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of assessing progression of multiple myeloma in a subject being treated for multiple myeloma, the method comprising assessing the level of DSG2 in a bone marrow sample from the patient wherein the evaluation of DSG2 levels would determine the treatment of the subject as taught by Shaughnessy, and modify the method to include using an antibody to determine the level of DSG2 in the bone marrow sample as taught by Schäfer. This is obvious, because Shaughnessy teaches a method of assessing the progression of multiple myeloma in a patient, the method comprising determining the level of DSG2 in a bone marrow sample from the patient wherein the expression level of DSG2 would determine the treatment for the subject, and Schäfer discloses an antibody that targets DSG2 at the cell surface, allowing for the visualization of non-desmosome bound DSG2 proteins in epithelial cells, including tumor cells in the bone marrow. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the a method of assessing the progression of multiple myeloma in a patient, the method comprising determining the level of DSG in a bone marrow sample from the patient wherein the expression level of DSG2 would determine the treatment as taught by Shaughnessy, and modify the method to include determining the level of DSG2 by using an antibody that targets DSG2 at the cell surface, allowing for the visualization of non-desmosome bound DSG2 proteins in epithelial cells, including tumor cells in the bone marrow as taught by Schäfer to form the instant method of assessing progression of multiple myeloma in a subject being treated for multiple myeloma, the instant method comprising using an antibody directed to DSG2 to assess the level in a bone marrow sample from the subject wherein an increased level of DSG2 in the plasma cell indicates progression in multiple myeloma in a subject, to determine the treatment based on the evaluation of DSG2 expression levels in the bone marrow.
Claims 5-8 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Shaughnessy et al (US Patent No. 9,650,677 B2, hereinafter Shaughnessy), Schäfer et al (Differentiation, 1996, 60:99-108, hereinafter Schäfer), and Moreau et al (Blood, 2011, 118(22):5752-5758; hereinafter Moreau) as applied to claim 1 above, and further in view of Tan et al (OncoTarget, 2016, 7:46492-46508; hereinafter Tan).
The teachings of Shaughnessy, Schäfer, and Moreau are discussed above.
However, Shaughnessy, Schäfer, and Moreau do not teach detecting cell surface expression of DSG2 comprising flow cytometry wherein determining if the plasma cells express high levels or low levels of DSG2 is based on the difference in mean or median fluorescence intensity between plasma cells wherein the difference in fluorescence intensity is determined by comparison to fluorescence intensity of cells stained with an isotype control. Additionally, Shaughnessy, Schäfer, and Moreau do not teach determining the level of DSG2 comprising immunohistochemistry. Furthermore, Shaughnessy, Schäfer, and Moreau do not teach determining the level of DSG2 wherein the antibody is clone 6D8.
The deficiency is resolved by Tan et al.
Tan teaches using flow cytometry to evaluate DSG2 protein expression in cell lines demonstrating high and low DSG2 gene expression based on the difference in mean fluorescence intensity (page 46493, right column, last paragraph; Figure 1) wherein the cells were stained with the anti-DSG2 antibody, clone 6D8, and the fluorescence intensity was determined by comparison to the fluorescence intensity of cells stained with an isotype-matched control antibody (page 46505, right column, Flow Cytometry section). Furthermore, Tan teaches using immunohistochemistry to examine DSG2 expression in tissue microarrays (pages 46494, paragraph 1-46495, paragraph 1; page 46505, right column, Section “Immunofluorescence and immunohistochemistry”; Figure 2).
Regarding instant claims 5-8 and 43, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the gene expression level of DSG2 on the cell surface in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, as taught by the combined teachings of Shaughnessy, Schäfer, and Moreau above, and modify the method to use a clone 6D8 anti-Dsg2 antibody to detect cell surface expression of DSG2 comprising flow cytometry, wherein the expression level of DSG2 is based on the difference in mean fluorescence intensity wherein the difference in fluorescence intensity is determined by comparison to the fluorescence intensity of cells stained with an isotype control, and immunohistochemistry as taught by Tan. This is obvious because, the combined teachings of Shaughnessy, Schäfer, and Moreau teach a method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the gene expression level of DSG2 on the cell surface in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, and Tan teaches using a clone 6D8 anti-Dsg2 antibody to detect cell surface expression of DSG2 comprising flow cytometry, wherein the expression level of DSG2 is based on the difference in mean fluorescence intensity wherein the difference in fluorescence intensity is determined by comparison to the fluorescence intensity of cells stained with an isotype-matched control antibody, and immunohistochemistry. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the gene expression level of DSG2 on the cell surface in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, as taught by the combined teachings of Shaughnessy, Schäfer, and Moreau above, and modify the method to include determining the level of DSG2 on the cell surface using an anti-DSG2 antibody, clone 6D8, comprising flow cytometry, wherein the expression level of DSG2 is based on the difference in mean fluorescence intensity wherein the difference in fluorescence intensity is determined by comparison to the fluorescence intensity of cells stained with an isotype-matched control antibody, and immunohistochemistry as taught by Tan to form the instant method of treating a subject suffering from multiple myeloma, the instant method comprising: 1) determining the expression level of DSG2 on the cell surface in malignant plasma cells from the patient wherein the instant method to measure DSG2 level comprises flow cytometry and immunohistochemistry using an antibody, clone 6D8, that binds to DSG2 at the cell surface, wherein the expression level of DSG2 is based on the difference in mean fluorescence intensity wherein the difference in fluorescence intensity is determined by comparison to the fluorescence intensity of cells stained with an isotype control antibody, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma.
Applicant Arguments
Applicant argues the following points:
Shaughnessy does not disclose or suggest the use of DSG2 as an independent prognostic marker for MM progression;
Shaughnessy does not disclose the protein expression of DSG2 is dysregulated in MM patients with poor prognostic outcomes. Applicant states that Shaughnessy only measures gene expression and does not measure protein levels, and that there is not a clear expectation that high mRNA levels will correlate with high protein levels. Therefore, Applicant argues that Shaughnessy does not teach or suggest an increased level of cell surface DSG2 protein as required by the presently amended claims;
Shaughnessy does not disclose that subsequent treatments other than treatment with molecules that down regulate CKS1B can be informed by the expression of any genes. Furthermore, the Applicant asserts that the only proposed treatment informed by the prognostic method of Shaughnessy is use of “agents that downregulate the expression of the CKS1B gene or the CKS1B gene product”;
Shaughnessy solely relates to predicting the prognosis of a patient pre-treated prior to stem cell transplant with melphalan, and teaches away from using stem cell treatment in patients having high CSK1B or proxies for CSK1B. Applicant also argues that there is no suggestion in the teachings of Moreau that patients should be stratified for treatment based on prognostic markers. Furthermore, Applicant argues that neither document discloses treatment with a monoclonal antibody as presently claimed.
Response to Arguments
Applicant's arguments filed 7/2/2026 have been fully considered but they are not persuasive.
Applicant has amended the claims to require “determining the level of cell surface desmoglein 2 (DSG2) protein in malignant plasma cells”. However, the art as applied to the previous 103 rejection (and reproduced above) already encompassed this limitation.
In regards to Applicant’s assertion of (a) above, the Examiner points out that Shaughnessy covers single-gene embodiments. Shaughnessy discloses a method of determining the prognosis of a multiple myeloma patient, comprising the steps of (1) obtaining plasma cells from said patient; (2) determining gene expression of one or more genes from the group consisting of … DSG2, … in the plasma cell; and (3) comparing the expression level to the expression levels of a control individual (page 27, column 6, second paragraph-fourth paragraph). “One or more genes” include the case where only DSG2 is measured. Shaughnessy’s teaching that overexpression of DSG2 relative to a favorable-prognosis control is associated with poor prognosis is a direct teaching that DSG2 level correlates with outcome. Furthermore, Shaughnessy’s teachings do not state that DSG2 lacks stand-alone prognostic value or that it must be combined with other genes to be meaningful. Instead, Shaughnessy teaches that multiple genes, each individually associated with poor prognosis, can be used singly or in combination to classify risk in MM patients. Therefore, the Applicant’s assertion that Shaughnessy fails to disclose DSG2 as an “independent” prognostic marker is not persuasive because it is inconsistent with the broadest reasonable interpretation of Shaughnessy’s teachings.
Regarding Applicant’s assertion of (b) above, the Examiner points out that this is incorrect. Shaughnessy teaches measuring gene expression levels of DSG2 among other genes to determine the prognosis of a human MM patient, wherein overexpression of DSG2 relative to a control is associated with poor prognosis. Furthermore, Shaughnessy discloses that the gene expression level is determined at the protein level, wherein examples of such methods to determine the protein level are, although not limited to, flow cytometry, immunohistochemistry and tissue array (page 27, column 6, second paragraph-fourth paragraph; page 28, column 7, fourth paragraph).
Regarding Applicant’s assertion of (c) above, Shaughnessy discloses gene expression profiling of malignant plasma cells to identify high-risk disease, molecular signatures of early treatment failure, and poor prognosis in multiple myeloma (page 25, column 1, second paragraph of §Summary of the Invention; page 27, column 6, second paragraph; page 30, column 12, third paragraph). Shaughnessy teaches that these markers are useful for initial staging, disease follow-up, and prediction of relapse, and are also evaluated in patients treated with high-dose chemotherapy, autologous stem cell transplantation, bortezomib, etc (page 25, column 1, second paragraph of §Summary of the Invention; page 27, column 6, third paragraph). Although Shaughnessy discloses therapeutic strategies that directly target CSK1B as an example (page 28, column 7, fifth paragraph), this does not limit the broader disclosure that gene expression levels of the listed genes, e.g. DSG2, serve as prognostic markers that would lead to subsequent clinical management and treatment decisions.
Regarding Applicant’s assertion of (d) above, the Examiner points out that the Applicant mischaracterizes the scope of Shaghnessy’s teachings and overlooks how its gene expression-based risk stratification informs the treatment choices described in Moreau’s teachings. As described above, Shaughnessy discloses gene expression profiling of malignant plasma cells from MM patients and identifies a prognostic gene signature (including DSG2 and other genes) that stratifies patients into high-risk and standard-risk groups to predict early treatment failure and poor outcome. Moreover, Shaughnessy teaches that such gene-expression signatures are useful not only for patients undergoing high-dose melphalan plus autologous stem cell transplantation, but more generally for “initial staging, disease follow-up and prediction of relapse” (page 27, column 5, last paragraph – column 6, third paragraph), i.e. general prognostic use, thereby providing gene expression-based risk stratification for subsequent clinical management and treatment in MM. Consequently, Shaughnessy is not limited to a single transplant protocol nor confined to selecting only CKS1B-downregulating agents. Instead, it broadly teaches that the MM patients can be categorized by molecular risk factors and that this categorization serves as a general guide of how those patients should be treated over the course of the disease.
Applicant further asserts that Shaughnessy “teaches away” from stem cell transplant in patients having high CSK1B or proxies for CKS1B. Shaughnessy’s teachings of identifying a subset of patients (e.g. those with high CKS1B) for whom a particular regimen (e.g. stem cell transplant) may be unfavorable is in fact a clear example of using gene expression-derived risk information to stratify patients and adjust treatment choice. This is consistent with Shaughnessy’s overall teaching that the gene expression signatures define risk categories and inform which therapeutic approaches are suitable or unsuitable for those categories. Therefore, Shaughnessy does not teach away from using gene expression data to select a treatment (e.g. stem cell transplantation) for a MM patient.
Moreau, in turn, describes standard induction therapy for MM patients using bortezomib-containing regimens (VD, vtD) in the context of high-dose therapy and autologous stem cell transplantation, and reports that VD or vtD significantly increases CR plus VGPR rate compared with VAD regimens as discussed above in the 103 rejection. Importantly, the Intergroupe Francophone du Myelome study cited in Moreau shows that these bortezomib-based regimens improve outcomes across all prognostic subgroups, which include cytogenetic risk and international staging system groups as described above in the 103 discussion. Accordingly, the fact that VD/vtD performs well across such subgroups reinforces that these regimens are clinically relevant options for both standard-risk and high-risk MM patients and that the treatment choice can be considered in light of prognostic grouping. Therefore, since Moreau teaches specific bortezomib-based induction regimens and their efficacy across diverse prognostic categories, and Shaughnessy teaches how to define those prognostic categories using gene expression (or protein levels) of genes such as DSG2 and discloses that these molecular signatures can be used for general prognostic and treatment management purposes, it would have been obvious for a person of ordinary skill in the art at the time of filing to understand that Shaughnessy’s gene expression-based risk stratification can be applied to the treatment regimens of Moreau.
Finally, Applicant refers to instant Fig. 7 asserting that this supports stratification of patient treatment based on DSG2 expression. Instant Fig. 7 describes relative viability of cells transduced with non-targeting shRNA versus DSG2 shRNA at different bortezomib concentrations. However, the specification and the drawing do not provide any statistical significance of the data, such as p-values, nor does it state that any of the observed differences are statistically significant. Accordingly, the modest differences in the bar graph depicted in instant Fig. 7 cannot be reliably interpreted as demonstrating unexpected technical effects. Thus, one of ordinary skill in the art would not be able to determine whether the apparent differences between non-targeting shRNA and DSG2 shRNA at 2nM or 4nM bortezomib concentrations would exceed experimental variability or noise. Moreover, even if instant Fig. 7 is taken at face value, it merely suggests that altering DSG2 expression may change bortezomib sensitivity in vitro, which is consistent with the general understanding in that gene or protein expression can modulate drug response. Therefore, instant Fig. 7 does not persuasively demonstrate that DSG2-based stratification yields a non-obvious and unexpectedly improved outcome relative to the prior art.
New Rejections Necessitated by Claims Amendments
Claim Rejections - 35 USC § 103
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Shaughnessy et al (US Patent No. 9,650,677 B2, hereinafter Shaughnessy), Schäfer et al (Differentiation, 1996, 60:99-108, hereinafter Schäfer), and Moreau et al (Blood, 2011, 118(22):5752-5758; hereinafter Moreau) as applied to claim 1 above, and further in view of Giri (JAMA Oncol, September 24 2020, 6(11):1759-1765; hereinafter Giri).
Regarding instant claim 27, the teachings of Shaughnessy, Schäfer, and Moreau are discussed above.
However, Shaughnessy, Schäfer, and Moreau do not teach a method of assessing MM treatment in a subject being treated for MM, wherein the patient being treated with a proteasome inhibitor, a corticosteroid and an immunomodulatory drug is changed to being treated with a monoclonal antibody, a corticosteroid, and an immunomodulatory drug if determined to have a high level of DSG2 on the surface of plasma cells.
The deficiency is resolved by Giri et al.
Giri teaches that the addition of the monoclonal antibody, daratumumab, to backbone MM regimens is associated with improved response rates and progression-free survival (page 1759, abstract). Giri also teaches that the addition of daratumumab also improved response rates in both standard risk MM (SRMM) and high risk MM (HRMM) patients despite contradicting studies, wherein the addition of daratumumab improved PFS among newly diagnosed patients as well as for patients with relapsed or refractory MM (page 1760, left column, third paragraph; page 1762-1763, §Meta-analysis for the association of…HRMM and § Meta-analysis for the association of…SRMM; Figures 2 and 3).
Regarding instant claim 27, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the expression level of DSG2 on the cell surface in malignant plasma cells from the bone marrow of the patient using an antibody, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells are treated with treatments for intermediate genetic risk myeloma, wherein the treatment comprises administration to a subject a proteasome inhibitor, an immunomodulatory drug, and a corticosteroid as taught by the combined teachings of Shaughnessy, Schäfer, and Moreau above, and modify the method to include treating DSG2-high patients wherein the treatment comprises a monoclonal antibody in addition to the MM treatment regimen as taught by Giri. This is obvious because, the combined teachings of Shaughnessy, Schäfer, and Moreau teach a method of determining the prognosis of a multiple myeloma patient, comprising: 1) determining the expression level of DSG2 on the cell surface in malignant plasma cells from the patient, and 2) treating subjects determined to have DSG2-high plasma cells with treatments for high genetic risk myeloma and subjects determined to not have DSG2-high plasma cells with treatments for intermediate genetic risk myeloma, and Giri teaches the addition of the monoclonal antibody, daratumumab, to backbone MM regimens is associated with improved response rates and progression-free survival in HRMM patients. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to form the instant method of assessing multiple myeloma treatment in a subject being treated for MM, the method comprising: 1) sing an antibody to DMG2 to assess the level of cell surface DSG2 in plasma cells in a bone marrow sample from the subject; (2) determining if the bone marrow sample from the subject expresses high levels or low levels of DSG2 wherein an increased level of DSG2 on the surface of the plasma cell indicates DSG2-high; and 3) a patient treated with a proteasome inhibitor, a corticosteroid, and an immunomodulatory drug is changed to being treated with a monoclonal antibody, corticosteroid and an immunomodulatory drug if determined to have high level of DSG2 on the cell surface of the plasma cell.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Friday 7-2.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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