DETAILED ACTION
This office action is in response to the Applicant’s filing dated December 17th, 2025.
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 .
Priority
This application is a 371 of PCT/US2021/029503 filed on April 27th, 2021; and has a PRO 63/016,983 filed on April 28th, 2020.
Status of Claims
Claims 3, 10, 15-17, 22, 24, 30, 35, 38, 40, 44, 71, 82, 84, 94-95, 98, 100, 107 and 117-118 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed on December 17th, 2025. Acknowledgement is made of Applicant's amendment of claims 3, 10, 15-16, 22, 24, 30, 38, 44, 71, 82 and 107; cancelation of claims 1, 4, 8 and 11; and addition of new claims 117-118.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Maintained Objections and/or Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3, 15-17, 22, 24, 30, 35, 38, 40, 71, 82, 84, 94-95, 98, 100 and 107 are rejected under 35 U.S.C. 103 as being unpatentable over Bjorklund et al (Leukemia, (2019), 34(4), 1197–1201), cited in a previous Office action; in view of Quigley et al (WO 2018/085690 A1, cited in the IDS filed May 16th, 2023).
Regarding claim 3, Bjorklund teaches the compound Iberdomide shown below:
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Bjorklund teaches that Iberdomide is potent and effective in treating resistant multiple myeloma (MM) cell lines; reporting that Iberdomide shows strong antiproliferative activity and pro-apoptotic activity in multiple myeloma cell lines, including in lenalidomide resistant cell lines (page 1197, left column, second paragraph). Bjorklund further states that Iberdomide’s biochemical potency provides strong preclinical and translational evidence supporting its clinical potential in relapsed refractory multiple myeloma, including in combination with other agents (page 1200, left column, second paragraph).
Bjorklund does not teach a method of treating MM comprising a T cell therapy; wherein the T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to BCMA, and the administration of the immunomodulatory compound is initiated after administration of the T cell therapy; or wherein the MM is R/R MM, prior to the initiation of administration of T-cell therapy and the immunomodulatory compound, the subject has received one or more prior therapies for treating the R/R MM, the one or more prior therapies comprising an immunomodulatory agent.
Quigley teaches that “Chimeric Antigen Receptor (CAR) T-cells are molecules that combine antibody-based specificity for a desired antigen with a T cell receptor-activating intracellular domain to generate a chimeric protein that exhibits a specific anti-cancer immune activity” (page 1, last paragraph). Quigley further teaches Example 3 (pages 29-32) wherein “anti-BCMA02 CAR T cells were administered to patients with relapsed and/or refractory BCMA-positive MM who received at least 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory; 100% of patients received at least 1 prior autologous stem cell transplant” (page 29, last paragraph; page 30, lines 13-14). Quigley further teaches anti-BCMA02 CAR T cells demonstrate clinical efficacy against relapsed and/or refractory multiple myeloma stating, “Anti-BCMA02 CAR T cells showed remarkable efficacy at dose levels above 5.0 x 107 CAR+ T cells, including 2 CRs and ongoing clinical response at 6 months. In contrast to results with other CAR T cell therapies, the efficacy of the anti-BCMA02 CAR T cells was accompanied by unexpectedly mild and manageable CRS (Cytokine Release Syndrome), including in patients with ≥50% bone marrow involvement. These data support the therapeutic efficacy of anti-BCMA02 CAR T cells for relapsed/refractory multiple myeloma” (pages 31, last paragraph; page 32, first paragraph).
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
It would have been prima facie obvious to a person of ordinary skill in the art to combine the immunomodulatory compound Iberdomide taught by Bjorklund with the anti-BCMA CAR+ T cell therapy taught by Quigley for the treatment of R/R MM. Bjorklund establishes the efficacy of Iberdomide in Lenalidomide resistant MM; while Quigley demonstrates the efficacy of anti-BCMA CAR+ T cell therapy in R/R MM patients who had previously received at least 3 prior regimens, including at least 1 prior autologous stem cell transplant, a proteasome inhibitor and an immunomodulatory agent or who were double-refractory. A person of ordinary skill in the art, motivated by conventional rationale of combining known therapies to improve patient outcomes would have had a reasonable expectation of success in co-administering the two therapies. The claimed invention represents the predictable use of prior art elements according to their established functions, yielding predictable results.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Furthermore, it is obvious to vary and/or optimize the result-effective variables of administration timing and dosing regimens of the immunomodulatory compound in relation to the anti-BCMA02 CAR+ T cells according to guidance established by Bjorklund and Quigley in order to balance safety with efficacy. It is noted that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claims 15-17, Bjorklund and Quigley render the method of claim 3 obvious as described in the above rejection.
Quigley further teaches that anti-BCMA02 CAR+ T cells were administered to patients with relapsed and/or refractory BCMA-positive MM who received at least 3 prior regimens (addressing claim 15), including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory; 100% of patients received at least 1 prior autologous stem cell transplant, 67% received prior daratumumab or CD38 mab (addressing claim 16), 89% received prior lenalidomide and 78% received prior pomalidomide (addressing claim 17) (page 29, last paragraph; page 30, lines 13-14).
Regarding claims 22, 24, 30, 35, 38 and 40, Bjorklund and Quigley render the method of claim 3 obvious as described in the above rejection.
Bjorklund further teaches that, “CAR+ T cell expansion was consistently demonstrated, and is similar to other published CAR T cell trials” (page 31, lines 8-9).
Bjorklund and Quigley do not teach the dosing regimens of the instant claims for the immunomodulatory compound in relation to the anti-BCMA02 CAR+ T cells.
It is obvious to vary and/or optimize the result-effective variables of administration timing and dosing regimens of the immunomodulatory compound in relation to the anti-BCMA02 CAR+ T cells according to guidance established by Bjorklund and Quigley in order to balance safety with efficacy. It is noted that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 71, Bjorklund and Quigley render the method of claim 3 obvious as
described in the above rejection.
Quigley further teaches dose levels of anti-BCMA02 CAR+ T cells of 5.0 x 107, 15.0 x 107 and 45.0 x 107 (page 31, Table 5).
MPEP § 2144.05 states:
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Regarding claims 82, 94-95, 98 and 100, Bjorklund and Quigley render the method of claim 3
obvious as described in the above rejection.
Quigley further teaches the anti-BCMA CAR+ comprises an anti-BCMA scFv, which a person of ordinary skill in the art would recognize as an antigen binding domain that binds to BCMA (page 27, Table 3, Nucleotides 3188-3934); a CD8α hinge (spacer) and transmembrane domain (page 27, Table 3, Nucleotides 3935-4141); an intracellular signaling region comprising a CD3-ζ chain (page 28, Table 3, Nucleotides 4270-4606); and wherein the intracellular signaling region further comprises a costimulatory signaling domain, wherein the costimulatory signaling domain comprises an intracellular signaling domain of 4-1BB (page 27, Table 3, Nucleotides 4144-4269).
Regarding claim 84, Bjorklund and Quigley render the method of claim 3 obvious as
described in the above rejection.
Quigley further teaches the amino acid sequences of exemplary light chain CDR sequences, SEQ ID NOs: 1-3 (page 7, lines 2-3; page 49); and amino acid sequences of exemplary heavy chain CDR sequences, SEQ ID NOs: 4-6 (page 7, lines 4-5; page 50).
These light and heavy chain CDR sequences, SEQ ID NOs 1-6, of Quigley are an identical 100% sequence identity match for SEQ ID NOs 62-67 of instant claim 84 as seen on page 205 of the specification.
Regarding claim 107, Bjorklund and Quigley render the method of claim 3 obvious as
described in the above rejection.
Quigley further teaches the full polynucleotide sequence that encodes an exemplary anti-BCMA CAR, SEQ ID NO: 10 (page 7, lines 12-13; pages 54-56).
A BLASTp alignment conducted by the Examiner confirmed that Quigley’s SEQ ID NO: 10 is identical to applicant’s SEQ ID NO: 153 of instant claim 107 as seen on page 216 of the specification; 472/472 identities, 100% sequence identity match, no gaps.
Taken together, all this would result in the practice of the methods of instant claims 3, 15-17, 22, 24, 30, 35, 38, 40, 71, 82, 84, 94-95, 98, 100 and 107 with a reasonable expectation of success.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Bjorklund et al (Leukemia, (2019), 34(4), 1197–1201), cited in a previous Office action; in view of Quigley et al (WO 2018/085690 A1, cited in the IDS filed May 16th, 2023); further in view of Borovinskaya et al (US 2020/0330445 A1), cited in a previous Office action.
Regarding claim 44, Bjorklund and Quigley render the method of claim 3 obvious as described in the above rejection.
Bjorklund and Quigley do not teach the particular weight ranges recited in instant claim 44 of the immunomodulatory compound.
Borovinskaya teaches Iberdomide is an immunomodulatory compound used to treat refractory multiple myeloma (page 1, paragraph [0003]; page 2, paragraph [0008]), and discloses a method wherein the immunomodulatory compound is delivered in a dose of 500 mcg per day (page 4, paragraph [0048]; page 5, paragraph [0050]), which is equivalent to 0.5 mg per day, to treat multiple myeloma (page 5, paragraph [0051]).
MPEP § 2144.05 states:
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Taken together, all this would result in the practice of the method of instant claim 44 with a reasonable expectation of success.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al (WO 2019/226761 A1, cited in the IDS filed May 16th, 2023); in view of Quigley et al (WO 2018/085690 A1, cited in the IDS filed May 16th, 2023).
Regarding claim 10, Pierce teaches a method of treating multiple myeloma; wherein that multiple myeloma is relapsed, refractory or resistant (page 125, claim 3); comprising administering a compound of Formula I or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof shown below:
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In combination with a bi specific antibody comprising a first binding part specifically binding to human B cell maturation antigen (BCMA) and a second binding part specifically binding to human CD3ε (page 124, claim 1); wherein the compound is administered subsequent to the bispecific antibody (page 125, claim 10).
Moreover, Pierce teaches Example 7 (pages 122-123) further establishing the therapeutic utility of Mezigdomide in Lenalidomide resistant multiple myeloma cells. Co-cultures of effector T cells (E) and Lenalidomide-resistant multiple myeloma target T cells (page 122, last paragraph) were treated with increasing concentrations of the bi specific antibody specifically binding to human B cell maturation antigen (BCMA) and to human CD3ε; after a pretreatment with compounds selected from Pomalidomide, Mezigdomide (Compound 2) or DMSO as a control (page 123, first paragraph). Pierce states, “The results demonstrated that pretreatment of Lenalidomide-resistant H929-1051 target cells by Compound 2, but not by pretreatment with Pomalidomide, increased the potency and maximal target cell killing induced by the bispecific antibody as tested (Figure 6). The data suggest the cell line is also Pomalidomide-resistant” (page 132, first paragraph).
Pierce does not teach a method of treating MM comprising a T cell therapy; wherein the T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to BCMA; or wherein the MM is R/R MM, prior to the initiation of administration of T-cell therapy and the immunomodulatory compound, the subject has received one or more prior therapies for treating the R/R MM, the one or more prior therapies comprising an immunomodulatory agent.
Quigley teaches that “Chimeric Antigen Receptor (CAR) T-cells are molecules that combine antibody-based specificity for a desired antigen with a T cell receptor-activating intracellular domain to generate a chimeric protein that exhibits a specific anti-cancer immune activity” (page 1, last paragraph). Quigley further teaches Example 3 (pages 29-32) wherein “anti-BCMA02 CAR T cells were administered to patients with relapsed and/or refractory BCMA-positive MM who received at least 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory” (page 29, last paragraph). Quigley further teaches anti-BCMA02 CAR T cells demonstrate clinical efficacy against relapsed and/or refractory multiple myeloma stating, “Anti-BCMA02 CAR T cells showed remarkable efficacy at dose levels above 5.0 x 107 CAR+ T cells, including 2 CRs and ongoing clinical response at 6 months. In contrast to results with other CAR T cell therapies, the efficacy of the anti-BCMA02 CAR T cells was accompanied by unexpectedly mild and manageable CRS (Cytokine Release Syndrome), including in patients with ≥50% bone marrow involvement. These data support the therapeutic efficacy of anti-BCMA02 CAR T cells for relapsed/refractory multiple myeloma” (pages 31, last paragraph; page 32, first paragraph).
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
It would have been prima facie obvious to a person of ordinary skill in the art to combine the immunomodulatory compound Mezigdomide taught by Pierce with the anti-BCMA CAR T cell therapy taught by Quigley for the treatment of relapsed or refractory multiple myeloma. Pierce establishes the efficacy of Mezigdomide in Lenalidomide resistant MM; while Quigley demonstrates the efficacy of anti-BCMA CAR T cell therapy in R/R MM patients who had previously received at least 3 prior regimens, including an immunomodulatory agent or who were double-refractory. A person of ordinary skill in the art, motivated by conventional rationale of combining known therapies to improve patient outcomes would have had a reasonable expectation of success in co-administering the two therapies. The claimed invention represents the predictable use of prior art elements according to their established functions, yielding predictable results.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Taken together, all this would result in the practice of the method of instant claim 10 with a reasonable expectation of success.
New Objections and/or Rejections
Necessitated by Claim Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 117 is rejected under 35 U.S.C. 103 as being unpatentable over Bjorklund et al (Leukemia, (2019), 34(4), 1197–1201), cited in a previous Office action; in view of Quigley et al (WO 2018/085690 A1, cited in the IDS filed May 16th, 2023) as applied to claims 3, 15-17, 22, 24, 30, 35, 38, 40, 71, 82, 84, 94-95, 98, 100 and 107 above.
Regarding claim 117, Bjorklund and Quigley render the method of claims 3, 15-17, 22, 24, 30, 35, 38, 40, 71, 82, 84, 94-95, 98, 100 and 107 obvious as described in the above rejection.
It would have been prima facie obvious to one of ordinary skill in the art to optimize the treatment administration order of Iberdomide and Anti-BCMA CAR-T therapy, since Bjorklund and Quigley teach that each of these therapies are individually useful for treating multiple myeloma, and because both dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable treatment administration order would have been well within the practice of routine experimentation by the skilled artisan.
MPEP 2144.04(IV)(C) states:
“Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results” In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); “Selection of any order of mixing ingredients is prima facie obvious.” In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930).
As such, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosing regimen, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the practice of the method of instant claim 117 with a reasonable expectation of success.
Claim 118 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al (WO 2019/226761 A1, cited in the IDS filed May 16th, 2023); in view of Quigley et al (WO 2018/085690 A1, cited in the IDS filed May 16th, 2023) as applied to claim 10 above.
Regarding claim 118, Pierce and Quigley render the method of claim 10 obvious as described in the above rejection.
It would have been prima facie obvious to one of ordinary skill in the art to optimize the treatment administration order of Mezigdomide and Anti-BCMA CAR-T therapy, since Pierce and Quigley teach that each of these therapies are individually useful for treating multiple myeloma, and because both dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable treatment administration order would have been well within the practice of routine experimentation by the skilled artisan.
MPEP 2144.04(IV)(C) states:
“Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results” In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); “Selection of any order of mixing ingredients is prima facie obvious.” In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930).
As such, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosing regimen, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the practice of the method of instant claim 118 with a reasonable expectation of success.
Applicant argues:
Applicant contends there is no motivation to combine Bjorklund and Quigley. Bjorklund teaches that Iberdomide is potent and effective in treating resistant multiple myeloma (MM), but does not teach Iberdomide in combination with an anti-BCMA CAR-T therapy. Quigley teaches anti-BMA CAR-T cell therapy to treat MM, but does not teach Iberdomide in combination with an anti-BCMA CAR-T therapy. Applicant further states the citation of Kerkhoven is misplaced because Kerkhoven was based on methods of making detergent compositions.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As the Applicant has acknowledged, Bjorklund teaches Iberdomide is potent and effective in treating multiple myeloma (MM), while Quigley teaches anti-BMA CAR-T cell therapy to treat MM. Thus, it is well established in the art that both of these therapies are useful in the treatment of MM. Bjorklund further teaches that Iberdomide’s biochemical potency provides strong preclinical and translational evidence supporting its clinical potential in relapsed refractory multiple myeloma, including in combination with other agents. Combination therapy is routinely employed in the treatment of cancer, including multiple myeloma, to improve therapeutic efficacy, address drug resistance, and in some instances take advantage of complimentary mechanisms of action.
MPEP 2144 (I) states:
“The rationale to modify or combine the prior art does not have to be expressly stated
in the prior art; the rationale may be expressly or impliedly contained in the prior art or
it may be reasoned from knowledge generally available to one of ordinary skill in the art,
established scientific principles, or legal precedent established by prior case law. In re
Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21
USPQ2d 1941 (Fed. Cir. 1992); see also In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d
1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining
teachings).”
Furthermore, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Applicant’s argument that Kerkhoven is inapplicable because it relates to detergent compositions is not persuasive. The case law establishes the concept of combining individual compositions taught by the prior art to be useful for the same purpose, in order to form a third composition for the very same purpose. Given that both Iberdomide and anti-BCMA CAR-T therapy are independently taught to be effective in treating multiple myeloma, one of ordinary skill in the art would have had a reasonable expectation of success.
Applicant argues:
Applicant contends that Pierce provides no motivation to combine the immunomodulatory compound Mezigdomide with a CAR-T cell therapy, and that Quigley does not explicitly teach co-administration of CAR-T cell therapy with an immunomodulatory agent.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As discussed in the above rejection, Pierce teaches that Mezigdomide is effective in treating relapsed or refractory multiple myeloma, including in patients resistant to prior immunomodulatory agents. Notably, Pierce further demonstrates that Mezigdomide enhances immune-mediated anti-tumor activity when used in combination with another immunotherapy (i.e. the bispecific antibody in Example 7 as discussed in the above rejection) thereby evidencing that Mezigdomide is suitable for use in combination regimens to improve therapeutic efficacy. Quigley teaches that anti-BCMA CAR-T therapy is an effective treatment for relapsed or refractory multiple myeloma, including in pretreated patients. Thus, both Pierce and Quigley teach independent therapies that are useful for treating the same disease and patient population. Given Pierce’s teaching that Mezigdomide enhances immune-mediated anti-tumor activity when used in combination with another immunotherapy, one of ordinary skill in the art would have been motivated to combine Mezigdomide with other immunotherapeutic approaches, including anti-BCMA CAR-T cell therapy as taught by Quigley.
MPEP 2144 (I) states:
“The rationale to modify or combine the prior art does not have to be expressly stated
in the prior art; the rationale may be expressly or impliedly contained in the prior art or
it may be reasoned from knowledge generally available to one of ordinary skill in the art,
established scientific principles, or legal precedent established by prior case law. In re
Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21
USPQ2d 1941 (Fed. Cir. 1992); see also In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d
1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining
teachings).”
Furthermore, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Accordingly, in view of the demonstrated efficacy of both therapies in the same patient population, one of ordinary skill in the art would have had a reasonable expectation of success in combining Mezigdomide and anti-BCMA CAR-T utilizing them for their established functions, yielding predictable results.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Applicant argues:
Applicant contends that there is no mention in Borovinskaya of anti-BCMA CAR-T therapy, and provides no motivation to combine the immunomodulatory compound with anti-BCMA CAR-T therapy.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The motivation to combine comes from the previously applied art of Bjorklund and Quigley as described above, which teach therapies useful for treating the same disease and patient population; not from Borovinskaya, which explicitly discloses the particular weight ranges of the immunomodulatory compound and is only relied upon for that purpose, not for teaching or suggesting combination with anti-BCMA CAR-T therapy.
Applicant argues:
Applicant contends that an unexpected increase in performance is exhibited by the claimed methods. Specifically, that Iberdomide is shown to be significantly more potent than Lenalidomide when used in combination with Anti-BCMA CAR-T therapy in Example 7 (pages 198-199 in the Specification) as seen in Figure 8; and an even more pronounced effect is seen with Mezigdomide in Example 3 (pages 193-194 in the Specification) as seen in Figures 3A, 3B; and Example 4 (pages 194-195 in the Specification) as seen in Figures 4A and 4B.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
While increased potency of Iberdomide and Mezigdomide relative to Lenalidomide, and performance improvements when combined with Anti-BCMA CAR-T therapy are acknowledged, it is not unexpected in view of the prior art as described above. Bjorlkund teaches that Iberdomide shows strong antiproliferative activity and pro-apoptotic activity in multiple myeloma cell lines, including in lenalidomide resistant cell lines. Pierce teaches that pretreatment of Lenalidomide-resistant H929-1051 target cells by Mezigdomide, increased the potency and maximal target cell killing induced by the bispecific antibody as tested; demonstrating that immunomodulatory compounds such as Mezidomide enhance the potency of immune mediated multiple myeloma therapies.
Accordingly, in view of the prior art teaching that immunomodulatory agents enhance immune related anti-tumor activity when used in combination with other therapies, an increase in potency when combined with Anti-BCMA CAR-T therapy would have been reasonably expected by a person of ordinary skill in the art, and is insufficient to overcome the prima facie case of obviousness.
Conclusion
Claims 3, 10, 15-17, 22, 24, 30, 35, 38, 40, 44, 71, 82, 84, 94-95, 98, 100, 107 and 117-118 are rejected.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691