DETAILED ACTION
Claims 1-9, 12, 27, and 38-46 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The information disclosure statement filed on 5/16/2023 and 2/10/2025 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered.
The references listed in the “REFERENCES” section of the specification (page 52-57, paragraph [00265]) that are not listed in the information disclosure statements have not been considered by the examiner.
Drawings
The drawings are objected to because:
Instant Fig. 4 is a grayscale drawing of a heatmap wherein a value of zero is black and values above and below zero are both lighter gradients. Therefore, the figure is not able to be interpreted as currently drawn in grayscale.
Instant Fig. 6E is a grayscale plot of the gene expression values for DSG2 and CDH2 wherein the specification describes the samples in the MS-sub-group as “red” and the MS-negative samples as “black”. In addition to the color depicting the groups, since the shape indicating the samples are the same for both groups, the figure is not able to be interpreted as currently drawn in grayscale, especially in certain quadrants where both groups overlap or are plotted close together.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Regarding color figures, color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because of the following informalities:
“patent” should read “patient” (page 1, paragraph [003].
“agood” should read “ a good” (page 15, paragraph [0070].
Appropriate correction is required.
The use of the term Affymetrix and Matrigel which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademarks referenced herein should be identified as such as the appropriate notation:
Affymetrix (page 7, paragraph [0035])
Matrigel (page 9, paragraph [0039])
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Instant claim 12 reciting “using a computer means to determine if the plasma cells express high levels or low levels of DSG2” has been interpreted to invoke 35 U.S.C. 112(f) as a means plus function limitation because of the combination of a non-structural term “means” and functional language “to determine if the plasma cells express high levels or low levels of DSG2” without reciting sufficient structure to perform the recited function.
Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The specification discloses in paragraphs [0026]-[0028] (page 5-6) and [0088]-[0089] (page 17) that the “computer means to determine if the plasma cells express high levels or low levels of DSG2” is a computer-readable medium encoded with programming instructions executable by a computer processor to allow the computer processor to process data associated with the level of DSG2 in malignant plasma cells and provide a prognosis for a subject suffering from multiple myeloma. The language in instant claim 12 will be interpreted as requiring the disclosed structure in paragraphs [0026]-[0028] and [0088]-[0089], or equivalents.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9, 12, 27, 38-43, and 46 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. Abstract ideas include mathematical concepts (including mathematical relationships, formulas, equations, and calculations), mental processes (including concepts performed in the human mind), and certain methods of organizing human activity (including managing personal behavior, relationships, or interactions between people). The rationale for this determination is explained below.
Instant claims 1, 12, 27, 38-41 and 46 are directed to a natural phenomenon and an abstract idea because the claims recite natural phenomenon and an abstract idea (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: “an increase in the level of DSG2 gene expression in malignant plasma cells from the subject is: 1) associated with poor prognosis of multiple myeloma in the subject (instant claims 1 and 46), indicative of progression of multiple myeloma in the treated subject (instant claim 27), cause to modify the current treatment of a subject based on the evaluation of DSG2 in the subject (instant claims 38-39). Shaughnessy teaches a method of determining the prognosis of a multiple myeloma patient, comprising obtaining malignant plasma cells from the bone marrow (specification, page 29, lines 46-49) that comprise plasma cells with and without t(4;14) translocation from the patient (specification, page 30, section 11, lines 11-28), determining the gene expression of 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 further teaches determining the level of gene expression using CD138-enriched plasma cells isolated from patients (page 29, section 9, lines 46-49) and measuring DSG2 at the protein level by flow cytometry and immunohistochemistry (page 28, section 7, lines 42-45) and at the RNA level (claim 7; page 26, section 4, lines 4-9) (Shaughnessy et al, US Patent No. 9,650,677 B2).
The “abstract idea” is: comparing the changed level of the DSG2 gene expression. It is noted instant claims 1 and 38-39 recite a potential treatment step; however, the methods include an embodiment which would only observe the phenomenon without a treatment step following comparison between test and control samples if there is no change in the DSG2 gene expression level. Therefore, instant claims 1 and 38-39 would be classified as “mere data gathering” and do not integrate the judicial exception(s) into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the instant claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of measuring DSG2 gene expression (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques computer functions recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Performing repetitive calculations, Flook, 437 U.S. at 594, 198 USPQ2d at 199 (recomputing or readjusting alarm limit values); Bancorp Services v. Sun Life, 687 F.3d 1266, 1278, 103 USPQ2d 1425, 1433 (Fed. Cir. 2012) ("The computer required by some of Bancorp’s claims is employed only for its most basic function, the performance of repetitive calculations, and as such does not impose meaningful limits on the scope of those claims.");.
Recited active steps of the claims impose no meaningful limit on the scope of the claims and are recited at a high level of generality such that substantially all methods of measuring DSG2 gene expression would conventionally and routinely perform such steps. Further, the specification discloses DSG2 gene expression can be measured using protein detection, immunological detection, and/or RNA detection (specification, page 13, paragraph [0060]-page 15, paragraph [0068]). These techniques are well-known, routine, and conventional means of measuring DSG2 as evidenced by Schäfer et al (Fig. 2 and 4, Differentiation, 1996, 60:99-108). Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, using a “computer processor means” to determine the expression level of DSG2 recited in instant claim 12 is using a “generic computer” to perform routine calculations or comparisons of an abstract idea (e.g. data analysis), which is a well-known, routine, and conventional method to compare DSG expression levels. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting expression) are routinely performed in the art to obtain data regarding expression and treat subjects. In regards to “diagnosing", it is further noted that merely presenting results of a process otherwise unpatentable under 35 U.S.C. 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., No. 2015-1985, 2016 WL 5899185, at *3 (Fed. Cir. Oct. 11, 2016) (claim unpatentable under 35 U.S.C. 101 despite recitation of the step: “providing notification if [an] event has occurred”). Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The treating steps described in paragraphs [00118] and [00119] of the specification do not impose a meaningful limit on the judicial exception. Instead, they provide instructions on how to apply the natural law using well-known conventional therapeutic agents that are “already known in the art” (page 21, paragraphs [00118] and [00119]). Therefore, the claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Claims 2-9, and 40-43 are also rejected because they are dependents of claim 1 that narrow the scope of claimed invention to still be directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 46 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Shaughnessy et al (US Patent No. 9,650,677 B2, hereinafter Shaughnessy).
Regarding instant claim 46, Shaughnessy teaches a method of prognosis comprising identifying genes that contribute to high-risk myeloma using gene expression profiles of purified plasma cells that are correlated with disease-related and overall survival in multiple myeloma patients (page 30, section 12, Example 3). Furthermore, Shaughnessy teaches that using log rank tests, 70 genes were identified wherein the fourth and first quartile membership was correlated with a high incidence of disease-related death, among which DSG2 was amplified and identified in the fourth quartile (pages 30-31, Table 2).
Claim Rejections - 35 USC § 103
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 1-4, 9, 12, 27, 38-42, and 44-45 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) and Moreau et al (Blood, 2011, 118(22):5752-5758; hereinafter Moreau).
Regarding instant claims 1-9, 12, 27, and 38-46, 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 1-3, 9, 12, 40-41, and 44-46, 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 claims 4 and 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 claims 27, 38, and 39, 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.
Conclusion
No claims are allowable.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643