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 .
DETAILED ACTION
Claims 1, 4-6, 8-15, 18, and 22-33 are pending in the instant application.
Claims 2-3 were canceled. Claims 28-33 are new.
Claim Rejections Withdrawn
The claim rejections of claims 2-3 are moot in view of claim cancelation.
Claim Rejections Maintained
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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.
The rejection of claims 1, 4-6, 8-11, 18, 23, and 25-27 under 35 U.S.C. 103 as being unpatentable over US 20190127479 (Ahmadi T et al., reference of record) and Caracciolo D et al. (Haematologica. 2021 106(1): 185–195, Published online 2020 Feb 20, reference of record) and evidenced by CAS Registry Number: 945721-28-8, daratumumab (SciFinder 2024, reference of record) is maintained.
Ahmadi 479 taught a method of treating a subject having high-risk multiple myeloma, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody, a corticosteroid, and a non-corticosteroid chemotherapeutic agent for a time sufficient to treat the high-risk multiple myeloma (specification, page 1, paragraph 8), wherein, the agents can be provided separately (specification, page 3, paragraph 44) concurrently or sequentially (specification, page 64, paragraph 64). Ahmadi 479 taught the anti-CD38 antibody can induce killing of CD38-expressing cells by antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), or apoptosis (specification, page 8, paragraph 104). Ahmadi 479 taught the daratumumab is administered intravenously (specification, page 15, paragraph 199). Ahmadi 479 taught the CD38 antibody as daratumumab with a H-CDR1-3 of SEQ ID NO:6-8, L-CDR1-3 of SEQ ID NO:9-11, VH of SEQ ID NO:4, VL of SEQ ID NO:5, a heavy chain sequence of SEQ ID NO:12, and a light chain sequence of SEQ ID NO:13 (specification, page 6, paragraph 73-76). Daratumumab is evidenced by SciFinder CAS Registry Number: 945721-28-8 as the IgG1kappa subtype. Ahmadi 479 taught the efficacy of daratumumab in combination with bortezomib and dexamethasone in Relapsed or Refractory Multiple Myeloma Patients (RRMM) in High-Risk Patients(specification, page 23, paragraph 354, example 3). Ahmadi 479 taught daratumumab-containing therapies are able to remarkably induce deep levels of clinical response in multiple myeloma subjects and daratumumab-containing regimens consistently showed 3-fold or greater increases in MRD negativity rate compared with the control groups at all evaluated thresholds.(specification, page 28, paragraph 396). Ahmadi 479 taught the deep clinical responses induced by addition of daratumumab may lead to improved long-term outcomes (specification, page 28, paragraph 396). Ahmadi 479 taught the subject for treatment has naive multiple myeloma, relapsed multiple myeloma, or refractory multiple myeloma (page 11, paragraph 137).
Ahmadi 479 did not teach a method for treating multiple myeloma with CD38 inhibitors in combination with PARPi, but this is obvious with a reasonable expectation of success in view of Caracciolo.
Caracciolo taught a significant correlation between higher PARP1 mRNA expression and poor prognosis of multiple myeloma patients (abstract). PARP1 knockdown or its pharmacological inhibition by olaparib impaired multiple myeloma cell viability in vitro and in in vivo xenografts of human multiple myeloma (abstract). Caracciolo taught MYC-driven multiple myeloma cells are addicted to PARP1 alternative non-homologous end joining repair, which therefore represents a druggable target in this still incurable disease (abstract). Caracciolo taught PARP1 was expressed in three of four primary multiple myeloma patient samples and seven of eight multiple myeloma cell lines (Fig. 2). Thus, the majority of multiple myeloma samples tested expressed PARP1. Caracciolo taught PARP1 is crucial for survival of MYC-addicted multiple myeloma cells and provides the rational framework for the use of PARP inhibitors as a therapeutic strategy in this still incurable disease of multiple myeloma (page 186, left column, last paragraph before Methods section). Caracciolo taught their findings imply that MYC-driven MM cells switch their DNA repair machinery to error prone PARP-mediated alternative NHEJ to overcome DNA damage overload from oncogenic stress, promoting cell survival and, at the same time, the acquisition of new genetic changes leading to disease progression (Figure 6 and page 194, bridging paragraph left to right column). Caracciolo taught that MYC induces alternative NHEJ repair to balance the downregulation of homologous recombination induced by bortezomib, which contributes to the development of drug resistance and, at the same time, making MM cells more dependent on PARP1-mediated DNA repair to survive (page 194, right column, paragraph 1). Caracciolo taught drug resistant (bortezomib-resistant) cells are highly sensitive to PARP inhibitors such as olaparib (page 193, first and second paragraph under Bortezomib-resistant cells are highly sensitive to PARP inhibition). Caracciolo taught oral administration of olaparib (page 186, right column, paragraph 3).
Regarding instant claims 1-6, 8-11, 18, 23, and 25-27, it would have been obvious for a person having ordinary skill in the art to modify the method of Ahmadi 479 for treating the CD38 expressing high risk multiple myeloma that is naïve or relapsed or refractory multiple myeloma with daratumumab, dexamethasone and bortezomib – and: 1) use the teaching of Caracciolo to include oral PARP inhibitor olaparib in the treatment.
This would produce a method of treating CD38 expressing high risk multiple myeloma (instant claim 18 and 23) that is naïve or relapsed or refractory multiple myeloma (instant claim 25), in a subject in need thereof with daratumumab comprising the amino acid sequence identical to instant VH SEQ ID NO:12 and VL SEQ ID NO:13 and further comprises VH SEQ ID NO:4 and VL SEQ ID NO: 5 with HCDR1-3 SEQ ID NO: 6-8 and LCDR1-3 SEQ ID NO:9-11 and the IgG1kappa subtype (instant claims 2-5), intravenously (instant claim 6) and dexamethasone, bortezomib, and the oral PARP1 inhibitor olaparib (instant claims 8-10) separately (instant claim 11), for a time sufficient to treat the high-risk multiple myeloma that is naïve or relapsed or refractory multiple myeloma which is a CD38 positive malignancy (instant claims 1 and 26-27).
This is obvious because: 1a) Caracciolo taught MYC induces alternative NHEJ repair to balance the downregulation of homologous recombination induced by bortezomib, which contributes to the development of drug resistance and, at the same time, making multiple myeloma cells more dependent on PARP1-mediated DNA repair to survive; 1b) drug resistant (bortezomib-resistant) multiple myeloma cells are highly sensitive to PARP inhibitors such as olaparib. Thus, the combination would be expected to beneficial.
There is a reasonable expectation of success because: 1a) the combination of daratumumab, dexamethasone, bortezomib and the PARP inhibitor olaparib would be expected to be more effective for multiple myeloma treatment when MYC induces alternative NHEJ repair to balance the downregulation of homologous recombination induced by bortezomib, which contributes to the development of drug resistance and, at the same time, making MM cells more dependent on PARP1-mediated DNA repair to survive; 1b) any bortezomib resistant clones of the multiple myeloma would be more sensitive to olaparib treatment; and 1c) daratumumab-containing therapies are able to remarkably induce deep levels of clinical response in multiple myeloma subjects and daratumumab-containing regimens consistently showed 3-fold or greater increases in MRD negativity rate compared with the control groups at all evaluated thresholds.
Response to Arguments
Applicant respectfully disagrees with all rejections. Caracciolo identified a subset of MM patients who could benefit from PARP inhibitors -patients having higher PARP1 expression with high MYC expression (e.g., p. 185, Abstract). Applicant respectfully submits that substantial evidence does not support a factual finding that MM patients receiving daratumumab, dexamethasone, and bortezomib (DVd) share this feature
and therefore, would benefit from PARP inhibitor olaparib. Applicant incorporates herein the arguments submitted in the Responses dated April 9, 2025 and August 1, 2024, and the accompanying Exhibits 1-2 ("the previous replies"), and addresses the Office's response to Applicant's reasonings.
Applicant argues One of Skill in the Art Would Not Expect MM Cells Treated with DVd to Express High Levels of PARP1. As the Office acknowledges, Caracciolo taught a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. Caracciolo also discloses that higher levels of PARP1 mRNA predicted poor overall and progression-free survival for patients who received bortezomib-based therapy. (P. 188, first full paragraph, emphasis added.) Caracciolo discloses that the association between higher PARP1 mRNA expression and poor prognosis strongly suggests an involvement of PARP1 in the genomic instability of MM, disease
progression, and drug resistance. (Id.) Based on Caracciolo' s disclosure, one of skill in the art would expect lower PARP1 mRNA expression in MM cells of patients exhibiting improved prognosis and good overall and progression-free survival -- the logic being if "A" predicts "B," then "not-B" predicts "not-A"
The Office appears to acknowledge that Ahmadi discloses that MM patients receiving DVd exhibit good overall and progression-free survival.
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Because: (i) Ahmadi discloses that the combination of DVd prolongs overall and
progression-free survival of MM patients, and (ii) Caracciolo implies lower PARP1 mRNA expression in MM cells of patients exhibiting improved prognosis and good overall and progression-free survival, one of skill in the art would not expect MM cells treated with DVd to express a high level of PARP 1 mRNA.
The Office asserts that Caracciolo taught that PARP1 was expressed in three of four primary multiple myeloma patient samples and seven of eight multiple myeloma cell lines, and, thus, the majority of multiple myeloma samples tested expressed PARP1 protein. The Office also asserts that one of skill in the art would expect that MM cells that expressed PARP1 would depend on PARP1-mediated DNA repair to survive.
However, Caracciolo discloses that: (i) PARP1 was expressed in samples of 4 healthy donors; and (ii) no statistically significant increase of PARP 1 mRNA expression was
observed in samples of 129 MM cases. (Figure 1B, reproduced, Supplementary Appendix, p. 7, 1st paragraph.)
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Caracciolo states that "[c]onsistently, we found that high PARP 1 mRNA expression is significantly correlated with poor event-free and overall survival in MM patients, and increases during disease progression and in high-risk cases. Moreover, PARP1 mRNA is the most expressed among PARP family members, thus suggesting a critical role of PARP1 in MM pathogenesis." (P. 194, left column, l81 full paragraph, emphasis added.) Accordingly, Caracciolo associates higher PARP1 expression with MM pathogenesis. Therefore, the relevant question was not whether MM cells treated with DVd express PARP1, but whether they express higher levels of PARP1.
In response, Applicant's arguments filed 9/19/2025 have been fully considered
but they are not persuasive. The obvious rational is above wherein Ahmadi 479 taught a method for treating multiple myeloma with a composition comprising the CD38 inhibitor daratumumab – and addition of PARPi is obvious with a reasonable expectation of success in view of Caracciolo.
Regarding the arguments that: A) One of Skill in the Art Would Not Expect MM Cells Treated with DVd to Express High Levels of PARP1; and B) the relevant question was not whether MM cells treated with DVd express PARP1, but whether they express higher levels of PARP1 -
Caracciolo taught PARP1 was expressed in three of four primary multiple myeloma patient samples and seven of eight multiple myeloma cell lines (Caracciolo Fig. 2). Thus, the majority of multiple myeloma samples tested expressed PARP1 protein. Further, knockdown of PARP1 or olaparib treatment was effective against multiple myeloma cell lines and patient primary multiple myeloma samples that expressed PARP1. Therefore, subjects with multiple myeloma would be expected to benefit from a treatment that comprised a PARP1 inhibitor as taught by Caracciolo and a daratumumab-containing therapies that are taught to be effective as taught by Ahmadi 479. One of skill in the art would NOT expect lower PARP1 mRNA expression in MM cells of patients that are about to be treated in a method comprising a combination of a PARP1 inhibitor and DVd. The patients with multiple myeloma would be expected to express PARP1 in the multiple myeloma and would be treated with a method comprising administering a PARP1 inhibitor and DVd to produce an effective treatment outcome. This is NOT a situation of "A" predicts "B," then "not-B" predicts "not-A".
It would be incorrect to assume based on Caracciolo' s teaching, that a skilled artisan would expect treatments comprising daratumumab that prolong overall and progression-free survival of multiple myeloma patients when combined with a PARP1 inhibitor would result in low levels of PARP1 expression in multiple myeloma cells. As detailed above, Caracciolo taught that MYC induces alternative NHEJ repair to balance the downregulation of homologous recombination induced by bortezomib, which contributes to the development of drug resistance and, at the same time, making MM cells more dependent on PARP1-mediated DNA repair to survive (page 194, right column, paragraph 1). PARP1 knockdown or olaparib was effective at decreasing multiple myeloma in multiple myeloma in Caracciolo Fig 2B-2D. The effectiveness of DVd treatment alone taught by Ahmadi 479 would NOT indicate that patients with multiple myeloma wouldn’t benefit from treatment with a combination of DVd and PARPi because NHEJ would still be necessary. The method is a combination treatment that would produce benefits that would be expected in light of the teachings of Caracciolo and Ahmadi 479. Further, Caracciolo taught drug resistant (bortezomib-resistant) cells are highly sensitive to PARP inhibitors such as olaparib (page 193, first and second paragraph under Bortezomib-resistant cells are highly sensitive to PARP inhibition). Thus, any multiple myeloma cells present in the subject that have resistance to bortezomib, de novo resistance or otherwise, would benefit from addition of a PARP inhibitor to the method of Ahmadi 479. Thus, addition of a PARP1 inhibitor is beneficial to the method of Ahmadi 479 to a person having ordinary skill in the art.
Additionally, Neri P et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors (Blood. 2011 Sep 13;118(24):6368–6379.) taught proteasome inhibition induces a “BRCAness” state in myeloma cells (MM) that depletes essential steps for the initiation of homologous recombination (HR)–mediated DNA repair (abstract). Neri taught cotreatment of multiple myeloma cell lines with bortezomib, also known as Velcade®, and ABT-888, which is a PARP1 inhibitor, resulted in the sustained accumulation of unrepaired DNA DSBs and ensuing MM-cell death (abstract). Neri taught the heightened cytotoxicity of the PARP1 inhibitor ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice (abstract). Neri taught their studies indicate that bortezomib impairs HR in multiple myeloma and results in a contextual synthetic lethality when combined with PARP inhibitors (abstract). Thus, the DVd method of treating multiple myeloma of Ahmadi 479, which includes daratumumab, bortezomib, and dexamethasone, would benefit from including administration of a PARP1 inhibitor in the presence or absence of myc depletion.
Regarding PARP1 is expressed in samples of 4 healthy donors, Caracciolo taught PARP1 plays a crucial role in the alternative NHEJ pathway, wherein PARP1 senses DNA damage via its DNA binding domain, and subsequently synthesizes poly (ADP-ribose) polymers which are added to itself and other acceptor proteins, thus recruiting other DNA repair proteins, including LIG3 (page 186, left column, fourth paragraph). PARP1 is expressed in cells to repair DNA. Inhibition of the DNA repair mechanism in cancer would be beneficial.
Regarding PARP1 mRNA expression is not significantly increased in general MM patients – Caracciolo taught PARP1 protein expression in multiple myeloma patient samples and cell lines in Caracciolo Fig. 2A (see below).
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Caracciolo taught in Fig. A there was upregulation of PARP1 protein expression with a nuclear distribution in MM cells, as compared to the level of expression in peripheral blood mononuclear cells from healthy donors. Thus, PARP1 protein was elevated.
PARP1 knockdown or olaparib was effective at decreasing multiple myeloma in multiple myeloma in Caracciolo Fig 2B-2D (see below).
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Thus, a majority of multiple myeloma samples tested show PARP1 expression and have decreased cell viability when treated with a PARP inhibitor. Further, Caracciolo taught drug resistant (bortezomib-resistant) cells are highly sensitive to PARP inhibitors such as olaparib (page 193, first and second paragraph under Bortezomib-resistant cells are highly sensitive to PARP inhibition). Thus, any multiple myeloma cells present in the subject that have resistance to bortezomib, de novo resistance or otherwise, would benefit from addition of a PARP inhibitor to the method of Ahmadi 479. Additionally, the claims do not require the multiple myeloma cells do not express PARP1.
Applicant argues there Is No Evidence in the cited references that MM Cells Treated with DVd Are Addicted to MYC. The Office asserts that Caracciolo taught that PARP1 is crucial for survival of MYC addicted MM cells. The Office does not contend that Caracciolo taught that MM cells treated with DVd are addicted to MYC.
In response, Applicant's arguments filed 9/19/2025 have been fully considered
but they are not persuasive. Regarding the argument that there Is No Evidence in the cited references that MM Cells Treated with DVd Are Addicted to MYC – Caracciolo taught PARP1 was expressed in three of four primary multiple myeloma patient samples and seven of eight multiple myeloma cell lines (Caracciolo Fig. 2). Thus, the majority of multiple myeloma samples tested expressed PARP1 protein. Further, knockdown of PARP1 or olaparib treatment was effective against multiple myeloma cell lines and patient primary multiple myeloma samples that expressed PARP1. Therefore, subjects with multiple myeloma would be expected to benefit from a treatment that comprised a PARP1 inhibitor as taught by Caracciolo and a daratumumab-containing therapies that are taught to be effective as taught by Ahmadi 479. One of skill in the art would NOT expect lower PARP1 mRNA expression in MM cells of patients that are about to be treated in a method comprising a combination of a PARP1 inhibitor and DVd. The patients with multiple myeloma would be expected to express PARP1 in the multiple myeloma and would be treated with a method comprising administering a PARP1 inhibitor and DVd to produce an effective treatment outcome. The method is a combination treatment that would produce benefits that would be expected in light of the teachings of Caracciolo and Ahmadi 479. Further, Caracciolo taught drug resistant (bortezomib-resistant) cells are highly sensitive to PARP inhibitors such as olaparib (page 193, first and second paragraph under Bortezomib-resistant cells are highly sensitive to PARP inhibition). Thus, any multiple myeloma cells present in the subject that have resistance to bortezomib, de novo resistance or otherwise, would benefit from addition of a PARP inhibitor to the method of Ahmadi 479. Thus, addition of a PARP1 inhibitor is beneficial to the method of Ahmadi 479 to a person having ordinary skill in the art.
Additionally, Neri P et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors (Blood. 2011 Sep 13;118(24):6368–6379.) taught proteasome inhibition induces a “BRCAness” state in myeloma cells (MM) that depletes essential steps for the initiation of homologous recombination (HR)–mediated DNA repair (abstract). Neri taught cotreatment of multiple myeloma cell lines with bortezomib, also known as Velcade®, and ABT-888, which is a PARP1 inhibitor, resulted in the sustained accumulation of unrepaired DNA DSBs and ensuing MM-cell death (abstract). Neri taught the heightened cytotoxicity of the PARP1 inhibitor ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice (abstract). Neri taught their studies indicate that bortezomib impairs HR in multiple myeloma and results in a contextual synthetic lethality when combined with PARP inhibitors (abstract). Thus, the DVd method of treating multiple myeloma of Ahmadi 479, which includes daratumumab, bortezomib, and dexamethasone, would benefit from including administration of a PARP1 inhibitor in the presence or absence of myc depletion.
Applicant argues In the previous replies, Applicant presented evidence1 suggesting that MM cells treated with dexamethasone (an element of DVd) may have reduced myc expression, to which the Office argued that c-myc expression was not fully eliminated. However, Caracciolo does not disclose that any amount of MYC expression is sufficient for cell death mediated by PARP inhibition. Caracciolo states that "high MYC expression correlates with sensitivity to PARP inhibitors in MM" (p. 185, Abstract, emphasis added) and suggests that high MYC expression may be required for cell death mediated by PARP inhibition. For example, U266 cells were olaparib-insensitive unless MYC was overexpressed. In P936 B cell-like lymphoma cells, where MYC expression was tuned to be high (absence of doxycycline) or low (500 ng/mL doxycycline), olaparib effectively induced cell death only when MYC expression was high. See e.g., p.192, and Figure 4C (reproduced below). Accordingly, a reduction of MYC expression is relevant.
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The Office further states that any dexamethasone induced c-myc repression would be beneficial to MM patients overall, and asserts that "any remaining c-myc would be able to support MYC-driven MM cells to switch their DNA repair machinery to error prone PARP mediated alternative NHEJ to overcome DNA damage overload from oncogenic stress, promoting cell survival and, at the same time, the acquisition of new genetic changes leading to disease progression as taught by Caracciolo" (Office Action, page 18, emphasis added).
Applicant respectfully disagrees with this assertion. The Office alleges support by Zhou but does not refer to any disclosure in Zhou regarding potential effects of "remaining" c-myc.
Applicant argues the Office also asserts that: (i) the dexamethasone dose used in Ahmadi is about 20-fold lower than that used in Chauhan, and (ii) a 4-fold decrease of myc in MM cells would not be present when 20-fold lower concentrations of dexamethasone are used. However, a 4-fold decrease of myc may occur in MM cells treated with DV d for at least the following reasons. First, the asserted "20-fold lower" concentration was estimated blood plasma concentration in MM patients administered 20 mg dexamethasone, the low end of the "about 20 mg to about 40 mg" dexamethasone dose disclosed in Ahmadi. Second, compared to blood serum concentration, concentration of dexamethasone in the bone marrow, where most malignant plasma cells reside,
would be more relevant. Third, a saturating concentration of dexamethasone might have been used in the experiments in Chauhan. Figure 2C of Caracciolo illustrates this point: treatment of H929 with 0.5 or 10 μM olaparib resulted in similar relative cell viability.
Applicant argues In the Response dated April 9, 2025, Applicant presented additional evidence2 demonstrating that myc protein was suppressed by 20 nM and 1 μM dexamethasone (Figs. IA and lB in Zhou et al., reproduced below).
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This specific evidence was not addressed by the Office.
In response, Applicant's arguments filed 9/19/2025 have been fully considered
but they are not persuasive. The obvious rational is above wherein Ahmadi 479 taught a method for treating multiple myeloma with a composition comprising the CD38 inhibitor daratumumab – and addition of PARPi is obvious with a reasonable expectation of success in view of Caracciolo.
Regarding the arguments that: A) MM cells treated with dexamethasone (an element of DVd) may have reduced myc expression; B) Caracciolo does not disclose that any amount of MYC expression is sufficient for cell death mediated by PARP inhibition; and C) the Office alleges support by Zhou but does not refer to any disclosure in Zhou regarding potential effects of "remaining" c-myc, –
the majority of multiple myeloma samples tested by Caracciolo expressed PARP1 protein. Further, Caracciolo taught the DNA damage response is an attractive area of investigation because of the opportunity to selectively kill cancer cells addicted to compensatory DNA repair pathways by synthetic lethality (page 193, right column, Discussion, first paragraph). Thus, the cancer cells would utilize DNA repair mechanism to which they are addicted to survive. Concentrations of dexamethasone that incompletely reduce myc expression via DVd treatment would still benefit from blockade of PARP1 to fully and directly inhibit the DNA repair protein from performing its function. The combination treatment of multiple myeloma with DVd and PARP1 would provide beneficial effects that include: i) directly inhibiting the function of PARP1 downstream of any remaining myc activity; and ii) promoting cell death of bortezomib-resistant multiple myeloma cells, which Caracciolo taught are highly sensitive to PARP inhibitors such as olaparib (page 193, first and second paragraph under Bortezomib-resistant cells are highly sensitive to PARP inhibition). Thus, any multiple myeloma cells present in the subject that have resistance to bortezomib, de novo resistance or otherwise, would benefit from addition of a PARP inhibitor to the method of Ahmadi 479. Bortezomib-resistant multiple myeloma cells may further not support effective myc inhibition.
us, addition of a PARP1 inhibitor is beneficial to the method of Ahmadi 479 to a person having ordinary skill in the art.
Further regarding dexamethasone effects on c-myc:
1) Chauhan and Zhou cited by the Applicant do not fully eliminate c-myc expression. As stated previously, the primary mechanism of action of dexamethasone treatment in multiple myeloma is not reduction of myc. A 4-fold decrease of myc in multiple myeloma cells would not be present when 20-fold lower concentrations of dexamethasone are used. Thus, it would be expected that there is still c-myc downstream PARP-dependent DNA repair.
2) Additionally, the dexamethasone would be beneficial to the multiple myeloma patient overall. Holien T et al. (Blood (2012) 120 (12): 2450–2453 reference of record) taught in multiple myeloma, c-myc is activated and contributes to the malignant phenotype (abstract) and that inhibition of repression of c-myc causes decreased cell viability in Holien Fig. 2B and 2E. Thus, any dexamethasone induced c-myc repression would be beneficial to multiple myeloma patients overall. Any remaining c-myc would be able to support MYC-driven MM cells to switch their DNA repair machinery to error prone PARP-mediated alternative NHEJ to overcome DNA damage overload from oncogenic stress, promoting cell survival and, at the same time, the acquisition of new genetic changes leading to disease progression as taught by Caracciolo. Thus, addition of PARP inhibition would be beneficial to the DVd treatment method of Ahmadi 479. This is supported by Zhou, wherein Zhou taught: 1) suppression of c-myc has been shown to be critical in the glucocorticoid-induced apoptotic pathway in human leukemic lymphoblasts of the CEM cell line (page 200, left column, second paragraph); and 2) suppression of c-myc is crucial to glucocorticoid-induced apoptosis in this system (page 200, right column first paragraph). Thus, the remaining myc activity in multiple myeloma cells would benefit from a PARP inhibitor following dexamethasone treatment in the DVd treatment method of Ahmadi 479. The PARP inhibitor would be further beneficial for bortezomib resistant multiple myeloma cells.
3) the reference cited by the Applicant of Chauhan et al. (Oncogene 21(9): 1346-58 (2002), (Exhibit 2 reference of record) used dexamethasone concentrations that are far higher than are able to be achieved physiologically. The figure 1 legend of Chauhan indicates MM.1S cells were treated with 10 µM Dex for the indicated times and subjected to oligonucleotide array analysis. The treatment of Ahmadi 479 treated used combination treatment of DVd on multiple myeloma patients wherein 20 mg dexamethasone was administered to patient (page 11, paragraph 140). Blood plasma concentrations of 20 mg dexamethasone was taught by Bashir Q et al. Comparative Safety, Bioavailability, and Pharmacokinetics of Oral Dexamethasone, 4-mg and 20-mg Tablets, in Healthy Volunteers Under Fasting and Fed Conditions: A Randomized Open-label, 3-way Crossover Study. (Clin Lymphoma Myeloma Leuk. 2020 20(11):768-773 reference of record), wherein PK analysis of 20 mg dexamethasone in humans was able to reach peak concentrations of 200 ng/ml in plasma. A peak concentration of 200 ng/ml would equate to about 0.5 µM in plasma, (200 ng/ml in M = (200x10-9 g)/(392.5 g/mol)/1x10-3L ~ 0.5 µM) which is about 20-fold lower than the concentrations of Chauhan. The primary mechanism of action of dexamethasone treatment in multiple myeloma is not reduction of myc. A 4-fold decrease of myc in multiple myeloma cells would not be present when 20-fold lower concentrations of dexamethasone are used.
4) the doxycycline-inducible depletion of myc in Chauhan is far more than a 4-fold reduction of myc. Further, taking into account the dramatic difference in dexamethasone concentrations detailed above, myc is unlikely to be significantly impacted by the dexamethasone concentrations in the DVd treatment to a level that would affect myc and PARP1 to render PARPi ineffective.
Additionally, Neri P et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors (Blood. 2011 Sep 13;118(24):6368–6379.) taught proteasome inhibition induces a “BRCAness” state in myeloma cells (MM) that depletes essential steps for the initiation of homologous recombination (HR)–mediated DNA repair (abstract). Neri taught cotreatment of multiple myeloma cell lines with bortezomib, also known as Velcade®, and ABT-888, which is a PARP1 inhibitor, resulted in the sustained accumulation of unrepaired DNA DSBs and ensuing MM-cell death (abstract). Neri taught the heightened cytotoxicity of the PARP1 inhibitor ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice (abstract). Neri taught their studies indicate that bortezomib impairs HR in multiple myeloma and results in a contextual synthetic lethality when combined with PARP inhibitors (abstract). Thus, the DVd method of treating multiple myeloma of Ahmadi 479, which includes daratumumab, bortezomib, and dexamethasone, would benefit from including administration of a PARP1 inhibitor in the presence or absence of myc depletion.
Regarding U266 cells were olaparib-insensitive unless MYC was overexpressed: 1) the majority of multiple myeloma samples tested expressed PARP1 protein as described above; 2) residual PARP1 following myc suppression via dexamethasone would further support killing multiple myeloma cells that are addicted to DNA repair by a PARP1 inhibitor. Expression of the PARP1 target would support the reliance on MM cells to switch their DNA repair machinery to error prone PARP-mediated alternative NHEJ to overcome DNA damage overload as taught above; 3) Caracciolo taught bortezomib-resistant multiple myeloma cells are highly sensitive to PARP inhibitors such as olaparib (page 193, first and second paragraph under Bortezomib-resistant cells are highly sensitive to PARP inhibition). Thus, any multiple myeloma cells present in the subject that have resistance to bortezomib, de novo resistance or otherwise, would benefit from addition of a PARP inhibitor to the method of Ahmadi 479; and 4) Neri P et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors (Blood. 2011 Sep 13;118(24):6368–6379.) taught proteasome inhibition induces a “BRCAness” state in myeloma cells (MM) that depletes essential steps for the initiation of homologous recombination (HR)–mediated DNA repair (abstract). Neri taught cotreatment of multiple myeloma cell lines with bortezomib, also known as Velcade®, and ABT-888, which is a PARP1 inhibitor, resulted in the sustained accumulation of unrepaired DNA DSBs and ensuing MM-cell death (abstract). Neri taught the heightened cytotoxicity of the PARP1 inhibitor ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice (abstract). Neri taught their studies indicate that bortezomib impairs HR in multiple myeloma and results in a contextual synthetic lethality when combined with PARP inhibitors (abstract). Thus, the DVd method of treating multiple myeloma of Ahmadi 479, which includes daratumumab, bortezomib, and dexamethasone, would benefit from including administration of a PARP1 inhibitor in the presence or absence of myc depletion.
Regarding a 4-fold decrease of myc may occur in MM cells treated with DVd –
1) First a "20-fold lower" concentration was estimated blood plasma concentration in MM patients administered 20 mg dexamethasone, which is encompassed by Ahmadi.
2) Second, the Applicant has provided no evidence that the concentration of dexamethasone in the bone marrow is elevated in comparison to blood serum concentrations. Thus, blood serum concentrations would be a relevant indication of concentration.
3) Third, regarding a saturating concentration of dexamethasone might have been used in the experiments in Chauhan, if the Applicant believes that the concentrations are saturating then support is required. Further, the Applicant’s argument suggests that even if saturating doses of dexamethasone are present, dexamethasone can only suppress myc 4-fold reduction and not fully suppress myc activity.
4) Neri P et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors (Blood. 2011 Sep 13;118(24):6368–6379.) taught proteasome inhibition induces a “BRCAness” state in myeloma cells (MM) that depletes essential steps for the initiation of homologous recombination (HR)–mediated DNA repair (abstract). Neri taught cotreatment of multiple myeloma cell lines with bortezomib, also known as Velcade®, and ABT-888, which is a PARP1 inhibitor, resulted in the sustained accumulation of unrepaired DNA DSBs and ensuing MM-cell death (abstract). Neri taught the heightened cytotoxicity of the PARP1 inhibitor ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice (abstract). Neri taught their studies indicate that bortezomib impairs HR in multiple myeloma and results in a contextual synthetic lethality when combined with PARP inhibitors (abstract). Thus, the DVd method of treating multiple myeloma of Ahmadi 479, which includes daratumumab, bortezomib, and dexamethasone, would benefit from including administration of a PARP1 inhibitor in the presence or absence of myc depletion.
Regarding Figure 2C of Caracciolo, treatment of H929 with 0.5 or 10 μM olaparib resulted in 100% cell death of multiple myeloma cells. H929 multiple myeloma cells show that the PARP1 inhibitor olaparib is an effective treatment for multiple myeloma.
Regarding Zhou, as indicated in the Non-Final Office Action dated May 19, 2025 and above 1) Zhou cited by the Applicant does not fully eliminate c-myc expression. As stated previously, the primary mechanism of action of dexamethasone treatment in multiple myeloma is not reduction of myc; and
2) addition of PARP inhibition would be beneficial to the DVd treatment method of Ahmadi 479. This is supported by Zhou, wherein Zhou taught: 1) suppression of c-myc has been shown to be critical in the glucocorticoid-induced apoptotic pathway in human leukemic lymphoblasts of the CEM cell line (page 200, left column, second paragraph); and 2) suppression of c-myc is crucial to glucocorticoid-induced apoptosis in this system (page 200, right column first paragraph).
Additionally, the cells of Zhou are CEM-C7 cells, which are human leukemic lymphoblasts as indicated above, grown from a patient with acute lymphoblastic leukemia (Zhou et al. page 196, left column, 2.1 Cell lines, first paragraph). This is not a multiple myeloma cell line and represents a separate disease.
Additionally, Neri P et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors (Blood. 2011 Sep 13;118(24):6368–6379.) taught proteasome inhibition induces a “BRCAness” state in myeloma cells (MM) that depletes essential steps for the initiation of homologous recombination (HR)–mediated DNA repair (abstract). Neri taught cotreatment of multiple myeloma cell lines with bortezomib, also known as Velcade®, and ABT-888, which is a PARP1 inhibitor, resulted in the sustained accumulation of unrepaired DNA DSBs and ensuing MM-cell death (abstract). Neri taught the heightened cytotoxicity of the PARP1 inhibitor ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice (abstract). Neri taught their studies indicate that bortezomib impairs HR in multiple myeloma and results in a contextual synthetic lethality when combined with PARP inhibitors (abstract). Thus, the DVd method of treating multiple myeloma of Ahmadi 479, which includes daratumumab, bortezomib, and dexamethasone, would benefit from including administration of a PARP1 inhibitor in the presence or absence of myc depletion.
The rejection of claims 1, 4-6, 8-11, 18, 23-27 under 35 U.S.C. 103 as being unpatentable over US 20190127479 (Ahmadi T et al., reference of record) and Caracciolo D et al. (Haematologica. 2021 106(1): 185–195, Published online 2020 Feb 20, reference of record) as applied to claims 1, 4-6, 8-11, 18, 23, and 25-27 above and further in view of Palumbo A et al. (N Engl J Med 2016; 375:754-766, reference of record) is maintained.
Ahmadi 479 and Caracciolo are described above.
While Ahmadi 479 described the treatment of naïve multiple myeloma with daratumumab, bortezomib, and dexamethasone, Ahmadi 479 and Caracciolo did not specifically describe the multiple myeloma was newly diagnosed, but this deficiency is addressed by Palumbo.
Palumbo taught daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy in combination with bortezomib in patients with newly diagnosed multiple myeloma (abstract).
Regarding claim 24, it would have been obvious to modify the method of Ahmadi 479 and Caracciolo above of administering the anti-CD38 antibody daratumumab in combination with bortezomib, dexamethasone, and the PARPi olaparib for the treatment of multiple myeloma and – to administer the combination treatment for newly diagnosed multiple myeloma as taught by Palumbo.
This would produce a method of treating CD38 expressing high risk multiple myeloma that is newly diagnosed or relapsed or refractory multiple myeloma in a subject in need thereof with daratumumab, dexamethasone, bortezomib, and the PARP1 inhibitor olaparib for a time sufficient to treat the high-risk CD38 positive multiple myeloma.
This is obvious with a reasonable expectation of success because: 1) daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy in combination with bortezomib in patients with newly diagnosed multiple myeloma; and 2) the combination of daratumumab, dexamethasone, bortezomib and the PARP inhibitor olaparib would be expected to be more effective for multiple myeloma treatment when MYC induces alternative NHEJ repair to balance the downregulation of homologous recombination induced by bortezomib, which contributes to the development of drug resistance and, at the same time, making MM cells more dependent on PARP1-mediated DNA repair to survive.
Response to Arguments
Applicant argues the combination of Ahmadi and Caracciolo does not render obvious Applicant's independent claims 1, 26, and 27. Applicant argues Palumbo, Sun, or Usmani does not remedy the deficiencies in the teachings of Ahmadi and Caracciolo. Claims 4-6, 8-15, 18, and 22-27 depend from claim 1, 26, or 27, and therefore, are nonobvious for at least the same reasons.
In response, Applicant's arguments filed 9/19/2025 have been fully considered
but they are not persuasive. The arguments regarding the combination of Ahmadi and Caracciolo rendering obvious the subject matter of Applicant's independent claims 1, 26, and 27 is described above. The obvious rational for instant claim 24 with the teachings of Ahmadi, Caracciolo, and Palumbo is above.
The rejection of claims 1, 4-6, 8-15, 18, 23, and 25-27 under 35 U.S.C. 103 as being unpatentable over US 20190127479 (Ahmadi T et al., reference of record) and Caracciolo D et al. (Haematologica. 2021 106(1): 185–195, Published online 2020 Feb 20, reference of record) as applied to claims 1, 4-6, 8-11, 18, 23, and 25-27 above and further in view of WO 2018213732 (Sun K et al., reference of record) is maintained.
Ahmadi 479 and Caracciolo are described above.
Ahmadi 479 and Caracciolo did not teach a CD38 antibody in combination with a PARPi and adenosine receptor antagonist or caffeine as the A2AAR antagonist, but these are addressed by Sun.
Sun taught methods of treating a subject with a disease or condition comprising administering to the subject (a) a first agent that inhibits poly [ADP-ribose] polymerase (PARP); and (b) a second agent, wherein the second agent comprises a regulatory T cell (Treg) inhibitory agent (specification, page 1, paragraph 3).Sun taught olaparib as the PARP inhibitor (specification, page 2, paragraph 6). Sun taught inhibition of adenosine A2A receptor can be achieved using adenosine analogues (specification, page 63, paragraph 169). Sun taught the Treg function inhibitor is the adenosine receptor antagonist caffeine (specification, page 64, paragraph 170). Sun taught Adenosine A2A receptor can inhibit T cell responses in part by upregulating Foxp3 expression in CD4+ T cells (specification, page 63, paragraph 169). Sun taught Treg can produce adenosine via catabolism of adenine nucleotides (ATP, ADP and AMP). Sun taught adenosine is a major immunosuppressive factor that participates in the immunosuppressive activity of Foxp3+ T cells (specification, page 64, paragraph 170). Sun taught low molecular weight inhibitors and adenosine receptor antagonists can be used to block adenosine-mediated immune suppression (specification, page 64, paragraph 170). Sun taught Treg inhibitors include an antibody that targets the Treg cell surface marker CD38 (specification, pages 64-65, paragraph 171). Sun taught the combination treatment can be used to treat cancers that include multiple myeloma (specification, page 11, paragraph 28 and page 18, paragraph 54). Sun taught the Treg inhibitor substantially ablates or eliminates the population of regulatory T cells in a subject when administered for a time (specification, pages 64-65, paragraph 171). Sun taught methods that comprise of administering a therapy that inhibits PARP and a therapy that regulates activity in the tumor microenvironment (e.g., T cell activity and/or infiltration of T cells into the tumor environment) in combination to a patient according to a regimen that achieves a therapeutic effect (specification, pages 64-65, paragraph 184). Sun taught administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing (which would be administered separately) (specification, page 16, paragraph 50).
Regarding instant claim 12-15, it would have been obvious to modify the method of Ahmadi 479 and Caracciolo above of administering the anti-CD38 antibody daratumumab in combination with bortezomib, dexamethasone, and the PARPi olaparib for treating a CD38 expressing multiple myeloma above and – further include an adenosine A2A receptor antagonist for a time sufficient to treat the multiple myeloma as taught by Sun.
This would produce a method of treating CD38 expressing high risk multiple myeloma that is naïve or relapsed or refractory multiple myeloma in a subject in need thereof with daratumumab intravenously, dexamethasone, bortezomib, the PARP1 inhibitor olaparib and separately (claim 15) the adenosine A2A receptor antagonist (claims 12-13) caffeine (claim 14) for a time sufficient to treat the high-risk multiple myeloma that is naïve or relapsed or refractory multiple myeloma which is a CD38 positive malignancy.
This is obvious because: 1) Sun taught PARPi in combination with Treg inhibiting agents, wherein an adenosine A2A receptor inhibitor and an antibody that targets CD38 were described to inhibit immunosuppressive Treg cells; 2) Sun taught treatment of multiple myeloma; 3) adenosine receptor antagonists can be used to block adenosine-mediated immune suppression; 4) Sun taught the Treg function inhibitor is the adenosine receptor antagonist caffeine; 4) the mechanism of action of Adenosine A2A receptor is known to inhibit T cell responses in part by upregulating Foxp3 expression in CD4+ T cells, wherein adenosine is a major immunosuppressive factor that participates in the immunosuppressive activity of Foxp3+ T cells.
There is a reasonable expectation of success because: 1) and 2) PARPi in combination with a CD38 targeting antibody would target and kill multiple myeloma cells; 3) inhibition of immunosuppressive adenosine would allow T cells to kill cancer cells; 4) and 5) the mechanism of action of immunosuppression through the adenosine and Adenosine A2A receptor is known to inhibit T cell responses in part by upregulating Foxp3 expression in CD4+ T cells; and 6) the combination would target the cancer cells and the immunosuppressive environment together.
Response to Arguments
Applicant argues the combination of Ahmadi and Caracciolo does not render obvious Applicant's independent claims 1, 26, and 27. Applicant argues Palumbo, Sun, or Usmani does not remedy the deficiencies in the teachings of Ahmadi and Caracciolo. Claims 4-6, 8-15, 18, and 22-27 depend from claim 1, 26, or 27, and therefore, are nonobvious for at least the same reasons.
In response, Applicant's arguments filed 9/19/2025 have been fully considered
but they are not persuasive. The arguments regarding the combination of Ahmadi and Caracciolo rendering obvious the subject matter of Applicant's independent claims 1, 26, and 27 is described above. The obvious rational for instant claims 12-15 with the teachings of Ahmadi, Caracciolo, and Sun is above.
The rejection of claims 1, 4-6, 8-11, 18, 22-23, and 25-27 under 35 U.S.C. 103 as being unpatentable over US 20