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 .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 – 4, 19, and 25 – 27 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449) in view of Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025).
Regarding claims 1 – 4, 19, and 25 – 27, Xu’188 teach compounds that inhibit protein kinase activity, and to compositions and methods related thereto. See page 1 paragraph 0002. Xu’188 teach compounds, and pharmaceutical compositions comprising said compounds, where the compounds have the following general structures (I), (II) and (Ill):
PNG
media_image1.png
214
880
media_image1.png
Greyscale
.See page 3 paragraph 0008. In particular, Xu’188 teach compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
. See page 59 Table 1 column 2 row 5. See claim 1 limitation for a method comprising administering an effective amount of compound (1)
PNG
media_image3.png
186
394
media_image3.png
Greyscale
. Moreover, Xu’188 teach compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
. See page 61 Table 1 column 1 row 2. Additionally, Xu’188 teach that a compound of the present invention or a pharmaceutically acceptable salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s). See page 75 paragraph 00197. See claim 27 limitation for a method where the mammal is a human. Xu’188 teach that the protein kinase-modulation compounds of the disclosure, which includes compounds 8 – 10 and 8 – 31,may be provided as physiologically acceptable salts which include hydrochloride salts. See page 80 paragraph 00225. See claim 25 limitation for a method where compound (1) is the pharmaceutically acceptable salt. See claim 26 limitation where the pharmaceutical salt is an HCl salt.
Xu’188 teach the use of compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, are formulated in pharmaceutical compositions that can be administered orally. See page 78 paragraph 00214. See claim 19 limitation for a method where compound (1) is administered orally. Additionally, Xu’188 teach that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered in dosage ranges from 0.2 – 1000 mg/qid or 4 times per day. See page 82 paragraph 00233. Moreover, Xu’188 teach that the amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. See page 82 paragraph 00235. Xu’188 teach that the compounds and compositions of the invention will find utility in a broad range of diseases and conditions mediated by protein kinases, including diseases and conditions mediated by PIM kinase which includes hematological malignancies which further includes acute myeloid leukemia (AML). See page 84 paragraph 00241 and page 85 paragraph 00242. Moreover, Xu’188 teach that that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be used in combination with one or more chemotherapeutic agents. See page 85 paragraph 00242.
Furthermore, Xu’188 teach that compounds 8 – 10 and 8 – 31 had IC50 values against Pim1 of 9 nM and 1 nM respectively. See page 180. Additionally, Xu’188 teach that both compounds had an hERG IC50 vlaue of > 30 µM. See page 182 Table VI. Moreover, Xu’188 teach that compound 8 – 31 was screened against a panel of hematological cell lines using an in vitro viability assay which includes acute myeloid leukemia (AML) cell lines MV-4-ll, MOLM-2123, ML-2, GDM-1, and PL-21. See page 185 paragraph 00592 and Figure 6. Furthermore, Xu’188 teach that compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. See page 186 paragraph 00593 and Figure 7A. Xu’188 teach that treatment of established xenografts of MV-4-11 (FL T3-ITD) with compound 8-31 also induced regressions. See page 186 paragraph and Figure 7B.
Regarding claim 2 limitation for a method comprising administering to about 250 mg to 2500 mg per day of compound (1); Xu’188 teach that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered in dosage ranges from 0.2 – 1000 mg/qid or 4 times per day. See page 82 paragraph 00233. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of 0.2 – 1000 mg/qid or 4 times per day to mg/ day values 0.8 – 4000 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the dosage range of 0.8 – 4000 mg/day taught by Xue’188 overlaps with the recited dosage regimen of 250 mg to about 2500 mg per day as recited in claim 2. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
Regarding claim 3 limitation for a method comprising administering to about 300 mg to 1500 mg per day of compound (1); Xu’188 teach that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered in dosage ranges from 0.2 – 1000 mg/qid or 4 times per day. See page 82 paragraph 00233. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of 0.2 – 1000 mg/qid or 4 times per day to mg/ day values 0.8 – 4000 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the dosage range of 0.8 – 4000 mg/day taught by Xue’188 overlaps with the recited dosage regimen of 300 mg to about 1500 mg per day as recited in claim 3. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
Regarding claim 4 limitation for a method comprising administering to about 450 mg to 960 mg per day of compound (1); Xu’188 teach that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered in dosage ranges from 0.2 – 1000 mg/qid or 4 times per day. See page 82 paragraph 00233. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of 0.2 – 1000 mg/qid or 4 times per day to mg/ day values 0.8 – 4000 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the dosage range of 0.8 – 4000 mg/day taught by Xue’188 overlaps with the recited dosage regimen of 450 mg to about 960 mg per day as recited in claim 4. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
However, Xue’188 fails to teach the treatment of treating a myeloproliferative neoplasm in a mammal comprising administering an effective amount of compound (1). See claim 1 limitation.
Nevertheless, as taught above, Xu’188 teach compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
. See page 61 Table 1 column 1 row 2. Both of these prior art compounds differ by the -O- unit between the phenyl ring and the CF3 substitute. Moreover, as taught above both prior art compounds exhibit Pim1 IC50 values within the same order of magnitude. Furthermore, as taught above Xu’188 teach that compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. And Xu’188 teach that treatment of established xenografts of MV-4-11 (FL T3-ITD) with compound 8-31 also induced regressions. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to use prior art compound 8 – 10 in the MV-4-11 (FL T3-ITD) xenograft mouse model. Furthermore, given the teachings of Xu’188 it would have been obvious given that fact that compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity.
However, Xue’188 fails to teach whether acute myeloid leukemia (AML) is a myeloproliferative neoplasm. See claim 1 limitation.
Nevertheless, Rampal et.al. teach that myeloproliferative neoplasms (MPNs) are hematopoietic disorders characterized by clonal proliferation of mature myeloid elements which manifest clinically as an excess of RBC [polycythemia vera (PV)], platelets [essential thrombocytosis (ET)], or WBC [primary myelofibrosis (PMF)]. See page E5401 column 1 paragraph 1. Rampal et.al teach that mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF, underscoring the importance of activated JAK–STAT signaling to the pathogenesis of chronic phase MPN. See page E5401 column 1 paragraph 1. Moreover, Rampal et.al. teach that despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). See page E5401 column 1 paragraph 1. Furthermore, Rampal et.al. teach that MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. See page E5401 column 1 paragraph 1. Thus, Rampal et.al. suggest that AML is a myeloproliferative neoplasm. Additionally, Rampal et.al. teach that ruxolitinib has been approved for the treatment of myelofibrosis, and early-phase clinical trials reported significant, transient responses to ruxolitinib in post-MPN AML patients. See page E5409 column 1 paragraph 1. Moreover, Rampal et.al. teach the efficacy of ruxolitinib in the murine model of post-MPN AML. See page E5409 column 1 paragraph 1. Yet, Rampal et.al. teach that in the study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. See page E5409 column 1 paragraph 1.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model, in view of Rampal et.al. which is a myeloproliferative neoplasm. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models.
Claims 5 – 12, and 14 – 17 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449) and Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025) as applied to claims 1 – 4, 19, and 25 – 27 above, and in further view of Chinese Patent Publication Number CN 105919955 to Wang et. al. (Wang’955; cited on an IDS 1449 English Machine Translation used).
The teachings of Xu’188 as it relates to independent claim 1, from which claims 5 – 12, and 14 – 17 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Xu’188 fails to teach a method where the mammal is on a JAK inhibitor regimen. See claim 5 limitation. Moreover, Xu’188 fails to teach a method where the JAK inhibitor is ruxolitinib. See claims 6 – 8, and 14 limitation. Furthermore, Xu’188 fail to teach a method where the Jak inhibitor is dosed within specific dose range. See claims 9 – 12. Additionally, Xu’188 fails to teach a method where the myeloproliferative neoplasm is primary myelofibrosis, intermediate- risk myelofibrosis or high-risk myelofibrosis. See claims 15 – 17.
Nevertheless, Rampal et.al. teach that myeloproliferative neoplasms (MPNs) are hematopoietic disorders characterized by clonal proliferation of mature myeloid elements which manifest clinically as an excess of RBC [polycythemia vera (PV)], platelets [essential thrombocytosis (ET)], or WBC [primary myelofibrosis (PMF)]. See page E5401 column 1 paragraph 1. Rampal et.al teach that mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF, underscoring the importance of activated JAK–STAT signaling to the pathogenesis of chronic phase MPN. See page E5401 column 1 paragraph 1. Moreover, Rampal et.al. teach that despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). See page E5401 column 1 paragraph 1. Furthermore, Rampal et.al. teach that MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. See page E5401 column 1 paragraph 1.
Specifically, Rampal et.al. teach that viral supernatant containing MSCV-mJAK2V617F-IRES-GFP, and 7.5 × 105 cells were injected into the lateral tail veins of lethally irradiated (2 × 4.5 Gy) C57BL/6 mice. See page E5409 column 2 paragraph 1. See claims 15 and 17 limitation for a method where the myeloproliferative neoplasm is primary myelofibrosis. Moreover, Rampal et. al. teach that in the in vivo drug trials, mice were randomized to receive treatment with PU-H71 (75 mg/kg i.p., three times per week), ruxolitinib (60 mg/kg two times per day), or vehicle (10 mM phosphate buffer, pH ∼6.4), beginning 21 d after transplantation. See page E5409 column 2 paragraph 1. See claims 6 – 8, and 14 limitation for a method where the JAK inhibitor is ruxolitinib. Treatment with the JAK1/2 inhibitors ruxolitinib or CYT387 resulted in a concentration-dependent inhibition of colony formation. See page E5406 column 2 paragraph 2 and page E5407 Figures 5 A and B). Additionally, Rampal et.al. teach that ruxolitinib has been approved for the treatment of myelofibrosis, and early-phase clinical trials reported significant, transient responses to ruxolitinib in post-MPN AML patients. See page E5409 column 1 paragraph 1. Moreover, Rampal et.al. teach the efficacy of ruxolitinib in the murine model of post-MPN AML. See page E5409 column 1 paragraph 1. Yet, Rampal et.al. teach that in the study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. See page E5409 column 1 paragraph 1.
Regarding claim 5 limitation for a method where the mammal is on a JAK inhibitor regimen; as taught above, Rampal et.al. teach that in the study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Thus, Rampal et. al. suggest that when a JAK inhibitor is used continuously as a monotherapy there is still disease progression from MPN to secondary acute myeloid leukemia (AML) which has a worse prognosis. Therefore, Rampal et. al. suggest a need to modify the JAK inhibitor monotherapy to address the population of MPN patients that continue to progress. Moreover, as taught above, Xu’188 teach that the compounds and compositions of the invention will find utility in a broad range of diseases and conditions mediated by protein kinases, including diseases and conditions mediated by PIM kinase which includes hematological malignancies which further includes acute myeloid leukemia (AML). Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of an MD, PhD, or PharmD it would have been within the purview of such artisan to JAK inhibitor monotherapy to add an additional chemotherapeutic agent to address these patients.
However, the prior art of Rampal et.al. fails to teach a method where the Jak inhibitor is dosed within specific dose range. See claims 9 – 12. Additionally, Rampal et.al. fails to teach a method where the myeloproliferative neoplasm is intermediate- risk myelofibrosis or high-risk myelofibrosis. See claim 16.
Nevertheless, Wang’955 teach the use of ruxolitinib in the preparation of pharmaceuticals for oral administration. See page 2 paragraph 0002. Specifically, Wang’955 teach the use of ruxolitinib for the treatment of intermediate risk myelofibrosis or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. See page 3 paragraph 0003. See claim 15 – 17 limitation. Moreover, Wang’955 teach that pharmaceutical compositions containing about 0.5 mg to 1000 mg of ruxolitinib which are administered three times daily for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. See page 9 paragraph 0009. Furthermore, Wang’955 teach a most preferred pharmaceutical composition containing about 5 mg to 50 mg of ruxolitinib. See page 10 paragraph 0009.
Regarding claim 9 limitation for a method where the JAK inhibitor is at a dose of about 1 mg to about 200 mg per day; Wang’955 teach that pharmaceutical compositions containing about 0.5 mg to 1000 mg of ruxolitinib 3 times a day and a most preferred pharmaceutical composition containing about 5 mg to 50 mg of ruxolitinib.. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of about 0.5 mg to 1000 mg of ruxolitinib 3 times a day to mg/day values 1.5 – 3000 mg/day or to convert the preferred teaching of about 5 mg to 50 mg of ruxolitinib 3 times a day to mg/day values 15 – 150 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the prior art ranges of dosage range of 1.5 – 3000 mg/day or 15 – 150 mg/day taught by Wang’955 overlaps with the recited dosage regimen of 1 mg to about 200 mg per day as recited in claim 9. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
Regarding claim 10 limitation for a method where the JAK inhibitor is at a dose of about 1 mg to about 100 mg per day; Wang’955 teach that pharmaceutical compositions containing about 0.5 mg to 1000 mg of ruxolitinib 3 times a day and a most preferred pharmaceutical composition containing about 5 mg to 50 mg of ruxolitinib. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of about 0.5 mg to 1000 mg of ruxolitinib 3 times a day to mg/day values 1.5 – 3000 mg/day or to convert the preferred teaching of about 5 mg to 50 mg of ruxolitinib 3 times a day to mg/day values 15 – 150 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the prior art ranges of dosage range of 1.5 – 3000 mg/day or 15 – 150 mg/day taught by Wang’955 overlaps with the recited dosage regimen of 1 mg to about 100 mg per day as recited in claim 10. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
Regarding claim 11 limitation for a method where the JAK inhibitor is at a dose of about 5 mg to about 60 mg per day; Wang’955 teach that pharmaceutical compositions containing about 0.5 mg to 1000 mg of ruxolitinib 3 times a day and a most preferred pharmaceutical composition containing about 5 mg to 50 mg of ruxolitinib. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of about 0.5 mg to 1000 mg of ruxolitinib 3 times a day to mg/day values 1.5 – 3000 mg/day or to convert the preferred teaching of about 5 mg to 50 mg of ruxolitinib 3 times a day to mg/day values 15 – 150 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the prior art ranges of dosage range of 1.5 – 3000 mg/day or 15 – 150 mg/day taught by Wang’955 overlaps with the recited dosage regimen of 5 mg to about 60 mg per day as recited in claim 11. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
Regarding claim 12 limitation for a method where the JAK inhibitor is at a dose of about 10 mg to about 50 mg per day; Wang’955 teach that pharmaceutical compositions containing about 0.5 mg to 1000 mg of ruxolitinib 3 times a day and a most preferred pharmaceutical composition containing about 5 mg to 50 mg of ruxolitinib. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of about 0.5 mg to 1000 mg of ruxolitinib 3 times a day to mg/day values 1.5 – 3000 mg/day or to convert the preferred teaching of about 5 mg to 50 mg of ruxolitinib 3 times a day to mg/day values 15 – 150 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the prior art ranges of dosage range of 1.5 – 3000 mg/day or 15 – 150 mg/day taught by Wang’955 overlaps with the recited dosage regimen of 10 mg to about 50 mg per day as recited in claim 12. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model, in view of Rampal et.al., that is to treat primary myelofibrosis that is already on a JAK inhibitor regimen in further view of Wang’955 that is to use ruxolitinib to alternatively treat intermediate risk myelofibrosis or high-risk myelofibrosis, or primary myelofibrosis. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because in in vivo study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML.
Claims 20 – 24 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449) and Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025) as applied to claims 1 – 4, 19, and 25 – 27 above, and in further view of International Publication Number WO 2016/161248 A1 to Warner et. al. (Warner’248; cited on an IDS 1449).
The teachings of Xu’188 and Rampal et. al. as they relate to independent claim 1, from which claims 20 – 24 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Xu’188 and Rampal et. al. fail to teach a method where compound (1) is administered once daily. See claim 20 limitation. Moreover, the prior art of Xu’188 and Rampal et. al. fail to teach a method where compound (1) is administered once, twice daily. See claim 21 limitation. Furthermore, the prior art of Xu’188 and Rampal et. al. fail to teach a method where compound (1) is administered for about seven days to about one year. See claim 22 limitation. Additionally, the prior art of Xu’188 and Rampal et. al. fail to teach a method where compound (1) is administered for 28 days. See claim 23 limitation. The prior art of Xu’188 and Rampal et. al. fail to teach a method where compound (1) is administered for one year. See claim 24 limitation.
Nevertheless, Warner’248 teach methods for treatment of cancer by administration of a PIM kinase inhibitor in combination with a BTK inhibitor. See page 1 lines 9 – 11. Specifically, Warner’248 teach an embodiment where the PIKM kinase inhibitor compound 1, with the structure
PNG
media_image5.png
200
310
media_image5.png
Greyscale
. See page 15 lines 11 – 14. Thus, Warner’248 teach a compound that is of the exact structure of compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
of Xu’188. Moreover, Warner’248 teach that cancer includes solid tumors and leukemias (e.g., acute myeloid leukemia) are amenable to the methods disclosed herein. See page 17 lines 13 – 15. Additionally, Warner’248 teach that compounds of the disclosure which include compound 1, in the treatment of adult humans, at dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day. See page 19 lines 14 – 16. Moreover, Warner’248 teach that the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. See page 19 lines 17 – 20. Additionally, Warner’248 teach in some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. See page 19 lines 27 – 28. See claims 20 – 21 limitation. Moreover, Warner’248 teach another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. See page 19 lines 33 – 35. See claims 22 – 24 limitation.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model, in view of Rampal et.al. which is a myeloproliferative neoplasm, in further view of Warner’248, that is to administer example 8 – 10 at the recited dosage intervals. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449), Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025), Chinese Patent Publication Number CN 105919955 to Wang et. al. (Wang’955; cited on an IDS 1449 English Machine Translation used), as applied to claims 15 above, and in further view of Breccia et. al. ((2017), Ruxolitinib in clinical practice for primary and secondary myelofibrosis: an analysis of safety and efficacy of Gruppo Laziale of Ph-negative MP, Ann Hematol. 96, 387 – 391; cited on the IDS dated September 24th, 2025).
The teachings of Xu’188, Rampal et. al., and Wang’955 as they relate to claim 15, from which claim 18 depends, are given previously in this office action and are fully incorporated here.
However, the prior art of Xu’188, Rampal et. al., and Wang’955 fail to teach a method where the myelofibrosis is secondary myelofibrosis. See claim 18 limitation.
Nevertheless, Breccia et. al. teach the use of ruxolitinib for secondary myelofibrosis. See page 387 abstract. See claim 18 limitation. Furthermore, Breccia et. al. teach ruxolitinib administration over the course of a year led to 52% of the patients achieving and maintaining the clinical benefits of complete remission, clinical improvement (i.e., MRD-negative), partial response, and a spleen response. See page 387 column 2 paragraph 1.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model, in view of Rampal et.al., that is to treat primary myelofibrosis that is already on a JAK inhibitor regimen in further view of Wang’955 that is to use ruxolitinib to alternatively treat intermediate risk myelofibrosis or high-risk myelofibrosis, or primary myelofibrosis. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because in in vivo study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Additionally, One of ordinary skill in the art would be motivated to make this treatment modification to improve the prognosis of patients. One of ordinary skill in the art would have a reasonable expectation of success because of the demonstrated improved clinical benefit for the patient.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449), Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025), Chinese Patent Publication Number CN 105919955 to Wang et. al. (Wang’955; cited on an IDS 1449 English Machine Translation used), as applied to claim 5 above, and in further view of Vainchenker et.al. ((Jan 18th 2018), JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders, F1000 Research, 82, 1 – 19).
The teachings of Xu’188, Rampal et. al., and Wang’955 as they relate to claim 5, from which claim 13 depends, are given previously in this office action and are fully incorporated here.
However, the prior art of Xu’188, Rampal et. al., and Wang’955 fail to teach a method where the JAK inhibitor is momelotinib. See claim 13 limitation.
Nevertheless, Vainchenker et. al. teach Janus kinases (JAKs) play a central role in the regulation of hematopoiesis as being mandatory for signaling by receptors for hematopoietic/immunological cytokines1. See page 3 column 1 paragraph 1. Moreover, Vainchenker et. al. teach that the JAK/STAT pathway is frequently dysregulated in malignant diseases and in disorders with an abnormal immunological response, See page 3 column 1 paragraph 2. Furthermore, Vainchenker et. al. teach that many inhibitors target JAK2, JAK1, and eventually TYK2 (ruxolitinib, momelotinib, AZD1480, and baricitinib) or JAK3 and JAK1 (tofacitinib). See page 7 column 2 paragraph 2. Thus, Vainchenker et. al. suggest that both ruxolitinib and momelotinib as equivalent JAK inhibitors.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model, in view of Rampal et.al., that is to treat primary myelofibrosis that is already on a JAK inhibitor regimen in further view of Wang’955 that is to use ruxolitinib to alternatively treat intermediate risk myelofibrosis or high-risk myelofibrosis, or primary myelofibrosis in further view of Vainchenker et. al. that is to substitute momelotinib for ruxolitinib. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because in in vivo study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Additionally, One of ordinary skill in the art would be motivated to make this treatment modification to improve the prognosis of patients. One of ordinary skill in the art would have a reasonable expectation of success because of the demonstrated improved clinical benefit for the patient.
Claims 28 – 30 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449), Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025), Chinese Patent Publication Number CN 105919955 to Wang et. al. (Wang’955; cited on an IDS 1449 English Machine Translation used), and in further view of Vainchenker et.al. ((Jan 18th 2018), JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders, F1000 Research, 82, 1 – 19).
Regarding claims 28 – 30, Xu’188 teach compounds that inhibit protein kinase activity, and to compositions and methods related thereto. See page 1 paragraph 0002. Xu’188 teach compounds, and pharmaceutical compositions comprising said compounds, where the compounds have the following general structures (I), (II) and (Ill):
PNG
media_image1.png
214
880
media_image1.png
Greyscale
.See page 3 paragraph 0008. In particular, Xu’188 teach compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
. See page 59 Table 1 column 2 row 5. See claim 28 limitation for a method comprising administering an effective amount of compound (1)
PNG
media_image3.png
186
394
media_image3.png
Greyscale
. Moreover, Xu’188 teach compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
. See page 61 Table 1 column 1 row 2. Additionally, Xu’188 teach that a compound of the present invention or a pharmaceutically acceptable salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s). See page 75 paragraph 00197. See claim 28 limitation for a method where a human is treated. Xu’188 teach that the protein kinase-modulating compounds of the disclosure, which includes compounds 8 – 10 and 8 – 31,may be provided as physiologically acceptable salts which include hydrochloride salts. See page 80 paragraph 00225.
Xu’188 teach the use of compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, are formulated in pharmaceutical compositions that can be administered orally. See page 78 paragraph 00214. Additionally, Xu’188 teach that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered in dosage ranges from 0.2 – 1000 mg/qid or 4 times per day. See page 82 paragraph 00233. Moreover, Xu’188 teach that the amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. See page 82 paragraph 00235. Xu’188 teach that the compounds and compositions of the invention will find utility in a broad range of diseases and conditions mediated by protein kinases, including diseases and conditions mediated by PIM kinase which includes hematological malignancies which further includes acute myeloid leukemia (AML). See page 84 paragraph 00241 and page 85 paragraph 00242. Moreover, Xu’188 teach that that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be used in combination with one or more chemotherapeutic agents. See page 85 paragraph 00242.
Furthermore, Xu’188 teach that compounds 8 – 10 and 8 – 31 had IC50 values against Pim1 of 9 nM and 1 nM respectively. See page 180. Additionally, Xu’188 teach that both compounds had an hERG IC50 vlaue of > 30 µM. See page 182 Table VI. Moreover, Xu’188 teach that compound 8 – 31 was screened against a panel of hematological cell lines using an in vitro viability assay which includes acute myeloid leukemia (AML) cell lines MV-4-ll, MOLM-2123, ML-2, GDM-1, and PL-21. See page 185 paragraph 00592 and Figure 6. Furthermore, Xu’188 teach that compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. See page 186 paragraph 00593 and Figure 7A. Xu’188 teach that treatment of established xenografts of MV-4-11 (FL T3-ITD) with compound 8-31 also induced regressions. See page 186 paragraph and Figure 7B.
Regarding claim 30 limitation for a method comprising administering to about 450 mg to 960 mg per day of compound (1); Xu’188 teach that compounds of Formula I or the pharmaceutical salt thereof, which includes compounds 8 – 10 and 8 – 31, can be administered in dosage ranges from 0.2 – 1000 mg/qid or 4 times per day. See page 82 paragraph 00233. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to convert the teaching of 0.2 – 1000 mg/qid or 4 times per day to mg/ day values 0.8 – 4000 mg/day. Moreover, it would have been obvious to one of ordinary skill in the art that the dosage range of 0.8 – 4000 mg/day taught by Xue’188 overlaps with the recited dosage regimen of 450 mg to about 960 mg per day as recited in claim 30. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05(I).
However, Xue’188 fails to teach a method for treating a myelofibrosis in a human comprising administering an effective amount of compound (1). See claim 28 limitation. Moreover, Xue’188 fails to teach a method where the human is on a momelotinib regimen. See claim 29 limitation.
Nevertheless, as taught above, Xu’188 teach compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
. See page 61 Table 1 column 1 row 2. Both of these prior art compounds differ by the -O- unit between the phenyl ring and the CF3 substitute. Moreover, as taught above both prior art compounds exhibit Pim1 IC50 values within the same order of magnitude. Furthermore, as taught above Xu’188 teach that compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. And Xu’188 teach that treatment of established xenografts of MV-4-11 (FL T3-ITD) with compound 8-31 also induced regressions. Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a MD, PhD, or PharmD it would have been within the purview of such artisan to use prior art compound 8 – 10 in the MV-4-11 (FL T3-ITD) xenograft mouse model. Furthermore, given the teachings of Xu’188 it would have been obvious given that fact that compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity.
However, Xue’188 fails to teach a method for treating a myelofibrosis in a human comprising administering an effective amount of compound (1). See claim 28 limitation. Moreover, Xue’188 fails to teach a method where the human is on a momelotinib regimen. See claim 29 limitation.
Nevertheless, Rampal et.al. teach that myeloproliferative neoplasms (MPNs) are hematopoietic disorders characterized by clonal proliferation of mature myeloid elements which manifest clinically as an excess of RBC [polycythemia vera (PV)], platelets [essential thrombocytosis (ET)], or WBC [primary myelofibrosis (PMF)]. See page E5401 column 1 paragraph 1. Rampal et.al teach that mutations in JAK2 have been identified in the majority of patients with PV, ET, and PMF, underscoring the importance of activated JAK–STAT signaling to the pathogenesis of chronic phase MPN. See page E5401 column 1 paragraph 1. Moreover, Rampal et.al. teach that despite the increasing use of empiric and targeted therapies, a subset of MPN patients transform to secondary acute myeloid leukemia (AML). See page E5401 column 1 paragraph 1. Furthermore, Rampal et.al. teach that MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. See page E5401 column 1 paragraph 1. Thus, Rampal et.al. suggest that AML is a myeloproliferative neoplasm. Additionally, Rampal et.al. teach that ruxolitinib has been approved for the treatment of myelofibrosis, and early-phase clinical trials reported significant, transient responses to ruxolitinib in post-MPN AML patients. See page E5409 column 1 paragraph 1. Moreover, Rampal et.al. teach the efficacy of ruxolitinib in the murine model of post-MPN AML. See page E5409 column 1 paragraph 1. Yet, Rampal et.al. teach that in the study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. See page E5409 column 1 paragraph 1.
Regarding claim 29 limitation for a method where the mammal is on a momelotinib regimen; as taught above, Rampal et.al. teach that in the study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Thus, Rampal et. al. suggest that when a JAK inhibitor is used continuously as a monotherapy there is still disease progression from MPN to secondary acute myeloid leukemia (AML) which has a worse prognosis. Therefore, Rampal et. al. suggest a need to modify the JAK inhibitor monotherapy to address the population of MPN patients that continue to progress. Moreover, as taught above, Xu’188 teach that the compounds and compositions of the invention will find utility in a broad range of diseases and conditions mediated by protein kinases, including diseases and conditions mediated by PIM kinase which includes hematological malignancies which further includes acute myeloid leukemia (AML). Given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of an MD, PhD, or PharmD it would have been within the purview of such artisan to JAK inhibitor monotherapy to add an additional chemotherapeutic agent to address these patients.
However, Rampal et.al. fail to teach a method for treating a myelofibrosis in a human comprising administering an effective amount of compound (1). See claim 28 limitation. Moreover, Rampal et.al. fails to teach a method where the human is on a momelotinib regimen. See claim 29 limitation.
Nevertheless, Wang’955 teach the use of ruxolitinib in the preparation of pharmaceuticals for oral administration. See page 2 paragraph 0002. Specifically, Wang’955 teach the use of ruxolitinib for the treatment of intermediate risk myelofibrosis or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. See page 3 paragraph 0003. See claim 15 – 17 limitation. Moreover, Wang’955 teach that pharmaceutical compositions containing about 0.5 mg to 1000 mg of ruxolitinib which are administered three times daily for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. See page 9 paragraph 0009. Furthermore, Wang’955 teach a most preferred pharmaceutical composition containing about 5 mg to 50 mg of ruxolitinib. See page 10 paragraph 0009.
However, the prior art of Wang’955 fail to teach a method where the human is on a momelotinib regimen. See claim 29 limitation.
Nevertheless, Vainchenker et. al. teach Janus kinases (JAKs) play a central role in the regulation of hematopoiesis as being mandatory for signaling by receptors for hematopoietic/immunological cytokines1. See page 3 column 1 paragraph 1. Moreover, Vainchenker et. al. teach that the JAK/STAT pathway is frequently dysregulated in malignant diseases and in disorders with an abnormal immunological response, See page 3 column 1 paragraph 2. Furthermore, Vainchenker et. al. teach that many inhibitors target JAK2, JAK1, and eventually TYK2 (ruxolitinib, momelotinib, AZD1480, and baricitinib) or JAK3 and JAK1 (tofacitinib). See page 7 column 2 paragraph 2. Thus, Vainchenker et. al. suggest that both ruxolitinib and momelotinib as equivalent JAK inhibitors.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model, in view of Rampal et. al. that is to treat a patient on a JAK regimen, in view of Wang’955 that is to use ruxolitinib to treat myelofibrosis in human in further view of Vainchenker et. al. that is to treat a human patient who is on a momelotinib regimen. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. Furthermore, one of ordinary skill in the art would have been motivated to make this modification since both ruxolitinib and momelotinib as equivalent JAK inhibitors.
One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because in in vivo study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Additionally, One of ordinary skill in the art would be motivated to make this treatment modification to improve the prognosis of patients. One of ordinary skill in the art would have a reasonable expectation of success because of the demonstrated improved clinical benefit for the patient.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 22 of US Patent No. US 10875864 B2 to Xu et. al. (Xu’864; cited on an IDS 144) in view of International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449), Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025), Chinese Patent Publication Number CN 105919955 to Wang et. al. (Wang’955; cited on an IDS 1449 English Machine Translation used), International Publication Number WO 2016/161248 A1 to Warner et. al. (Warner’248; cited on the IDS dated September 24th, 2025), Breccia et. al. ((2017), Ruxolitinib in clinical practice for primary and secondary myelofibrosis: an analysis of safety and efficacy of Gruppo Laziale of Ph-negative MP, Ann Hematol. 96, 387 – 391; cited on the IDS dated September 24th, 2025), and Vainchenker et.al. ((Jan 18th 2018), JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders, F1000 Research, 82, 1 – 19).
Xu’864 recite a pharmaceutical composition comprising a compound having the following structure
PNG
media_image6.png
194
370
media_image6.png
Greyscale
as the HCl salt. See reference claims 1 – 2. Moreover, Xu’864 recite a pharmaceutical composition comprising one or more additional therapeutic agents are selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an anti-hormone, an antiangiogenic agent, an anti-androgen, a platinum coordination complex, a substituted urea, a methylhydrazine derivative, an adrenocortical suppressant, a hormone, a hormone antagonist, an aromatase inhibitor, and a natural product-based chemotherapeutic. See reference claims 3 – 8.
Additionally, Xu’864 recite a method for inhibiting proviral insertion in murine kinase activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the following structure:
PNG
media_image6.png
194
370
media_image6.png
Greyscale
or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. See reference claims 9 and 15. Furthermore, Xu’864 recite a method where the subject has chronic leukemia, a hyperproliferative disorder. See reference claims 10 – 12. Moreover, Xu’864 recite a method where the one or more additional therapeutic agents are selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an anti-hormone, an antiangiogenic agent, an anti-androgen, a platinum coordination complex, a substituted urea, a methylhydrazine derivative, an adrenocortical suppressant, a hormone, a hormone antagonist, an aromatase inhibitor, and a natural product-based chemotherapeutic. See reference claims 16 – 22.
However, Xue’864 fails to teach a method for treating a myeloproliferative neoplasm in a mammal comprising administering an effective amount of compound (1). See claim 1 limitation. Additionally, Xue’864 fails to teach a method for treating a myelofibrosis in a human comprising administering an effective amount of compound (1). See claim 28 limitation.
The teachings of Xu’188, Rampal et. al., Wang’955, Warner’248, Breccia et. al., Vainchenker et. al. as they relate to the prior art rejections of examine claims 1 – 30, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Xu’864 in view of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model in view of Rampal et. al. that is to treat a patient on a JAK regimen, in view of Wang’955 that is to use ruxolitinib to treat myelofibrosis in human or in view of Breccia et.al. to treat secondary myelofibrosis, in further view of Vainchenker et. al. that is to treat a human patient who is on a momelotinib regimen. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. Furthermore, one of ordinary skill in the art would have been motivated to make this modification since both ruxolitinib and momelotinib as equivalent JAK inhibitors.
One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because in in vivo study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Additionally, One of ordinary skill in the art would be motivated to make this treatment modification to improve the prognosis of patients. One of ordinary skill in the art would have a reasonable expectation of success because of the demonstrated improved clinical benefit for the patient.
Claims 1 – 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4, 7, 9 – 10, 16, 18, 25, 28, 32 – 33, 36, 38 – 40, and 43 – 49 of copending Application No. 19125538 to Brooks et. al. (Brooks’538) in view of International Publication Number WO 2013/013188 A1 to Xu et. al. (Xu’188; cited on an IDS 1449), Rampal et.al. ((2014), Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms, PNAS, 50, E5401 – E5410; cited on the IDS dated September 24th, 2025), Chinese Patent Publication Number CN 105919955 to Wang et. al. (Wang’955; cited on an IDS 1449 English Machine Translation used), International Publication Number WO 2016/161248 A1 to Warner et. al. (Warner’248; cited on the IDS dated September 24th, 2025), Breccia et. al. ((2017), Ruxolitinib in clinical practice for primary and secondary myelofibrosis: an analysis of safety and efficacy of Gruppo Laziale of Ph-negative MP, Ann Hematol. 96, 387 – 391; cited on the IDS dated September 24th, 2025), and Vainchenker et.al. ((Jan 18th 2018), JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders, F1000 Research, 82, 1 – 19).
Brooks’538 recite a method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound
PNG
media_image7.png
178
320
media_image7.png
Greyscale
or a pharmaceutically acceptable salt thereof, wherein the subject has poor bone marrow functioning characterized by: (i) thrombocytopenia (ii) anemia; (iii) transfusion dependence; or (iv) a combination thereof; and wherein the treatment induces a clinically meaningful response in the subject. See reference claim 1.
However, Brooks’538 fails to teach a method for treating a myeloproliferative neoplasm in a mammal comprising administering an effective amount of compound (1). See claim 1 limitation. Additionally, Brooks’538 fails to teach a method for treating a myelofibrosis in a human comprising administering an effective amount of compound (1). See claim 28 limitation.
The teachings of Xu’188, Rampal et. al., Wang’955, Warner’248, Breccia et. al., Vainchenker et. al. as they relate to the prior art rejections of examine claims 1 – 30, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of copending Brooks’538 in view of Xu’188, that is to use compound 8 – 10 instead of compound 8 – 31 in the MV-4-11 (FL T3-ITD) xenograft mouse model in view of Rampal et. al. that is to treat a patient on a JAK regimen, in view of Wang’955 that is to use ruxolitinib to treat myelofibrosis in human or in view of Breccia et.al. to treat secondary myelofibrosis, in further view of Vainchenker et. al. that is to treat a human patient who is on a momelotinib regimen. One of ordinary skill in the art would have been motivated to make this modification because compound example 8 – 10 of structure
PNG
media_image2.png
182
234
media_image2.png
Greyscale
and compound example 8 – 31 of structure
PNG
media_image4.png
192
412
media_image4.png
Greyscale
are close in structure with comparable Pim1 activity. Moreover, one of ordinary skill in the art would have been motivated to make this modification because MPN patients who develop leukemic transformation have a dismal outcome, with a median survival of less than 6 mo. Furthermore, one of ordinary skill in the art would have been motivated to make this modification since both ruxolitinib and momelotinib as equivalent JAK inhibitors.
One of ordinary skill in the art would have had a reasonable expectation of success because compound 8 – 31 demonstrated significant tumor growth inhibition in mouse xenograft studies with ML-2 cells (wild-type FLT3), similar to the level of reduction observed in the solid tumor models. Furthermore, one of ordinary skill in the art would have been motivated to make this modification because in in vivo study all mice progressed during therapy to AML, suggesting a need to improve on ruxolitinib monotherapy in post-MPN AML. Additionally, One of ordinary skill in the art would be motivated to make this treatment modification to improve the prognosis of patients. One of ordinary skill in the art would have a reasonable expectation of success because of the demonstrated improved clinical benefit for the patient.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1 – 30 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at 571-270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
Prosecution Insights