DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. The Amendment filed November 19, 2025 in response to the Office Action of May 19, 2025, is acknowledged and has been entered. Claims 1-4, 15-17, 22-27 are now pending. Claims 1, 3, 4, 17 are amended. Claims 26 and 27 are new. Claim 26 is withdrawn from examination as being drawn to a non-elected species - claim 26 is drawn to methods not elected in Species A of the restriction. Claims 1-4, 15-17, 22-25, and 27 are currently being examined as drawn to the elected species of:
A. method for (i) treating, ameliorating, stopping or slowing the progression of, or preventing a cancer or a cancer associated with a stem cell (claim 1).
B. (a) administering to a subject in need thereof, or in need of treatment, a combination of agents that inhibit or decrease the expression or activity of:
(i) Janus kinase 2 (JAK2) and comprises pacritinib and:
(ii) BCR-ABL1 and comprises dasatinib (claim 1).
C. myeloproliferative neoplasm (claim 2 and new claim 27).
D. assessing efficacy of the method by detection of a decrease in editing efficiency in (or the amount of adenosine-to-inosine (A-to-1) RNA editing of) pri-let-7 microRNA (miRNA) transcripts or detecting a decrease in A-I RNA editing of APOBEC3 (claims 3).
E. method further comprising administering JAK2 inhibitor ruxolitinib (claim 4(a)).
F. method further comprising administering BCR-ABL1 inhibitor imatinib (claim 4(b)).
G. Claim 4(c) species are canceled.
H. Species claim 5 is canceled.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
7. Claim(s) 1, 2, 4, 15, 16, 22, 23, and 27 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Sweet et al (Critical Reviews in Oncology/Hematology, 2013, 88:667-679); in view of Zhou et al (Blood Cancer Journal, 2015, 5:e351); Gallipoli et al (Blood, 2014, 124:1492-1501); Quintarelli et al (Leukemia Research, 2014, 38:236-242); Cortes et al (Blood, 2007, 109:3207-3213); Verstovsek et al (Blood; ASH Annual Meeting Abstracts; 2009;114: abstract 3905); Rosenthal et al (Expert Opinion on Pharmacotherapy, 2014, 15:1265-1276).
Sweet teaches CML develops resistance to BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib, and imatinib alone is unlikely able to eradicate CML. Sweet teaches more potent TKIs, nilotinib and dasatinib, have been approved to treat CML patients, wherein both demonstrated a significantly higher rate of major molecular response (MMR) compared to imatinib. Despite improved response to the newer BCR-ABL1 TKIs, minimal residual disease remains evident, and new strategies are needed to eliminate residual disease and achieve a cure (section 1.1, p. 668). Sweet teaches a solution is to administer combination therapy (“one-two punch”) to CML patients comprising inhibitors of BCR-ABL1 and JAK2 in order to reduce residual disease. Sweet teaches that normally, BCR-ABL1 activity in CML cells leads to suppression of downstream pro-survival signaling pathways, tupping the balance toward pro-apoptotic mechanisms that lead to cell death. More-primitive progenitor cells that reside in the bone marrow, however, are resistant to TKI-induced apoptosis, even though BCR-ABL1 activity is successfully inhibited. Sweet teaches this is because signaling pathways that are downstream of BCR-ABL1 remain intact in leukemic stem cells (LSCs), allowing LSC survival. Therefore, there is a need to combine therapy (the “second punch”) with the BCR-ABL1 TKIs to achieve cure (section 1.2; p. 668. Sweet reviews second therapies for combination with BCR-ABL1 TKIs, including JAK2 inhibitors (section 2; p. 669). Sweet teaches that in vitro and in vivo preclinical studies suggest JAK2 signaling pathway is activated in CML, and inhibition of the JAK2 pathway reduced phosphorylation of BCR-ABL1 and activation of downstream pathways, ultimately interfering with oncogenic signaling (section 2.1; p. 669). Sweet summarizes known clinical application of JAK2 inhibitors to treat CML patients in Table 1, including treatment of CML with JAK2 inhibitors ruxolitinib and pacritinib (SB1518).
Sweet teaches: “The preclinical evidence to support the combination of JAK/STAT inhibitors with BCR-ABL1 TKIs is very promising” (section 2.4, p. 670). Sweet teaches the rationale for clinical treatment of relapsed/refractory CML patients with combined JAK2 inhibitor ruxolitinib and BCR-ABL1 TKI nilotinib was supported by the in vitro and in vivo preclinical studies. In vitro studies demonstrated that blastic-phase (blast crisis) CML-derived cell lines and in LSCs obtained directly from CML patients demonstrated active STAT3 signaling, and STAT activation protected cells against nilotinib-mediated cell death. However, ruxolitinib was able to block STAT3 activation and, when combined with nilotinib, sensitized cell lines and patient derived LSCs to the cytotoxic effects of nilotinib. Another study demonstrated that inhibition of JAK2 sensitized cells to nilotinib. These results demonstrate that combined JAK2 and BCR-ABL1 inhibition can overcome the protective effects of the bone marrow microenvironment and eliminate LSCs that are responsible for minimal residual disease. Sweet teaches a clinical trial combining nilotinib and ruxolitinib, and suggests future clinical administration of other combinations as more JAK2 inhibitors become available (section 2.4.1; p. 671). In Summary (section 8), Sweet teaches:
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Sweet does not teach treating the CML by administering JAK2 inhibitor pacritinib and BCR-ABL1 TKI dasatinib.
Sweet recognizes CML patients become resistant to imatinib therapy and need combination BCR-ABL1 TKI and JAK2 inhibition therapy (one-two punch) and teach known inhibitors including ruxolitinib, but does not teach the CML treatment comprises all of imatinib, pacritinib, ruxolitinib, and dasatinib.
Sweet teaches it was demonstrated in the prior art that blastic-phase CML-derived cell lines and LSCs obtained from CML patients were successfully killed with a combined BCR-ABL1 TKI and JAK2 inhibitor even though they were resistant to the BCR-ABL1 TKI, but does not teach explicitly teach treating BC-CML therapy-resistant patients with the combined therapy.
Sweet summarizes known clinical trials administering TKIs and Jak2 inhibitors but does not state they were administered orally.
Zhou teaches treating a patient having a myeloproliferative neoplasm (MPN), chronic myeologenous leukemia (CML), by orally administering to the patient 2nd generation BCR-ABL1 TKI dasatinib in combination with JAK2 inhibitor ruxolitinib. The patient was treated first with dasatinib that suppressed BCR-ABL presence, but eventually progressed with increased JAK2 mutated allele burden, then was treated with both dasatinib and ruxolitinib. Zhou teach the combination of dasatinib and ruxolitinb successfully treated the patient, the patient maintained a complete cytogenic response with low level BCR-ABL detectable by qRT-PCR and controlled JAK2 mutation burden, therefore combined treatment slowed progression to a resistant cancer (first page, columns 1-2; Figure 1).
Gallipoli teaches and demonstrate that the combination of JAK2 inhibitor ruxolitinib and BCR-ABL1 TKI nilotinib leads to enhanced eradication of primitive CML stem cells (Key Points box), wherein the combination reduced activity of the JAK2/STAT5 pathway relative either single agent alone in vitro in CML cells (abstract). The combination treatment also increased apoptosis of CML stem/progenitor cells (SPCs) in vitro and resulted in a reduction in primitive quiescent CML stem cells (abstract). Gallipoli et al establish the JAK2/STAT5 pathway is a therapeutic target in CML SPCs and suggest administering a combination of ruxolitinib and nilotinib to CML patients to eradicate persistent (residual) disease (abstract). Gallipoli et al demonstrate that combination treatment of ruxolitinib and nilotinib in mice reduced engraftment of CML cells compared to nilotinib alone (Figure 5; p. 1498, col. 1-2). Gallipoli suggests combination treatment of CML patients to eradicate residual disease (p. 1499, col. 2). Gallipoli further teaches assessing engraftment of CML cells in mice exposed to various treatments by measuring BCR-ABL mRNA transcripts by (RT-PCR, wherein combination treatment resulted in a reduction of BCR-ABL mRNA levels statistically greater than nilotinib alone (Methods; Figure 5D).
Quintarelli teaches successful treatment of K562 cells (CML cells in blast crisis) with combined treatment of BCR-ABL1TKI dasatinib and JAK2 inhibitor ruxolitinib, wherein the combination: (1) was significantly more toxic to cells than single agents, (2) demonstrated synergy of the combination therapy, and (3) overcame drug resistance to tyrosine kinase inhibitors (TKIs) (Figure 3; Results; p. 241, col. 2).
Cortes demonstrates and teaches that dasatinib alone successfully treated CML patients in myeloid blast crisis resistant to imatinib and that have BCR-ABL mutation (abstract; Patients; Results).
Verstovsek teaches clinical treatment of chronic myeloid disease patients with JAK2 inhibitor SB1518 (pacritinib). Verstovsek teaches that in vitro studies demonstrated SB1518 inhibits proliferation of human leukemia and lymphoma cell lines dependent on JAK2 or FLT3 activation.
Rosenthal reviews known JAK inhibitors for the treatment of myeloproliferative neoplasms, including SB1518 (pacritinib) (section 4.2; Table 1) and ruxolitinib (section 3; Table 1). Rosenthal teaches oral dosing of pacritinib and teaches that pacritinib seems less likely to result in severe (grade 3 or 4) anemia or thrombocytopenia (section 4.2). Rosenthal suggests combining therapies with different mechanisms as a rational strategy (abstract).
Administering pacritinib + dasatinib to treat CML (claims 1, 2, and 15):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a combination of pacritinib and dasatinib to CML patients as the JAK2 inhibitor and BCR-ABL1 TKI in the method of Sweet. One would have been motivated to and have a reasonable expectation of success to because: (1) Sweet teaches the need to combine JAK2 inhibitors and BCR-ABL1 TKIs for the treatment of CML in order to eliminate residual disease and to inhibit JAK2 and BCR-ABL1 pathways known to be interrelated and activated in CML; (2) Sweet reviews known BCR-ABL1 TKI’s including imatinib, nilotinib, and dasatinib, and reviews known JAK2 inhibitors including ruxolitinib and pacritinib; (3) Sweet reviews studies demonstrating success of inhibition of JAK2 sensitizing CML cells to the cytotoxic effects of BCR-ABL1 TKI nilotinib; (4) Zhou teaches successfully treating a CML patient with a combination of BCR-ABL1 TKI dasatinib and JAK2 inhibitor ruxolitinib; (5) Gallipoli successfully demonstrates that the combination of a JAK2 inhibitor and BCR-ABL1 TKI leads to enhanced eradication of primitive CML stem cells and suggests combining JAK2 inhibitor and BCR-ABL1 TKI to eradicate residual disease; (6) Quintarelli successfully demonstrates that the combination of BCR-ABL1TKI dasatinib and JAK2 inhibitor ruxolitinib was significantly more toxic to CML cells than single agents, demonstrated synergy of the combination therapy, and overcame drug resistance to TKIs; (7) Cortes demonstrated that dasatinib alone successfully treated CML patients and that have BCR-ABL mutation; (8) Verstovsek teaches chronic myeloid disease patients are being clinically treated with JAK2 inhibitor SB1518 (pacritinib) and demonstrates SB1518 inhibits proliferation of human leukemia and lymphoma cell lines dependent on JAK2; and (9) Rosenthal suggests combining therapies with different mechanisms as a rational strategy to treat myeloproliferative neoplasms, and teaches clinical results demonstrate pacritinib has an advantage over ruxolitinib as less likely to result in severe (grade 3 or 4) anemia or thrombocytopenia.
Given: (1) the cited prior art teach the motivation to combine BCR-ABL1 TKI with a JAK2 inhibitor for the treatment of CML, in order to eliminate minimal residual disease and to inhibit the related pathways; (2) the cited prior art established the known BCR-ABL1 TKI activity of dasatinib and JAK2 inhibition by pacritinib; (3) the cited prior art provide successful examples of BCR-ABL1 TKI combined with JAK2 inhibitor for the treatment of CML and elimination of residual disease; (4) the cited prior art provide a successful example of treating CML with a combination of BCR-ABL1 TKI dasatinib and JAK2 inhibitor (ruxolitinib); (5) the cited art teach each agent alone, dasatinib and pacritinib, are effective in treatment of myeloproliferative neoplasms; and (6) the cited art teach a clinical advantage of JAK2 inhibitor pacritinib over ruxolitinib; one of skill in the art could have:
combined the known BCR-ABL1 TKI dasatinib and JAK2 inhibitor pacritinib, and recognized that the results of the combination would predictably treat CML through combined inhibition of BCR-ABL1 and JAK2; and
substituted functional equivalent pacritinib for ruxolitinib in successful methods of treating CML with ruxolitinib + dasatinib (demonstrated by Zhou) and the results for treating CML would have been predictable.
Method further comprising administering ruxolitinib (claim 4):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of the combined references cited above to further administer JAK2 inhibitor ruxolitinib in the treatment of CML. One would have been motivated to and have a reasonable expectation of success to because Sweet, Zhou, Gallipoli, and Quintarelli teach and/or demonstrates JAK2 inhibitor ruxolitinib combined with BCR-ABL1 TKIs nilotinib or dasatinib successfully treats CML patients, eradicates primitive CML stem cells, and demonstrated synergy in killing blast crisis CML cells and overcame drug resistance to TKIs.
Method further comprising administering imatinib (claim 4):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the method of Sweet to comprise administering imatinib in the treatment of CML. One would have been motivated to and have a reasonable expectation of success to because the cited prior art recognizes that CML patients developed resistance to first line imatinib therapy (a 1st generation TKI), and demonstrate that 2nd generation TKIs nilotinib and dasatinib are effective in treating resistant/refractory patients, as well as combining BCR-ABL1 TKIs with JAK2 inhibitors. Therefore, imatinib included in the method of treating CML patients taught by the combined cited references is obvious.
Treating blast crisis (BC) CML that is therapy resistant (claims 15 and 16):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat CML patients in blast crisis that are therapy resistant, in the method of Sweet. One would have been motivated to and have a reasonable expectation of success to because: (1) Sweet teaches it was demonstrated in the prior art that blastic-phase CML-derived cell lines and LSCs obtained from CML patients were successfully killed with a combined BCR-ABL1 TKI and JAK2 inhibitor even though they were resistant to the BCR-ABL1 TKI; (2) Zhou demonstrates successful treatment of a CML patient with combined BCR-ABL1 TKI and JAK2 inhibitor even though they became resistant to the BCR-ABL1 TKI; (3) Cortes teaches and demonstrates that CML patients in myeloid blast crisis and having BCR-ABL mutation were successfully treated with dasatinib alone; and (4) Quintarelli teaches and demonstrates that the combination of dasatinib with a JAK inhibitor synergized to significantly suppress BC-CML cells and overcome drug resistance.
Combination of agents formulated for oral administration (claims 22 and 23):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the pacritinib and dasatinib by oral formulation in the method of Sweet. One would have been motivated to and have a reasonable expectation of success to because: (1) Sweet teaches the known clinical treatment of patients with BCR-ABL1 TKI dasatinib and JAK2 inhibitors pacritinib or ruxolitinib; (2) Zhou demonstrates treating a patient having CML, by orally administering to the patient BCR-ABL1 TKI dasatinib and a JAK2 inhibitor ruxolitinib; (3) Cortes demonstrates that oral administration of dasatinib successfully treated CML; and (4) Rosenthal teaches known clinical oral dosing of pacritinib to patients.
Response to Arguments
3. Applicants argue that Sweet does not teach combining dasatinib and pacritinib for treatment of CML and the secondary references cited fail to remedy this deficiency because none of them teach combining dasatinib and pacritinib specifically.
Applicants argue there are hundreds of possible combinations of JAK2 inhibitors with BCR-ABL1 inhibitors and none of the cited art teaches the combination of pacritinib with dasatinib and to treat, ameliorate, stop or slow the progression of cancer associated with a stem cell. Applicants argue the cited references do not provide motivation to select pacritinib and dasatinib for combination.
4. The arguments have been considered but are not persuasive. Applicants argue that no single reference cited in the rejection explicitly teaches or suggests the specific combination of dasatinib and pacritinib to treat CML, however, Sweet and the secondary references provide motivation and reasonable expectation of success to combine BCR-ABL1 TKI and JAK2 inhibitors and to select dasatinib and pacritinib as the inhibitors for combination treatment based on the rationale provided in the rejection. Further, Sweet teaches patients progress on BCR-ABL1 TKIs including dasatinib, and names pacritinib as a known JAK2 inhibitor in their list of eight JAK2 inhibitors for combined therapy to deliver the one-two punch advantage. In the rationale for obviousness, Sweet recognizes the need improve CML treatment, eliminate minimal residual disease, and to inhibit the related pathways:
Sweet teaches CML develops resistance to BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib, and imatinib alone is unlikely able to eradicate CML. Sweet teaches more potent TKIs, nilotinib and dasatinib, have been approved to treat CML patients, wherein both demonstrated a significantly higher rate of major molecular response (MMR) compared to imatinib. Despite improved response to the newer BCR-ABL1 TKIs, minimal residual disease remains evident, and new strategies are needed to eliminate residual disease and achieve a cure (section 1.1, p. 668).
Sweet teaches a solution to the problem and reasons to expect success:
Sweet teaches a solution is to administer combination therapy (“one-two punch”) to CML patients comprising inhibitors of BCR-ABL1 and JAK2 in order to reduce residual disease. Sweet teaches that normally, BCR-ABL1 activity in CML cells leads to suppression of downstream pro-survival signaling pathways, tupping the balance toward pro-apoptotic mechanisms that lead to cell death. More-primitive progenitor cells that reside in the bone marrow, however, are resistant to TKI-induced apoptosis, even though BCR-ABL1 activity is successfully inhibited. Sweet teaches this is because signaling pathways that are downstream of BCR-ABL1 remain intact in leukemic stem cells (LSCs), allowing LSC survival. Therefore, there is a need to combine therapy (the “second punch”) with the BCR-ABL1 TKIs to achieve cure (section 1.2; p. 668. Sweet reviews second therapies for combination with BCR-ABL1 TKIs, including JAK2 inhibitors (section 2; p. 669). Sweet teaches that in vitro and in vivo preclinical studies suggest JAK2 signaling pathway is activated in CML, and inhibition of the JAK2 pathway reduced phosphorylation of BCR-ABL1 and activation of downstream pathways, ultimately interfering with oncogenic signaling (section 2.1; p. 669). Sweet summarizes known clinical application of JAK2 inhibitors to treat CML patients in Table 1, including treatment of CML with JAK2 inhibitors ruxolitinib and pacritinib (SB1518).
Sweet teaches: “The preclinical evidence to support the combination of JAK/STAT inhibitors with BCR-ABL1 TKIs is very promising” (section 2.4, p. 670). Sweet teaches the rationale for clinical treatment of relapsed/refractory CML patients with combined JAK2 inhibitor ruxolitinib and BCR-ABL1 TKI nilotinib was supported by the in vitro and in vivo preclinical studies. In vitro studies demonstrated that blastic-phase (blast crisis) CML-derived cell lines and in LSCs obtained directly from CML patients demonstrated active STAT3 signaling, and STAT activation protected cells against nilotinib-mediated cell death. However, ruxolitinib was able to block STAT3 activation and, when combined with nilotinib, sensitized cell lines and patient derived LSCs to the cytotoxic effects of nilotinib. Another study demonstrated that inhibition of JAK2 sensitized cells to nilotinib. These results demonstrate that combined JAK2 and BCR-ABL1 inhibition can overcome the protective effects of the bone marrow microenvironment and eliminate LSCs that are responsible for minimal residual disease. Sweet teaches a clinical trial combining nilotinib and ruxolitinib, and suggests future clinical administration of other combinations as more JAK2 inhibitors become available (section 2.4.1; p. 671). In Summary (section 8),
Sweet teaches:
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Therefore, Sweet teaches combining JAK2 inhibitors with BCR-ABL1 TKI to improve CML treatment with BCR-ABL1 TKI (particularly dasatinib) and provides a finite list of 8 known JAK2 inhibitors including ruxolitinib and pacritinib in Table 1, which are the only two JAK2 inhibitors listed as being administered clinically to treat CML, ALL, MDS, and AML, therefore Sweet suggests a known finite solution.
The secondary references teach the same need as Sweet to improve BCR-ABL1 TKI treatment. Sweet and the secondary references also provide a reasonable expectation of success to combine BCR-ABL1 TKI and JAK2 inhibitors for CML treatment, demonstrating:
blastic-phase (blast crisis) CML-derived cell lines and in LSCs obtained directly from CML patients demonstrated active STAT3 signaling, and STAT activation protected cells against BCR-ABL1 TKI nilotinib-mediated cell death. However, ruxolitinib was able to block STAT3 activation and, when combined with nilotinib, sensitized cell lines and patient derived LSCs to the cytotoxic effects of nilotinib (Sweet).
inhibition of JAK2 sensitized cells to BCR-ABL1 TKI nilotinib, showing that combined JAK2 and BCR-ABL1 inhibition can overcome the protective effects of the bone marrow microenvironment and eliminate LSCs that are responsible for minimal residual disease (Sweet).
the combination of BCR-ABL1 TKI dasatanib and JAK2 inhibitor ruxolitinib successfully treated CML that originally progressed on dastanib, wherein the patient maintained a complete cytogenic response (Zhou);
another combination of JAK2 inhibitor and BCR-ABL1 TKI inhibitor, ruxolitinib and nilotinib, demonstrated enhanced eradication of primitive CML stem cells, wherein the combination reduced activity of the JAK2/STAT5 pathway relative to either single agent alone; increased apoptosis of CML stem/progenitor cells (SPCs); and resulted in a reduction in primitive quiescent CML stem cells (Gallipoli);
combination treatment of JAK2 inhibitor ruxolitinib and BCR-ABL1 TKI inhibitor nilotinib in mice reduced engraftment of CML cells compared to nilotinib alone; and combination treatment resulted in a reduction of BCR-ABL mRNA levels statistically greater than nilotinib alone (Gallipoli);
combined treatment of BCR-ABL1TKI dasatinib and JAK2 inhibitor ruxolitinib to K562 cells (CML cells in blast crisis): (1) was significantly more toxic to cells than single agents, (2) demonstrated synergy of the combination therapy, and (3) overcame drug resistance to tyrosine kinase inhibitors (TKIs) (Quintarelli).
Therefore, Sweet, Zhou, Gallipolli, and Quintarelli provide a reasonable expectation of success for combinations of a JAK2 inhibitor and BCR-ABL1 TKI to predictably result in enhanced treatment of CML relative to single agents, and result in synergistic or significant antitumor function, wherein different combinations of dasatinib + ruxolitinib and nilotinib + ruxolitinib predictably demonstrated synergistic or significantly improved antitumor effects when combined versus single agents.
The secondary references, Cortes, Verstovsek, Rosenthal, provide further reasonable expectation of success that each of BCR-ABL1 TKI dasatinib and JAK2 inhibitors SB1518 (pacritinib) and ruxolitinib successfully function to treat the same CML cancer patients, wherein Rosenthal demonstrates and teaches pacritinib is less likely to result in severe (grade 3 or 4) anemia or thrombocytopenia than ruxolitinib.
In summary, the cited prior art:
(a) teaches a need to improve the treatment of CML with BCR-ABL1 TKI (particularly dasatinib) and a solution of combining JAK2 inhibitors for a one-two punch;
(b) provides a finite solution of known JAK2 inhibitors already being administered clinically to treat CML including SB1518 (pacritinib) and ruxolitinib,
(c) demonstrates different combinations of BCR-ABL1 TKIs and JAK2 inhibitor are successful in improving CML treatment including demonstrating synergistic and significant antitumor effects for the combination over single agents (i.e., dasatinib + ruxolitinib and nilotinib + ruxolitinib) providing an expectation of success for the combination of known BCR-ABL1 TKIs and JAK2 inhibitors to improve CML treatment;
(d) demonstrate BCR-ABL1 TKI dastanib and JAK2 inhibitor pacritinib both independently successfully treat CML, where pacritinib is determined to have an advantage of being less likely to result in severe (grade 3 or 4) anemia or thrombocytopenia (section 4.2).
The cited secondary references provide a reasonable expectation of success to select the JAK2 inhibitor pacritinib, suggested by Sweet, for combination with BCR-ABL1 TKI dastanib to improve CML treatment through the combined therapy.
5. Applicants argue they demonstrate the combination of dasatinib and pacritinib generated results that were greater than those which would have been expected from the prior art to an unobvious extent, and these results are a significant, practical advantage. Applicants present results from Balaian et al (Cancer Research, 2016, 76(Supplement): Abstract 3338). Balaian tested the capacity of pacritinib to eradicate therapy resistant leukemia stem cells (LSCs), residing in the bone marrow niche. Human primary CD34+ cells were selected from blast crisis CML (BC CML), MF and relapsed AML patients before and after clinical treatment with azacitidine. Survival and self-renewal of the cells were investigated by colony forming and replating assays after treatment with either different doses of pacritinib alone or in combination with dasatinib.
In BC CML cells, combined treatment with a 1 nM dose of dasatinib and pacritinib at doses of 10 or 20 nM resulted in a significant (p<0.001, Anova) difference in self-renewal of all BC CML cells, raising a possibility of an additive/synergistic mechanisms. In AML cells, pacritinib alone showed a significant decrease in self-renewal, however, the addition of dasatinib did not enhance the inhibition, suggesting a prospect of using pacritinib as a single agent in the treatment of relapsed AML. Balaian concludes:
Together these data indicate that possibly through inhibition of CSF1 and IRAK1 signaling in addition to suppression of JAK2, even in the presence of a LSC supportive niche, readily clinically achievable low nM concentrations of pacritinib alone are effective in reducing self-renewal of MF and relapsed AML. However, a combination of dasatinib and pacritinib is required to eliminate self-renewing LSC in BC CML with minimal toxicity toward normal progenitors. Targeting niche-dependent signaling could represent a robust avenue for treatment of refractory myeloid leukemia
Applicants argue this data demonstrates substantially improved results for eliminating self-renewing LSC in BC CML using a combination of dasatinib and pacritinib. Applicants argue the combined treatment demonstrates a significant difference in self-renewal of all BC CML cells, showing an additive/synergistic mechanism. Applicants argue the results are of a significant practical advantage because of the demonstrated minimal toxicity toward normal progenitors which is difficult to obtain when administering any combination of drugs to a patient.
Applicants argue the results are unexpected because elimination of self-renewing LSC in BC CML with minimal toxicity to normal progenitors is an infrequent achievement and desired goal when administering anti-cancer drugs.
6. The arguments have been carefully considered but are not persuasive.
First, it is noted that the results of Balaian do not demonstrate any advantage or improvements in the treatment of AML cells by adding dasatinib to pacritinib treatment. Therefore, the argued advantage, improvement, and unexpected result is not reasonably expected across all cancers and cancers associated with a stem cell as broadly claimed.
Second, with regard to treating BC CML cells with combined dasatinib and pacritinib in vitro, the results of Balaian are not greater than those expected based upon the disclosure of the cited prior art. The claims are drawn to an in vivo method for treating, ameliorating, stopping, or slowing the progression of a cancer or a cancer associated with a stem cell comprising administering the combination treatment to a subject, wherein the combination treatment comprises: (i) dasatinib + pacritinib; (ii) dasatinib + pacritinib + ruxolitinib (claim 4); or (iii) dasatinib + pacritinib + imatinib (claim 4).
The cited prior art: (1) provides an expected improved result in treating a patient having a cancer associated with a stem cell, CML or BC CML, with combined BCR-ABL1 TKI and JAK2 inhibitor treatment versus ABL1 TKI treatment alone, (2) provides an expected synergistic or significantly improved anticancer effect on CBC CML or LSCs when combining BCR-ABL1 TKI and JAK2 inhibitor versus either agent alone, and (3) provides an expectation of success for these results to predictably extrapolate to a combination of known BCR-ABL1 TKI dasatinib and known JAK2 inhibitor pacritinib:
Sweet teaches that patients having AML “showed significant response” to JAK2 inhibitor ruxolitinib alone, but refractory/relapsed CML patients only had modest response from the JAK2 inhibitor alone (section 2.4.1), providing an expected significant treatment response for ruxolitinib in the claimed combination, and for a JAK2 inhibitor in the treatment of AML.
Sweet teaches a series of preclinical studies has provided a rationale for the clinical study of the combination of ruxolitinib and nilotinib in CML, where conditioned medium from BM-derived mesenchymal stromal cells was shown to activate STAT3 in blastic-phase CML-derived cell lines and in LSCs obtained from patients with CML; STAT activation protected cells against nilotinib-mediated cell death; ruxolitinib was able to block STAT3 activation and, when combined with nilotinib, sensitized both cell lines and patient-derived LSCs to the cytotoxic effects of nilotinib (citing Nair et al, Leukemia Research, 2012, 36:756-763, as reference #68) (section 2.4.1), therefore, Sweet teaches the expected mechanism and advantage of JAK2 inhibitor treatment to sensitize patient-derived BC CML and LSCs to the cytotoxic effects of BCR-ABL1 TKI treatment through blocking STAT3 activation.
Sweet teaches Nair demonstrated that blockade of JAK2 reduced expression of JAK2 and TYK2 which was required to sensitize cell lines and patient-derived LSCs to nilotinib (section 2.4.1), therefore the mechanism of action and advantage for combination treatment is established and expected.
Zhou, as stated in the rejection, teaches clinically treating a patient having CML by administering BCR-ABL1 TKI dasatinib in combination with JAK2 inhibitor ruxolitinib. The patient was treated first with dasatinib that suppressed BCR-ABL presence, but eventually progressed with increased JAK2 mutated allele burden, then was treated with both dasatinib and ruxolitinib. Zhou teaches the combination of dasatinib and ruxolitinb successfully treated the patient, the patient maintained a complete cytogenic response with low level BCR-ABL detectable by qRT-PCR and controlled JAK2 mutation burden, and the combined treatment slowed progression to a resistant cancer. Therefore, Zhou provides an expected improved response of CML patients to BCR-ABL1 TKI dastanib single agent therapy by adding JAK2 inhibition.
Gallipoli establish the JAK2/STAT5 pathway is a therapeutic target in CML stem/progenitor cells (SPCs) and suggests administering a combination of JAK2 inhibitor ruxolitinib and BCR-ABL1 TKI nilotinib to CML patients to eradicate persistent (residual) disease (abstract). Gallipoli demonstrates that the combination of JAK2 inhibitor ruxolitinib and BCR-ABL1 TKI nilotinib leads to enhanced eradication of primitive CML stem cells (Key Points box). Gallipoli demonstrated that combination treatment significantly reduced activity of the JAK2/STAT5 pathway relative either single agent alone in vitro in CML cells (abstract; Figure 1). The combination treatment also significantly increased apoptosis of CML stem/progenitor cells (SPCs) in vitro and resulted in a reduction in primitive quiescent CML stem cells compared to single agents (abstract; Figure 4). Gallipoli demonstrated that combination treatment of ruxolitinib and nilotinib in mice significantly reduced engraftment of CML cells compared to nilotinib alone (Figure 5; p. 1498, col. 1-2). Gallipoli further teaches assessing engraftment of CML cells in mice exposed to various treatments by measuring BCR-ABL mRNA transcripts by (RT-PCR, wherein combination treatment resulted in a reduction of BCR-ABL mRNA levels statistically greater than nilotinib alone (Methods; Figure 5D). Therefore, Gallipoli demonstrates expected synergy and significant results when combining BCR-ABL1 TKI with JAK2 inhibitor in the treatment of CML and LSCs.
Quintarelli teaches successful treatment of K562 cells (CML cells in blast crisis) with combined treatment of BCR-ABL1TKI dasatinib and JAK2 inhibitor ruxolitinib, wherein the combination: (1) was significantly more toxic to cells than single agents, (2) demonstrated synergy of the combination therapy, and (3) overcame drug resistance to tyrosine kinase inhibitors (TKIs) (Figure 3; Results; p. 241, col. 2). Therefore, Quintarelli demonstrates expected significant results when combining BCR-ABL1 TKI with JAK2 inhibitor in the treatment of BC CML.
Verstovsek teaches clinical treatment of chronic myeloid disease patients with JAK2 inhibitor SB1518 (pacritinib); confirms pacritinib is a potent inhibitor of FLT3 (expressed by immature hematopoietic cells), JAK2, and a JAK2 mutant; teaches pacritinib inhibits proliferation of human leukemia cell lines dependent on either JAK2 or FLT3; demonstrates pacritinib has antitumor activity in mouse models of JAK2-dependent leukemia; and teaches pacritinib successfully clinically treats AML and MF patients demonstrating inhibition of pSTAT3 and pSTAT5 after treatment. Therefore, Verstovsek provides the expected success of pacritinib to function as a JAK2 inhibitor clinically, and treat a cancer associated with a stem cell.
Rosenthal reviews known JAK inhibitors for the treatment of myeloproliferative neoplasms, including SB1518 (pacritinib) (section 4.2; Table 1) and ruxolitinib (section 3; Table 1). Rosenthal teaches oral dosing of pacritinib and teaches that pacritinib seems less likely to result in severe (grade 3 or 4) anemia or thrombocytopenia (section 4.2). Therefore, Rosenthal teaches an advantage of pacritnib is its reduced likelihood of cytotoxicity related to anemia and thrombocytopenia.
The cited prior art: (1) established that combining BCR-ABL1 TKI and JAK2 inhibitor treatment of cancers associated with stem cells, CML, and BC CML is expected to provide a more effective treatment than BCR-ABL1 TKI alone, and explained the mechanisms of why; (2) demonstrated expected synergy and significant improvement in anti-cancer effects by combining BCR-ABL1 TKI and JAK2 inhibitor therapy including killing LSCs; (3) demonstrated the expected benefit of combination therapy is due to the function of the BCR-ABL1 TKI and JAK2 inhibitors, and the function is not unique to any individual BCR-ABL1 TKI or JAK2 inhibitors, providing a reasonable expectation of success for any known, established BCR-ABL1 TKI and JAK2 inhibitors to function together the same and to achieve the same beneficial results; (4) established pacritinib is a known JAK2 inhibitor, already clinically administered to treat AML, CML, and other cancer associated with a stem cell; and (5) established JAK2 inhibitor pacritinib harbors an advantage of reduced likelihood of cytotoxicity related to anemia and thrombocytopenia.
Therefore, contrary to arguments, the combination therapy of dasatinib + pacritinib or dasatinib + pacritinib + ruxolitinib is expected to provide improved treatment of cancers in subjects associated with stem cells, CML, and BC CML, have synergistic anti-tumor effects including killing LSCs, and have reduced likelihood of cytotoxicity related to anemia and thrombocytopenia. The data presented by Applicants as disclosed in Balaian does not demonstrate cancer treatment results or anti-tumor effects that are substantially improved or unexpected over what is taught, demonstrated, and expected by the cited prior art.
7. Claim(s) 3 remains rejected under 35 U.S.C. 103 as being unpatentable over Sweet et al (Critical Reviews in Oncology/Hematology, 2013, 88:667-679); Zhou et al (Blood Cancer Journal, 2015, 5:e351); Gallipoli et al (Blood, 2014, 124:1492-1501); Quintarelli et al (Leukemia Research, 2014, 38:236-242); Cortes et al (Blood, 2007, 109:3207-3213); Verstovsek et al (Blood; ASH Annual Meeting Abstracts; 2009;114: abstract 3905); Rosenthal et al (Expert Opinion on Pharmacotherapy, 2014, 15:1265-1276), as applied to claims 1, 2, 4, 15, 16, 22, 23, and 27 above, and further in view of Crews et al (Journal of Translational Medicine, 2015, 13:52, internet pages 1-12).
Sweet; Zhou; Gallipoli; Quintarelli; Cortes; Verstovsek; and Rosenthal (the combined references) teach a method for treating CML patients by administering to the patients a combination of dasatinib and pacritinib, thereby treating CML, as set forth above. Sweet teaches the need to administer the combined therapy in order to eradicate residual disease. Zhou further teaches and demonstrates the need to determine the impact of combination treatment on eliminating residual disease by assessing the efficacy of treatment through measuring molecular response (MR) to therapy. Zhou et al measured therapeutic response and minimal residual clonal/allele burden from CML by detecting BCR-ABL and JAK2 mutated transcripts by qRT-PCR (first page, col. 1-2).
The combined references do not teach monitoring response to therapy by using RESSqPCR to measure Adenosine to Inosine (A to I) RNA editing of APOBEC3 to assess presence of cancer stem cells.
Crews teaches and successfully demonstrates utilizing RESSqPCR to measure Adenosine to Inosine (A to I) editing of APOBEC3 as a marker of the presence of cancer stem cells, residual disease, relapse and progression in CML (p. 8). Crews suggests utilizing RESSqPCR as an array-based technology to detect a cancer stem cell (CSC)-specific RNA editing fingerprint of malignant reprogramming to provide a rapid clinical assay for early detection of cancer progression and prognostication (p. 10, col. 1, first paragraph). Crews suggests RNA editing activity can be influenced by treatment status at the time a sample is collected and provide prognostic information related to risk for acquisition of drug resistance. The assessment of samples before and after treatment will allow precise determination of the RNA editing levels that correlate with poorer prognosis in several blood cancer and other CSC-driven malignancies (p. 10, col. 2). Crews teaches (Conclusions): “RESSq-PCR RNA editing diagnostic platform provides an innovative method for testing specificity of candidate CSC-targeted therapeutics to inhibit RNA editing, and could serve as an informative companion diagnostic for clinical trials. In summary, this study demonstrates the rapid translation of next generation sequencing data into a functionally relevant tool for detection of an RNA editing fingerprint of malignant progenitor reprogramming that could identify patients at risk for cancer progression and therapeutic resistance.”
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to assess efficacy of CML treatment in the method of the combined references by utilizing RESSqPCR to measure Adenosine to Inosine (A to I) editing of APOBEC3 as a marker of the presence of cancer stem cells, residual disease, and therapeutic response in CML. One would have been motivated to because: (1) the combined references recognize the need to eliminate residual disease during CML treatment and to assess the presence of residual disease; (2) Zhou teaches the need to measure the molecular response of CML patients to treatment, and the need to determine the impact of combination treatment of ruxolitinib and dasatinib on eliminating minimal residual disease or leukemic stem cells; and (3) Crews suggests RESSq-PCR measurement of Adenosine to Inosine (A to I) to test for specificity of candidate CSC-targeted therapeutics to inhibit RNA editing, identify CML patients at risk for cancer progression and therapeutic resistance, and serve as an informative companion diagnostic for clinical trials. One of ordinary skill in the art would have a reasonable expectation of success utilizing RESSq-PCR measurement of Adenosine to Inosine editing of APOBEC3 in the method of the combined references to assess residual disease given Crews demonstrates the success of this method in assessing the presence of CSCs in CML.
Response to Arguments
8. Applicants reiterate arguments that they demonstrate results for their claimed method that are unobvious over the cited prior art and Crews does not remedy this deficiency.
9. The arguments have been considered but are not persuasive because the cited prior art does not have the deficiency argued and Crews does not need to address the argued deficiency.
10. Claim(s) 24 and 25 remain rejected under 35 U.S.C. 103 as being unpatentable over Sweet et al (Critical Reviews in Oncology/Hematology, 2013, 88:667-679); Zhou et al (Blood Cancer Journal, 2015, 5:e351); Gallipoli et al (Blood, 2014, 124:1492-1501); Quintarelli et al (Leukemia Research, 2014, 38:236-242); Cortes et al (Blood, 2007, 109:3207-3213); Verstovsek et al (Blood; ASH Annual Meeting Abstracts; 2009;114: abstract 3905); Rosenthal et al (Expert Opinion on Pharmacotherapy, 2014, 15:1265-1276), as applied to claims 1, 2, 4, 15, 16, 22, 23, and 27 above, and further in view of Zhou 2010 (Journal of Controlled Release, 2010, 148:380-387); and Almer et al (Current Medicinal Chemistry, 2015, 22:3631-3651).
Sweet; Zhou; Gallipoli; Quintarelli; Cortes; Verstovsek; and Rosenthal (the combined references) teach a method for treating CML patients by administering to the patients a combination of dasatinib and pacritinib, thereby treating CML, as set forth above.
The combined references do not teach the combination therapy is formulated as a nanoparticle or particle.
Zhou 2010 teaches CML stem/progenitor cells, which overexpress BCR-ABL, respond to imatinib by reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse (abstract). Zhou 2010 demonstrates QSC readily uptake sLDL, and teach there was a greater uptake of sLDL in malignant CML CD34+ cells, suggesting that normal CD34+ would not be dosed with increased levels of any drug carried by the sLDL, widening the therapeutic window (p. 385, col. 2). Zhou 2010 further teaches (p. 385, col. 2 to p. 386, col. 1): “We have previously shown CML QSC to be insensitive to molecularly targeted tyrosine kinase inhibitors (TKI) such as imatinib or nilotinib. Over-expression of Bcr-Abl message, protein and kinase activity in the more primitive CD34+38lo/− cells may explain this insensitivity to standard drug concentrations.” Zhou 2010 further teaches (p. 386, col. 1): “To overcome this significant clinical problem of stem cell persistence in CML, we 27tilized27zed that such cells must be exposed to an intracellular concentration of drug greater than is achieved with standard oral dosing. Simply augmenting the dose to the patient to saturate the uptake pump (Oct-1) risks side effects as every drug, even a potent molecularly targeted agent, has its therapeutic window beyond which non-specific effects are experienced. Nevertheless increasing intracellular concentrations in QSC may be made possible through pharmaceutical drug targeting strategies i.e. use of physical, biocompatible, drug-carrying vehicles, circumventing the problem of inadequate active uptake by influx proteins through low expression. We decided to investigate the known increased cholesterol requirements of cancer cells, specifically LDLR activity in the myeloid lineage. Thus the aim of the current study was to determine if sLDL may be 27tilized as a drug targeting vector to ultimately deliver augmented doses of TKI into CML QSC to initiate apoptotic cell death. Interestingly, Nikanjam et al. demonstrated receptor mediated, targeted delivery of sLDL prepared according to our recipe to gliobastoma multiforme cell lines, following up with delivery of incorporated paclitaxel to the same brain tumour cell line model. The results presented in this paper in combination with literature data demonstrate the utility of the sLDL system as a drug delivery vehicle for persistent leukemic stem cells. Although it is perhaps counter-intuitive that cells residing out of the cell cycle should be targeted by this system, we nonetheless have demonstrated the propensity for QSC to be loaded with our sLDL nanoparticles.”
Based on the success of targeting CML with the sLDL, Zhou 2010 suggests using sLDL as a carrier and loading the nanoparticles with TKIs or other drugs to induce apoptosis in leukemic QSC (section 5. Conclusion).
Almer also teaches utilizing LDL as a drug carrier for cancer therapeutics and explains how to use LDL as a drug carrier (Figure 3; p. 3634-3636). Almer also recognizes that LDL is an attractive carrier for targeting leukemic cells because they have a higher level of LDL receptor activity and uptake than normal cells (p. 3636, col. 2). Almer summarizes known applications of using LDL as a drug delivery system for cancers including leukemia (Table 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize nanoparticle LDL as a drug carrier in the method of the combined references for treating CML. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Zhou 2010 and Almer teach malignant leukemic quiescent stem cells or leukemic cells have a propensity for uptake of LDL over normal cells making LDL an ideal carrier to target these cells; (2) based on the success of targeting CML with the sLDL, Zhou 2010 suggests using sLDL as a carrier and loading the nanoparticles with TKIs or other drugs to induce apoptosis in leukemic QSC; and (3) Almer teaches LDL is already being applied as a drug carrier in the treatment of cancers including leukemia.
Response to Arguments
11. Applicants reiterate arguments that they demonstrate results for their claimed method that are unobvious over the cited prior art and Zhou 2010 and Almer do not remedy this deficiency.
12. The arguments have been considered but are not persuasive because the cited prior art does not have the deficiency argued and Zhou 2010 and Almer do not need to address the argued deficiency.
13. All other objections and rejections recited in the Office Action mailed May 19, 2025 are hereby withdrawn in view of amendments.
14. Conclusion: No claim is allowed.
Conclusion
15. 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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/Laura B Goddard/Primary Examiner, Art Unit 1642