DETAILED CORRESPONDENCE
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 .
Election/Restrictions
2. Applicant’s election of the species of FCGR2B and methods of detecting nucleic acid levels in the reply filed on 28 January 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The election of species requirement between a) methods for detecting nucleic acid levels and b) methods for detecting protein levels, as set forth at page 4 of the restriction requirement of 30 July 2025, is withdrawn. The claims herein have been examined to the extent that they encompass detecting either FCGR2B nucleic acids or proteins.
Claim Status
3. Claims 21-40 are pending and have been examined herein to the extent that the claims read on the elected species of methods that detect the expression of the FCGR2B gene. The claims encompass the non-elected subject matter of methods that detect the expression of an Ig gene and methods that detect the expression of the combination of an Ig gene and the FCGR2B gene. Prior to the allowance of the claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 112(b) - Indefinite
4. 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 22-23, 25-27, 29, 30, and 34-39 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 pre-AIA the applicant regards as the invention.
Claims 22-23 and 34-37 are indefinite over the recitation of “wherein the proteasome inhibitor is carfilzomib, bortezomib, disulfiram, and oprozomib” (see claims 22 and 34) because it is unclear as to what is meant by “the” proteasome inhibitor being all four of the recited inhibitors. Note that dependent claims 23 and 35 recite that the proteasome inhibitor is the single proteasome inhibitor of carfilzomib - i.e., “wherein the proteasome inhibitor is carfilzomib.” This rejection may be obviated by amendment of claims 22 and 34 to recite the proteasome inhibitors in the alternative, for example “wherein the proteasome inhibitor is carfilzomib, bortezomib, disulfiram, or oprozomib.” Claims 25-27 and 34-37 are indefinite over the recitation that the tumor is multiple myeloma (in general) and then reciting that the tumor is “optionally, relapsed or refractory multiple myeloma” (see claims 25 and 34). The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by the narrower language of “optionally, relapsed or refractory multiple myeloma” is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 29, 30, 38 and 39 are indefinite and vague because, in the context of these claims, it is unclear as to what constitutes the reference level. The claims recite that the reference level is a cutoff level “correlative” – i.e., that is correlated – with at least 50% specificity and at least 50% sensitivity “as determined” by a ROC curve based on FCGR2B expression levels in responders and non-responders. However, the claims do not set forth what the reference level is “correlative” with. Nor do the claims indicate what the responders or non-responders are responsive to. The reference level is a variable number that could depend on a variety of characteristics of the responder and non-responder populations, including the population size, ethnicity and health status of the responders and non-responders, the presence or absence of a particular type of tumor in the responders or non-responders, what the cutoff level is correlated with and how this is measured / evaluated (e.g., correlated with short term survival or correlated with long term survival or correlated with a reduction in tumor size or correlated with a complete or partial or minimal response or any combination thereof, of a human subject or any non-human subject having a multiple myeloma or having lung cancer or having any cancer and treated with carfilzomib or with any proteasome inhibitor alone or in combination with any other agent). Since the claims do not set forth clear parameters for how the reference level is calculated and do not actually require that the method is one in which the reference level is calculated using the ROC curve, the metes and bounds of what constitutes the reference level are unclear and it is unclear as to when a subject will have a level of expression of FCGR2B that is greater than the unspecified reference level.
Priority
5. Claims 21, 23-25, 28, 32, 33, 35 and 36 are entitled to priority to provisional application 61/875,954, filed 10 September 2013. Claims 21, 23-25, 28, 32, 33, 35 and 36 are not entitled to priority to provisional application 61/863,809, filed 08 August 2013 because the ‘809 application does not disclose the presently claimed methods comprising administering a proteasome inhibitor to a subject to treat a tumor in the subject wherein the level of expression of FCGR2B in the tumor of the subject is higher as compared to a reference level. Claims 22, 26, 27, 29-31, 34 and 37-40 are entitled to priority to provisional application 62/005,904, filed 30 May 2014. Claims 22, 26, 27, 29-31, 34 and 37-40 are not entitled to priority to provisional applications 61/875,954 or 61/863,809 because neither of these applications disclose each of the limitations in these dependent claims, including methods wherein the proteasome inhibitor is disulfiram (present claims 22 and 34); methods wherein the subject has newly diagnosed multiple myeloma (present claim 26); methods wherein the subject received one to three prior lines of therapy (present claim 27); methods with the cutoffs and ROC requirements of present claims 28, 29, 38 and 39; or methods wherein the level of expression of FCGR2B is 2-fold greater than the reference level (present claims 31 and 40). If Applicant asserts that the present claims are entitled to priority to the provisional applications, Applicant should point to specific teachings (e.g., by page and line number) in the priority applications to establish priority for each of the recitations set forth in the claims.
Double Patenting
6. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 21-30 and 32-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,870,889 (cited in the IDS of 01/28/2026). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘889 both are drawn to methods comprising administering a proteasome inhibitor to a subject having a tumor wherein the subject or tumor or a sample of tumor cells from the subject have an expression level of FCGR2B that is greater than a reference level. The claims of ‘889 do not recite this selecting step. Note that the claims of ‘889 recite “(c) determining the subject as responsive to treatment with a proteasome inhibitor when the level of expression of FCGR2B of the sample is greater than or equal to an FPKQ cutoff of 75 and (ii) administering to the subject an effective amount of a proteasome inhibitor.”
Regarding present claims 22, 23, 34 and 35, claims 2 and 13 of ‘889 encompass methods wherein the proteasome inhibitor is carfilzomib.
Regarding claims 24-27 and 36-37, claims 3 and 5 of ‘889 recite methods wherein the tumor is a hematological tumor, and specifically a multiple myeloma and claim 9 of ‘889 recites “(i) has previously been treated for multiple myeloma or (ii) has previously been diagnosed with multiple myeloma or (iii) is a human patient having or suspected of having multiple myeloma, refractory multiple myeloma, or relapsed multiple myeloma.”
Regarding claim 28, claim 6 of ‘889) recites that the method is one wherein measuring the level of expression of FCGR2B is performed in CD138-positive tumor cells obtained from the subject (claim 6 of ‘889).
Regarding present claims 29, 30, 38 and 39, claim 1 of ‘889 recites “the level of expression of FCGR2B of the sample is greater than or equal to an FPKQ cutoff of 75.” When read in light of the specification of ‘889, it is clear that the claims of ‘889 encompass methods wherein the reference level encompasses a level with a cutoff for correlation with response to a proteasome inhibitor of at least 50% specificity and sensitivity that can be determined by a receiver operating characteristic (ROC) curve based on FCGR2B expression levels of responders or non-responders. Note also that the present claims do not actually require determining a reference level or comparing the expression level of FCGR2B in a (tumor cell) sample of a subject to a reference level. Rather, the claims require only that it is an attribute of the subject that they have the stated expression level of FCGR2B relative to the reference level. In the absence of evidence to the contrary, subjects having a “level of expression of FCGR2B of the sample is greater than or equal to an FPKQ cutoff of 75,” as required by the methods claimed in ‘889, are considered to meet the level of expression of FCGR2B recited in the present claims.
7. Claims 31 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,870,889 (cited in the IDS of 01/28/2026) in view of Krishnappa et al (ecancer . 2011. 5:189, p. 1-7).
The claims of ‘889 are discussed above.
The claims of ‘889 do not recite that the method is one in which the level of expression of FCGR2B is at least 2-fold greater than that of the reference level.
However, Krishnappa teaches methods of analyzing for gene expression levels in tumor samples (e.g., “Methods” at p. 2). Krishnappa states: ‘Researchers generally’ use a cut off at least 2-fold change (linear value) between control and experiment to ‘screen significantly differentially expressed genes’.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically performed the method claimed in ‘889 by administering to the subject the proteasome inhibitor when the subject had an expression level of FCGR2 in tumor cells at least 2-fold higher than the reference value. One would have been motivated to have done so because Krishnappa teaches that a 2-fold change in the expression level compared to a control / reference level is a generally considered by researches to be a significant level of differential expression. Thereby, such an application of the method claimed in ‘889 would have provided an effective means for selecting those patients most likely to benefit from treatment with the proteasome inhibitor based on their increased level of expression of FCGR2B.
Claim Rejections - 35 USC § 102
8. 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 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(s) 21, 22, 24, 25, 27, 29, 30, 32-34 and 37-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bryant et al (PGPUB 2006/0281122; cited in the IDS of 04/14/2023)
Claim(s) 21, 22, 24, 25, 27, 29, 30, 32-34 and 37-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bryant (U.S. Patent No. 8,278,038; published October 2, 2012, effective filing date of June 8, 2005; cited in the IDS of 04/14/2023).
Claim(s) 21, 22, 24, 25, 27, 29, 30, 32-34 and 37-39 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bryant (U.S. Patent No. 8,278,038; published October 2, 2012, effective filing date of June 8, 2005; cited in the IDS of 04/14/2023).
It is noted that U.S. Patent 8,278,038 is the issued patent of U.S. application 11/449,195, which published as 2006/0281122. Unless otherwise stated, citations below are with respect to the published application.
Bryant teaches a method for treating a tumor in a subject from which a sample was obtained, wherein the level of expression of one of the marker genes recited in Table 1B has been measured from the sample and the level of the marker gene in the sample was greater than a reference level and the method comprises administering an effective amount of a proteasome inhibitor to the subject (e.g., para [0009-0010], [0015], [0059], [0073], [0122-0129], [0168-0170]). Table 1B includes the marker gene No. 873, which is the FCGR2B gene:
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Bryant states:
[0015] The present invention is also directed to methods of treating a cancer patient, with a therapeutic regimen, in particular a proteasome inhibitor therapy (e.g., a proteasome inhibitor agent, alone, or in combination with an additional agent such as a chemotherapeutic agent) and/or glucocorticoid therapy regimen (a glucocorticoid agent, alone or in combination with an additional agent), which includes the step of selecting a patient whose predictive marker profile indicates that the patient will respond to the therapeutic regimen, and treating the patient with the proteasome inhibition therapy and/or glucocorticoid therapy.
[0041] The invention further provides methods for treating a tumor in a patient with a proteasome inhibition based regimen and/or glucocorticoid based regimen therapy. Such therapeutic methods comprise measuring the level of expression of at least one predictive marker in a patient's tumor; determining whether a proteasome inhibition based regimen and/or glucocorticoid based regimen for treating the tumor is appropriate based on the expression level of the predictive marker or markers, and treating a patient with a proteasome inhibition based therapy and/or glucocorticoid based therapy when the patient's expression level indicates a responsive patient.
Bryant further states:
[0064] A cancer may be predisposed to respond to an agent if one or more of the corresponding predictive markers identified in Table 1B, Table 2B, and Table 3 (as indicated by (+) in Table 3) demonstrate increased expression.
Claim 1 of the PGPUB recites:
A method for determining a cancer therapy regimen for treating a tumor in a patient comprising: a) determining the level of expression of at least one predictive marker in a patient sample; b) comparing the level of expression of the predictive marker or markers to a control expression level to determine whether the level of expression of the predictive marker is an informative expression level; and b) determining a cancer therapy regimen for treating the tumor based on the expression of the predictive marker or markers, wherein the predictive marker or markers is selected from the predictive markers identified in any one of Table 1A, Table 1B, Table 2A, Table 2B, and Table 3; and wherein an informative expression level is indicative that the patient is either a responsive patient or a non-responsive patient.
U.S. Patent No. 8,278,038 includes the following claim (emphasis added):
1. A method for determining a cancer therapy regimen for treating myeloma in a patient comprising:
a) measuring the level of expression of at least one nucleic acid sequence selected from the group consisting of sequences recognized by probe sets of predictive markers numbered 1-547 in Table 1A, 658-871 in Table 1B and 873-876 in Table 1B in a patient sample comprising tumor cells,
wherein the sequences recognized by probe sets of the predictive markers:
i) numbered 1-547 consist of SEQ ID NOs: 1-513,
ii) numbered 658-871 and 873-876 consist of SEQ ID NOs:614-830;
b) comparing the level of expression of the at least one nucleic acid sequence to a reference expression level of that sequence to determine whether the level of expression of the at least one nucleic acid sequence is upregulated in the patient sample comprising tumor cells; and
c) determining a cancer therapy regimen for treating myeloma based on the expression level of the predictive marker or markers,
wherein the cancer therapy regimen is proteasome inhibition-based therapy, wherein
i) upregulation of at least one nucleic acid sequence selected from the group consisting of sequences recognized by probesets of predictive markers numbered 1-547 indicates nonresponsiveness to proteasome inhibition therapy and the patient would not benefit from this cancer therapy regimen; and
ii) upregulation of at least one nucleic acid sequence selected from the group consisting of sequences recognized by probesets of predictive markers numbered 658-871 and 873-876 indicates responsiveness to proteasome inhibition therapy and the patient would benefit from this cancer therapy regimen.
Regarding reference levels, Bryant teaches:
[0011]….These methods typically include the determining the level of expression of one or more predictive markers in a patient's tumor (e.g., a patient's cancer cells), comparing the level of expression to a reference expression level, and identifying whether expression in the sample includes a pattern or profile of expression of a selected predictive marker or marker set which corresponds to response or non-response to proteasome inhibition therapy.
[0024] The "normal" level of expression of a marker is the level of expression of the marker in cells in a similar environment or response situation, in a patient not afflicted with cancer. A normal level of expression of a marker may also refer to the level of expression of a "reference sample", (e.g., sample from a healthy subjects not having the marker associated disease). A reference sample expression may be comprised of an expression level of one or more markers from a reference database. Alternatively, a "normal" level of expression of a marker is the level of expression of the marker in non-tumor cells in a similar environment or response situation from the same patient that the tumor is derived from.
[0106] Alternatively, the expression level can be provided as a relative expression level. To determine a relative expression level of a marker, the level of expression of the marker is determined for 10 or more samples of normal versus cancer cell isolates, preferably 50 or more samples, prior to the determination of the expression level for the sample in question. The mean expression level of each of the markers and marker sets assayed in the larger number of samples is determined and this is used as a baseline expression level for the marker. The expression level of the marker determined for the test sample (absolute level of expression) is then divided by the mean expression value obtained for that marker. This provides a relative expression level.
In the examples provided by Bryant, gene expression levels in test samples were compared to those in control samples as set forth below:
[0209] The Pooled Fold Change ("PFC") method is a measure of differential expression between two groups of samples, arbitrarily designated "control" and "tester." PFC finds genes with higher expression in the tester than in the control samples. For the two-class comparisons described in this invention, each class was used in turn as the tester. To qualify as having higher expression, tester samples must be above the k.sup.th percentile of the control sample. The fold-change values of tester samples are subjected to a nonlinear transformation that rises to a user-specified asymptote, in order to distinguish moderate levels of fold-change, but not make distinctions between very large fold-changes. The squashed fold-change values of the over-expressed tester samples are averaged to get the POOF score. In particular, PFC for a given tester sample, s, and gene, g, is computed as the average across tester samples of the compressed tester:control ratio R(s,g): R(s,g)=C(x.sub.gs/(k+x.sub.g.sup.Q)), where C(x) is the compression function C(z)=A(1-e.sup.-z/A) for z.gtoreq.T, and C(z)=0 for z<T, where T is a threshold value no less than 1.0. A is an upper asymptote on the fold-change value, k is a constant reflecting the additive noise in the data, i.e., the fixed component of the variance in repeated measurements. x.sub.gs is the expression value of gene g in sample s, x.sub.g.sup.Q is the Qth percentile of the control samples' expression value.
Thus, Bryant teaches that subjects having tumors and having an increase in the expression of the marker gene no. 873 – i.e., FCGR2B – relative to the reference level, are to be treated with proteasome inhibitor therapy.
Accordingly, with respect to claims 21, 32 and 33, Bryant teaches a method of treating a tumor in a subject from which a sample was obtained, the method comprising administering a proteasome inhibitor to the subject, wherein the level of expression of FCGR2B of the tumor / a sample of tumor cells is greater than a reference level.
Regarding claims 22 and 34, Bryant teaches that the proteasome inhibitor is bortezomib (e.g., para [0036], [0080] and [0123-0124]).
Regarding claims 24, 25 and 34, Bryant teaches that the tumor is a hematological tumor and particularly a multiple myeloma (para [0017].
Regarding claims 27 and 37, Bryant teaches that the patient is one that has received at least two prior therapies and have demonstrated disease progression (para [0123]).
Regarding claims 29, 30, 38 and 39, it is noted that the present claims do not recite a method that requires performing active process steps of calculating the reference level using a ROC curve and the claims do not require any particular reference level. The recited reference level may essentially be any value since the claims do not recite what the cutoff level is correlated with, or what constitutes a responder or non-responder (e.g., with respect to the identity of the subjects, the number of subjects, the presence or absence of a particular tumor or other disease in the subject, what the subjects respond or do not respond to, what the subjects are treated with, and how the response or lack of response is measured / evaluated). Since the reference level recited in the present claims does not have any fixed or clear value and the claims don’t require any degree of increase in expression relative to the unspecified reference level, the method of Bryant which compares the subject's FCGR2B expression level to reference levels, including reference levels obtained from subjects that do not have a tumor or from samples of the same subject that do not include tumor cells, meets the limitations of the claims in which the reference level is defined broadly in terms of how it can be calculated but not in terms of a particular value.
9. Claim(s) 22 and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tuch et al (Cancer Research. 2014. 74. 19_Supplement, Abstract 898; poster presented at meeting held April 5-9, 2014).
Tuch teaches the results of a clinical trial in which patients having multiple myeloma were treated with the proteasome inhibitor of carfilzomib. CD138+ tumor cells were obtained from the treated patients and screened by RNAseq for RNAs whose expression level was correlated with response to carfilzomib treatment. Tuch teaches that FCGR2B binds Ig and down-modulates its production in B cells. It is stated that “(h)igh FCGR2B expression, therefore, may demarcate a tumor that is experiencing particularly high levels of proteotoxic stress from Ig production. Combining FCGR2B and IGH expression, we are able to classify carfilzomib response with 70% sensitivity and 94% specificity. Median time to progression for IGH/FCGR2B+ patients was 7.3-fold longer than for IGH/FCGR2B- patients (8.9 vs. 1.2 months; P = 3x10-5).”
Accordingly, the method of Tuch is one for treating a tumor in a subject from which a sample was obtained, the method comprising administering the proteasome inhibitor of carfilzomib to the subject, wherein the level of expression of FCGR2B of the tumor / a sample of tumor cells is greater than a reference level.
Claim Rejections - 35 USC § 103
10. 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 following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 26 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Bryant et al (U.S. PGPUB 2006/0281122) OR Bryant (U.S. Patent No. 8,278,038).
The teachings of Bryant are presented above.
Bryant does not specifically recite administering the proteasome inhibitor to a patient newly diagnosed with multiple myeloma.
However, Bryant does teach that the methods disclosed therein are “designed for use in diagnostics and therapeutics for a patient suffering from cancer” and that the cancer includes multiple myeloma (para [0035]). Bryant also teaches that the predictive markers identified in Table 1b as correlated with a longer time to progression, and thereby the FCGR2B (#873) marker, are likely to be responsive to the proteasome inhibitor therapy (para [0054-0055]).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically applied the method of Bryant to patients newly diagnosed with multiple myeloma having an increase in the level of expression of FCGR2B relative to a reference level. One would have been motivated to have done so since Bryant teaches that the methods therein are applicable to all patients with multiple myeloma having an increase in the level of expression of FCGR2B relative to a reference level and this would have provided an effective means for treating the newly diagnosed multiple myeloma patients.
11. Claims 23 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Bryant et al (U.S. PGPUB 2006/0281122) OR Bryant (U.S. Patent No. 8,278,038), each in view of Fostier et al (OncoTargets and Therapy. 27 September 2012. 5:237-244; cited in the IDS of 04/14/2023).
The teachings of Bryant are presented above.
Bryant teaches treating the patients having multiple myeloma and having an increased level of expression of FCGR2B as compared to a reference level with any proteasome inhibitor (e.g., para [0122-0129]). Bryant does not specifically teach treating these patients with the proteasome inhibitor carfilzomib.
However, Fostier teaches methods for treating multiple myeloma comprising
administering the proteasome inhibitor carfilzomib (e.g., p. 237). It is disclosed that
carfilzomib is a selective and irreversible proteasome inhibitor (p. 237, Table 1); which is
well tolerated by patients (p. 242, col. 1) and has a fast response (p. 240, col. 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before
the effective filing date of the claimed invention to have modified the method of Bryant
so as to have administered the particular proteasome inhibitor of carfilzomib to the
multiple myeloma patients having increased expression levels of FCGFR2 in view of the
benefits set forth by Fostier that carfilzomib is a selective, irreversible proteasome
inhibition, with a low toxicity profile and is an effective, fast acting therapy for multiple
myeloma patients.
12. Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Bryant et al (U.S. PGPUB 2006/0281122) OR Bryant (U.S. Patent No. 8,278,038), each in view of Shaughnessy et al (U.S. 20120015906; cited in the IDS of 04/14/2023).
The teachings of Bryant are presented above. In particular, Bryant teaches that the level of expression of FCGR2B is measured in multiple myeloma tumor cells. Bryant does not specifically teach that the FCGR2B expression levels in CD138-positive tumor cells from the subject having multiple myeloma are higher than the reference level.
However, Shaughnessy teaches methods for predicting survival of patients having multiple myeloma comprising assaying for the level of gene expression in CD138 plasma cells obtained from bone marrow from patients prior to and following treatment with the proteasome inhibitor bortezomib (e.g., para [0051] and [0064]). Shaughnessy states that:
[0007] Emerging evidence suggests that the prognosis of patients with multiple myeloma is best captured by gene expression profiling analysis of CD138-purified plasma cells (PC).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bryant so as to have measured FCGR2B expression in CD138-positive tumor cells obtained from bone marrow of patients having multiple myeloma because Shaughnessy teaches that this is an effective source of tumor cells for measuring gene expression so as to evaluate a patient’s responsiveness to treatment with a proteasome inhibitor. Such a modification of the method of Bryant would have resulted in a method of treating a multiple myeloma tumor in a subject from which a sample of CD138-positive tumor cells was obtained, the method comprising administering a proteasome inhibitor to the subject, wherein the level of expression FCGR2B in the sample is greater than a reference level.
13. Claims 29, 30, 38 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Bryant et al (U.S. PGPUB 2006/0281122) OR Bryant (U.S. Patent No. 8,278,038), each in view of Gomeni et al (Br J Clin Pharmacol. 2006. 63(5): 595-613).
The following rejection is applied to the claims to the extent that the claims may intend to require determining a reference level by performing a ROC curve analysis with a cutoff of a correlation with responsiveness to a proteasome inhibitor of at least 50% specificity and sensitivity.
The teachings of Bryant are presented above.
Bryant does not specifically teach that the reference level is a cutoff correlated with a specificity of at least 50% and a sensitivity of at least 50%, as determined by a receiver operating characteristic (ROC) curve (claims 29 and 38), particularly wherein the ROC curve is based on the distribution of FCGR2B expression levels of responders and non-responders (claims 30 and 39).
However, Gomeni teaches methods for assessing responsiveness versus non-responsiveness of patients to therapy using ROC curve analysis (see, e.g., abstract; p. 599 final para to p. 600, col. 1). It is stated that “ROC curve was developed as a measure of the accuracy of diagnostic tests in medicine and other fields. ROC curves display the relationship between [sensitivity] (true-positive rate) and [1 − specificity] (false-negative rate) across all possible cut-off values defining the response to a treatment. The cut-off value is used to allocate a patient in the group of responders or nonresponders at week 8 given the early HAMD-17 measurement and the associated probability of being a responder derived from the two modelling approaches” (p. 599, final para).
Regarding the ROC curve, Gomeni (p. 600 col. 1) further teaches:
The larger is the area the better is the predictive performance. The area of 1.0 is associated with the ideal predictor because it achieves both 100% sensitivity and 100% specificity. The area of 0.5 is associated with a predictor with 50% sensitivity and 50% specificity. This is a test that is no better than flipping a coin. In practice, a reliable predictor should have an area somewhere between these two extremes. The closer the area is to 1.0, the better the predictor, and the closer the area is to 0.5, the worse the predictor.
The ROC curve is generally used to select the cut-off point that best suits the investigator’s purpose. That is, if one wished to eliminate false positives, one would
choose a leftward cut-off which minimizes false positives (high specificity and therefore lower sensitivity). If, on the other hand, one wished to eliminate false negatives, a more rightward cut-off which minimizes false negatives would be chosen (high sensitivity and therefore lower specificity). The determination of an ‘ideal’ cut-off value is almost always a trade-off between sensitivity (true positives) and specificity (true negatives).”
In view of the teachings of Gomeni, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bryant so as to have used a reference level that was determined using ROC curve analysis wherein the ROC curve is based on the distribution of FCGR2B expression levels in responders and non-responders and the cutoff for a correlation with responsiveness to the proteasome inhibitor was set to at least 50% specificity and 50% sensitivity. One would have been motivated to have done so because Gomeni teaches that ROC curve analysis is an effective means for distinguishing between patients who are responsive and not responsive to a therapy and that a cut-off should be selected which is above 50% specificity and 50% sensitivity in order to minimize false positive and false-negative results.
14. Claims 31 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Bryant et al (U.S. PGPUB 2006/0281122) OR Bryant (U.S. Patent No. 8,278,038), each in view of Krishnappa et al (ecancer . 2011. 5:189, p. 1-7).
The teachings of Bryant are presented above.
Bryant is silent as to the degree to which the expression level of FCGR2B is increased relative to the reference level and thereby Bryant does not specifically teach that the method is one in which the level of expression of FCGR2B in the sample / tumor of the subject is at least 2-fold greater than that of the reference level.
However, Bryant does state:
[0212] Markers using the 7,017 probe sets were analyzed for differential
expression across the 224 patient samples using the t-test and PFC methods described
above. Probe sets found to be significant by t-test with a p-value less than 0.01, or
having a PFC score other than 0, are reported in Table 1A, Table 1B, Table 2A, Table
2B and Table 3. These probe sets can be used in building marker sets as exemplified
below.
Further, Krishnappa teaches methods of analyzing for gene expression levels in tumor samples (e.g., “Methods” at p. 2). Krishnappa states: ‘Researchers generally’ use a cut off at least 2-fold change (linear value) between control and experiment to ‘screen significantly differentially expressed genes’.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bryant so as to have administered the proteasome inhibitor to subjects having an expression level of FCGR2B in tumor cells that was at least 2-fold higher than the reference value. One would have been motivated to have done so because Krishnappa teaches that a 2-fold change in the expression level of a biomarker compared to a control / reference level is generally considered by researches to be a significant level of differential expression. Thereby, such a modification of the method of Bryant would have provided an effective means for treating those patients most likely to benefit from treatment with the proteasome inhibitor based on their at least 2-fold increase in the level of expression of FCGR2B as compared to the reference level.
15. Claims 26 is rejected under 35 U.S.C. 103 as being unpatentable over Tuch et al (Cancer Research. 2014. 74. 19_Supplement, Abstract 898; poster presented at meeting held April 5-9, 2014).
The teachings of Tuch are presented above.
Tuch teaches that the patients administered the proteasome inhibitor of carfilzomib had multiple myeloma but does not specifically recite administering the proteasome inhibitor to a patient newly diagnosed with multiple myeloma.
However, Tuch does teach the effectiveness of proteasome inhibitors in treating multiple myeloma in patients having high FCGR2B expression levels and states that “(p)roteasome inhibitors (PrIs), including carfilzomib and bortezomib, are one such class of drugs that has become a standard therapy across all lines of myeloma treatment.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Tuch so as to have specifically administered carfilzomib to patients newly diagnosed with multiple myeloma having an increase in the level of expression of FCGR2B relative to a reference level. One would have been motivated to have done so since Tuch teaches that carfilzomib therapy is effective in multiple myeloma patients having an increase in the level of expression of FCGR2B relative to a reference level and thereby such a modification of the method of Tuch would have provided an effective means for treating newly diagnosed multiple myeloma patients.
16. Claims 27 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Tuch et al (Cancer Research. 2014. 74. 19_Supplement, Abstract 898; poster presented at meeting held April 5-9, 2014) in view of Fostier et al (OncoTargets and Therapy. 27 September 2012. 5:237-244; cited in the IDS of 04/14/2023).
The teachings of Tuch are presented above.
Tuch teaches that the patients administered the proteasome inhibitor of carfilzomib had multiple myeloma but does not specifically recite administering the carfilzomib to a multiple myeloma patient that has received one to three prior lines of therapy.
However, Fostier teaches methods for treating multiple myeloma comprising
administering the proteasome inhibitor carfilzomib (e.g., p. 237). It is disclosed that
carfilzomib is a selective and irreversible proteasome inhibitor (p. 237, Table 1); which is
well tolerated by patients (p. 242, col. 1) and has a fast response (p. 240, col. 2). Fostier teaches that carfilzomib is particularly useful in relapsed / refractory multiple myeloma patients (p. 242 “Conclusion” and abstract) - i.e., patients treated previously with at least one type / line of a different therapy. Fostier (p. 238, final para to p. 239 first para) teaches that patients in their study “Patients were eligible if they had relapsed from more than two prior therapies, failed bortezomib and at least one immunomodulatory agent (thalidomide or lenalidomide), and were refractory to last treatment (defined as progressing on or within 60 days of last therapy or had less than a 25% response to the last treatment regimen). Patients in the PX-171-004 study had received 1 to 3 prior lines of therapy (p. 239, col. 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before
the effective filing date of the claimed invention to have modified the method of Tuch
so as to have administered the proteasome inhibitor of carfilzomib to relapsed / refractory multiple myeloma patients having increased expression levels of FCGFR2 and who had had previously received 1 to 3 lines of a different therapy. One would have been motivated to have specifically treated these relapsed / refractory multiple myeloma patients with carfilzomib in view of the benefits set forth by Fostier that carfilzomib is a selective, irreversible proteasome inhibition, with a low toxicity profile and is an effective, fast acting therapy for relapsed / refractory multiple myeloma patients.
17. Claims 29, 30, 38 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Tuch et al (Cancer Research. 2014. 74. 19_Supplement, Abstract 898; poster presented at meeting held April 5-9, 2014) in view of Gomeni et al (Br J Clin Pharmacol. 2006. 63(5): 595-613).
The teachings of Tuch are presented above.
Tuch does not specifically teach that the patients having a high level of FCGR2B expression had a level above a reference level that is a cutoff correlated with a specificity of at least 50% and a sensitivity of at least 50%, as determined by a receiver operating characteristic (ROC) curve (claims 29 and 38), particularly wherein the ROC curve is based on the distribution of FCGR2B expression levels of responders and non-responders (claims 30 and 39).
However, Gomeni teaches methods for assessing responsiveness versus non-responsiveness of patients to therapy using ROC curve analysis (see, e.g., abstract; p. 599 final para to p. 600, col. 1). It is stated that “ROC curve was developed as a measure of the accuracy of diagnostic tests in medicine and other fields. ROC curves display the relationship between [sensitivity] (true-positive rate) and [1 − specificity] (false-negative rate) across all possible cut-off values defining the response to a treatment. The cut-off value is used to allocate a patient in the group of responders or nonresponders at week 8 given the early HAMD-17 measurement and the associated probability of being a responder derived from the two modelling approaches” (p. 599, final para).
Regarding the ROC curve, Gomeni (p. 600 col. 1) further teaches:
The larger is the area the better is the predictive performance. The area of 1.0 is associated with the ideal predictor because it achieves both 100% sensitivity and 100% specificity. The area of 0.5 is associated with a predictor with 50% sensitivity and 50% specificity. This is a test that is no better than flipping a coin. In practice, a reliable predictor should have an area somewhere between these two extremes. The closer the area is to 1.0, the better the predictor, and the closer the area is to 0.5, the worse the predictor.
The ROC curve is generally used to select the cut-off point that best suits the investigator’s purpose. That is, if one wished to eliminate false positives, one would
choose a leftward cut-off which minimizes false positives (high specificity and therefore lower sensitivity). If, on the other hand, one wished to eliminate false negatives, a more rightward cut-off which minimizes false negatives would be chosen (high sensitivity and therefore lower specificity). The determination of an ‘ideal’ cut-off value is almost always a trade-off between sensitivity (true positives) and specificity (true negatives).”
In view of the teachings of Gomeni, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Tuch so as to have used a reference level that was determined using ROC curve analysis wherein the ROC curve is based on the distribution of FCGR2B expression levels in responders and non-responders and the cutoff for a correlation with responsiveness to the proteasome inhibitor was set to at least 50% specificity and 50% sensitivity. One would have been motivated to have done so because Gomeni teaches that ROC curve analysis is an effective means for distinguishing between patients who are responsive and not responsive to a therapy and that a cut-off should be selected which is above 50% specificity and 50% sensitivity in order to minimize false positive and false-negative results.
13. Claims 31 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Tuch et al (Cancer Research. 2014. 74. 19_Supplement, Abstract 898; poster presented at meeting held April 5-9, 2014) in view of Krishnappa et al (ecancer . 2011. 5:189, p. 1-7).
The teachings of Tuch are presented above.
Tuch teaches that patients having “high FCGR2B expression” were responsive to carfilzomib. Tuch is silent as to the degree to which the expression level of FCGR2B is increased relative to a reference level and thereby Tuch does not specifically teach that the method is one in which the level of expression of FCGR2B in the sample / tumor of the subject is at least 2-fold greater than that of the reference level.
However, Krishnappa teaches methods of analyzing for gene expression levels in tumor samples (e.g., “Methods” at p. 2). Krishnappa states: ‘Researchers generally’ use a cut off at least 2-fold change (linear value) between control and experiment to ‘screen significantly differentially expressed genes’.
In view of the teachings of Krishnappa, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Tuch so as to have administered the carfilzomib to subjects having an expression level of FCGR2B in tumor cells that was at least 2-fold higher than a reference, control value. One would have been motivated to have done so because Krishnappa teaches that a 2-fold change in an expression level of a biomarker compared to a control / reference level is a generally considered by researches to be a significant level of differential expression. Thereby, such a modification of the method of Tuch would have provided an effective means for treating those patients most likely to benefit from treatment with the proteasome inhibitor of carfilzomib based on the detection of an at least 2-fold increase in the level of expression of FCGR2B.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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