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 . Claims 32-73, filed July 26, 2024 are currently pending. Claims 32, 38, 44, 50, 56, 62 and 68 are each independent.
Priority
Acknowledgement is made of the continuation of Application 18105372 filed 02/03/2023. Application 18105372 is a continuation of PCT/US2022/037192 filed 07/14/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/27/2024, 12/22/2025 and 01/13/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Paragraph D
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 37, 43, 49, 55, 61, 67 and 73 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 32 is directed to a method of treating chronic graft-versus-host disease (cGVHD)in a female patient of reproductive potential, wherein the patient is not pregnant, comprising the steps of:(a) administering to the patient 2-{3-[4-(1H-indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof (Compound), at a dose of 200 mg once or twice daily; and (b) continuing administration of the Compound for as long as the patient is verified not to be pregnant.
Meanwhile claim 37 is directed to the method of claim 32 wherein the patient is in need of treatment of cGVHD.
Claim 37 fails to further limit the scope of claim 32 as the patient population in claim 32 is a subject already in need of treatment as the patient has been diagnosed as comprising chronic graft-vs-host disease. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. This situation is duplicated in the dependent claims 43, 49, 55, 61, 67 and 73.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 32, 34-35, 37-38, 40-41, 43-44, 46-47, 49-50, 52-53, 55-56, 58-59, 61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jagasia (Journal of Clinical Oncology Vol. 39 pages 1888-1898 published online 04/20/2021) as evidenced by Clinical Trial NCT02841995 (established 07/22/2016).
Jagasia teaches administering belumosudil to treat patients comprising chronic graft-vs-host disease in a phase IIa clinical trial (NCT02841995) (abstract, page 1889 right col).
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As evidenced by CAS Registry Database, the claimed 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide corresponds to Belumosudil of Jagasia.
Male and female patients aged 20—75 comprising chronic graft-vs-host disease were administered 200 mg belumosudil once or twice a day (Table 1). As evidenced by Clinical Trial NCT02841995 (established 07/22/2016) female subjects who were pregnant or breastfeeding were excluded from the study. Female subjects of childbearing potential in the trial had a negative pregnancy test at screening and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, which reads on the limitation of a female patient of reproductive potential in claims 32, 35, 37, 44, 47, 49, 56, 59 and 61. As female subjects who were pregnant or breastfeeding were excluded from the study and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, the examiner has interpreted that administration of the compound continued for as long as the patient is verified not to be pregnant.
Regarding male patients in the trial and the limitation of claims 38, 41, 43, 50, 53, 55-56, said male patients who were sexually active and were partners of premenopausal women agreed to two forms of contraception as in criteria above during the treatment and for at least 3 months after the last dose of drug. As the male patients agreed to the use of two forms of contraception during the treatment and for at least 3 months after the last dose of drug to administration of the compound, the examiner has interpreted that administration continued for as long as the patient is using contraception and that the subject is verified to be using contraception.
Regarding claims 34, 40, 46, 52, 58, Jagasia teaches belumosudil achieves response rates that are meaningful and consistent including in patients who have failed 2 or more prior therapies such as corticosteroids, tacrolimus and rituximab (page 1895 right col., Table A1) .
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.
Claim(s) 32-35, 37-41, 43-47, 49-53, 55-59 and 61 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Jagasia (Journal of Clinical Oncology Vol. 39 pages 1888-1898 published online 04/20/2021) as evidenced by Clinical Trial NCT02841995 (established 07/22/2016) and Zanin-Zhorov (US2017/0112832 published 04/27/2017).
Jagasia teaches administering the ROCK-2 kinase inhibitor belumosudil to treat patients comprising chronic graft-vs-host disease in a phase IIa clinical trial (NCT02841995) (abstract, page 1889 right col). As evidenced by CAS Registry Database, the claimed 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide corresponds to Belumosudil of Jagasia.
Male and female patients aged 20—75 comprising chronic graft-vs-host disease were administered 200 mg belumosudil once or twice a day (Table 1). As evidenced by Clinical Trial NCT02841995 (established 07/22/2016) female subjects who were pregnant or breastfeeding were excluded from the study. Female subjects of childbearing potential in the trial had a negative pregnancy test at screening and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, which reads on the limitation of a female patient of reproductive potential in claims 32, 35, 37, 44, 47, 49, 56, 59 and 61. As female subjects who were pregnant or breastfeeding were excluded from the study and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, the examiner has interpreted that administration of the compound continued for as long as the patient is verified not to be pregnant.
Regarding male patients in the trial and the limitation of claims 38, 41, 43, 50, 53, 55-56, said male patients who were sexually active and were partners of premenopausal women agreed to two forms of contraception as in criteria above during the treatment and for at least 3 months after the last dose of drug. As the male patients agreed to the use of two forms of contraception during the treatment and for at least 3 months after the last dose of drug to administration of the compound, the examiner has interpreted that administration continued for as long as the patient is using contraception and that the subject is verified to be using contraception.
Regarding claims 34, 40, 46, 52 and 58, Jagasia teaches belumosudil achieves response rates that are meaningful and consistent including in patients who have failed 2 or more prior therapies such as corticosteroids, tacrolimus and rituximab (page 1895 right col., Table A1)
The difference between the present claims and that of Jagasia is that Jagasia does not specifically teach wherein belumosudil is administered as the mesylate salt.
Zanin-Zhorov teaches treating chronic graft-vs-host disease in a subject in need comprising administering a therapeutically effective amount of SLX-2119 of a pharmaceutically acceptable salt thereof to said subject (claims 1, 2, 7).
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As evidenced by CAS Registry database, the aforementioned SLX-2119 corresponds to the claimed 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide and belumosudil of Jagasia. Zanin-Zhorov teaches that the mesylate salt is one of 20 suitable organic or inorganic acid salt forms of SLX-2119 to administer to the diseased patient ([0329]).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to administer belumosudil to treat female and male chronic graft-vs-host diseased patients of child bearing age as taught by Jagasia, above, as the mesylate salt in view of Zanin-Zhorov, arriving at the claimed methodology with a reasonable expectation of success.
MPEP 2143 provides rationale for a conclusion of obviousness including (E): "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
In the present case, Zanin-Zhorov teaches that the mesylate salt is one of 20 suitable organic or inorganic acid salt forms of SLX-2119 to administer to treat chronic graft-vs-host disease in a subject in need. Accordingly, said artisan would have readily predicted that belumosudil/SLX-2119, administered as the mesylate salt would have effectively treated chronic graft-vs-host disease in the afflicted patient.
Claim(s) 32, 34-38, 40-44, 46-50, 52-56, 58-61 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Jagasia (Journal of Clinical Oncology Vol. 39 pages 1888-1898 published online 04/20/2021) as evidenced by Clinical Trial NCT02841995 (established 07/22/2016), IBRUTINIB (prescribing information published 08/2017), Zeiser (Clinical Advances in Hematology and Oncology Vol. 19 pages 1-24 published 02/2021), Duess (Toxicology and Applied Pharmacology Vol. 409 115277 pages 1-14. Published online 10/10/2020), Kono (Developmental Biology Vol. 354 pages 142-155 published 2014) and Saadelin (Frontiers in Cell and Developmental Biology, published online 01/11/2021).
Jagasia teaches administering the ROCK-2 kinase inhibitor belumosudil to treat patients comprising chronic graft-vs-host disease in a phase IIa clinical trial (NCT02841995) (abstract, page 1889 right col). As evidenced by CAS Registry Database, the claimed 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide corresponds to Belumosudil of Jagasia.
Male and female patients aged 20—75 comprising chronic graft-vs-host disease were administered 200 mg belumosudil once or twice a day (Table 1). As evidenced by Clinical Trial NCT02841995 (established 07/22/2016) female subjects who were pregnant or breastfeeding were excluded from the study. Female subjects of childbearing potential in the trial had a negative pregnancy test at screening and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, which reads on the limitation of a female patient of reproductive potential in claims 32, 35, 37, 44, 47, 49, 56, 59 and 61. As female subjects who were pregnant or breastfeeding were excluded from the study and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, the examiner has interpreted that administration of the compound continued for as long as the patient is verified not to be pregnant.
Regarding male patients in the trial and the limitation of claims 38, 41, 43, 50, 53, 55-56, said male patients who were sexually active and were partners of premenopausal women agreed to two forms of contraception as in criteria above during the treatment and for at least 3 months after the last dose of drug. As the male patients agreed to the use of two forms of contraception during the treatment and for at least 3 months after the last dose of drug to administration of the compound, the examiner has interpreted that administration continued for as long as the patient is using contraception and that the subject is verified to be using contraception.
Regarding claims 34, 40, 46, 52 and 58, Jagasia teaches belumosudil achieves response rates that are meaningful and consistent including in patients who have failed 2 or more prior therapies such as corticosteroids, tacrolimus and rituximab (page 1895 right col., Table A1).
The difference between the present claims and that of Jagasia is that Jagasia does not specifically teach ceasing administration of the compound to the patient or the female partner of the patient when said patient is verified to be pregnant.
IBRUTINIB (prescribing information published 08/2017) is taught as an FDA approved treatment of chronic graft-vs-host disease. IBRUTINIB teaches that said graft-vs-host disease therapy comprises embryo fetal toxicity, wherein administration of said inhibitor can cause fetal harm when administered to pregnant patients (page 3). IBRUTINIB teaches to advise the risks of the fetus to the treated patient (page 3). IBRUTINIB also advices to said patients receiving the chronic graft-vs-host disease therapy to use contraceptives during treatment with IBRUTINIB and to continue to use contraceptives for one month after the last dose of IBRUTINIB (page 3). IBRUTINIB also advises males with female partners of reproductive potential to use effective contraception during the same time (page 3).
Zeiser (Clinical Advances in Hematology and Oncology Vol. 19 pages 1-24 published 02/2021) teaches ruxolitinib is effective at treating graft-vs-host disease in a subject in need (page 4-7, Figure 2). Zeiser teaches the graft-vs-host disease therapeutic regimen is not recommended for patients who are pregnant and should only be used if the potential benefit justifies the potential risk to the fetus (page 3). Zeiser also teaches lactation risks associated with the graft-vs-host disease therapeutic, as metabolites of the graft-vs-host disease therapeutic were found in the milk of lactating patients. Zeiser teaches that the potential for thrombocytopenia and anemia for patients of ruxolitinib, it is suggested to discontinue breast feeding during treatment with the graft-vs-host disease therapeutic and for 2 weeks after the final dose (page 3, page 5).
Duess (Toxicology and Applied Pharmacology Vol. 409 115277 pages 1-14. Published online 10/10/2020) teaches the ROCK-2 kinase inhibitor Y-27632 (abstract, page 1). Duess teaches that administration of Y-27632 in amounts that inhibit the ROCK pathway are teratogenic to fertilized chick embryos (abstract, page 7). Duess teaches that administration of Y-27632 produces gross malformations and morphological abnormalities in the later stages of embryogenesis (abstract, page 13).
Kono (Developmental Biology Vol. 354 pages 142-155 published 2014) teaches the ROCK-2 kinase inhibitors Y-27632 and Rho-1 (abstract). Kono teaches administration of Y-27632 in 20-100 mM to mammalian embryos yielded severe developmental defects including failures of cavitation and failure in compaction at the 8-cell stage (pages 12, 13 and 15). Kono also teaches that treatment of later stage embryos are still capable of being implanted, but are impaired in post-implantation development resulting in a significantly higher incidence of fetal loss (page 13).
Saadelin (Frontiers in Cell and Developmental Biology, published online 01/11/2021) teaches that ROCK kinase is required for early mammalian embryonic development, including pluripotent and embryonic stem cells, where it is implicated in proliferation, differentiation and survival (page 5 right col. through page 6). Saadelin further teaches that ROCK kinase targeting might be used for modulating early developmental stages to control pregnancy such as novel targeted contraceptive drugs (page 7 right col.).
Therefore, one of ordinary skill in the art of treating chronic graft-vs-host disease in female and male patients of reproductive potential comprising administering the ROCK2 inhibitor belumosudil in a dose of 200 mg as taught by Jagasia, said artisan would have found it prima facie obvious to cease administering the compound to the female patient when said female patient is verified to be pregnant, or alternatively, cease administering the compound to the male patient when the female partner of said male patient is verified to be pregnant in view of the combined teachings of Ibrutinib, Zeiser Duess, Kono and Saadelin.
Motivation to cease administering the compound to the female patient when said female patient is verified to be pregnant, or alternatively, cease administering the compound to the male patient when the female partner of said male patient is verified to be pregnant logically flows from the fact that it was known in the art of Ibrutinib and Zeiser that agents FDA cleared to treat chronic graft-vs-host disease can cause fetal harm when administered to pregnant women while Duess, Kono and Saadelin each teach that ROCK kinase is required for early mammalian embryonic development and that inhibition of ROCK kinase results in developmental defects in mammalian embryos.
Consistent with this reasoning, it would have been obvious to cease administration of the art-recognized ROCK kinase inhibitor belumosudil to the female patient comprising chronic graft-vs-host disease when the patient is verified to be pregnant, or cease administering the compound to the male patient when the female partner of said male patient is verified to be pregnant in order to avoid developmental defects and teratogenic effects associated with ROCK inhibitors in the developing fetus, arriving at the claimed methodology yielding no more than one would expect from such an arrangement.
Claim(s) 62, 64-68, 70-73 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Jagasia (Journal of Clinical Oncology Vol. 39 pages 1888-1898 published online 04/20/2021) as evidenced by Clinical Trial NCT02841995 (established 07/22/2016), IBRUTINIB (prescribing information published 08/2017), Zeiser (Clinical Advances in Hematology and Oncology Vol. 19 pages 1-24 published 02/2021), Duess (Toxicology and Applied Pharmacology Vol. 409 115277 pages 1-14. Published online 10/10/2020), Kono (Developmental Biology Vol. 354 pages 142-155 published 2014) and Saadelin (Frontiers in Cell and Developmental Biology, published online 01/11/2021).
Jagasia teaches administering the ROCK-2 kinase inhibitor belumosudil to treat patients comprising chronic graft-vs-host disease in a phase IIa clinical trial (NCT02841995) (abstract, page 1889 right col). As evidenced by CAS Registry Database, the claimed 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide corresponds to Belumosudil of Jagasia.
Male and female patients aged 20—75 comprising chronic graft-vs-host disease were administered 200 mg belumosudil once or twice a day (Table 1). As evidenced by Clinical Trial NCT02841995 (established 07/22/2016) female subjects who were pregnant or breastfeeding were excluded from the study. Female subjects of childbearing potential in the trial had a negative pregnancy test at screening and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, which reads on the limitation of a female patient of reproductive potential in claim 62, 65 and 67. As female subjects who were pregnant or breastfeeding were excluded from the study and agreed to use two forms of accepted methods of contraception during the course of study through 3 months after their last dose of study drug, the examiner has interpreted that administration of the compound continued for as long as the patient is verified not to be pregnant.
Regarding male patients in the trial and the limitation of claims 68, 71-73, said male patients who were sexually active and were partners of premenopausal women agreed to two forms of contraception as in criteria above during the treatment and for at least 3 months after the last dose of drug. As the male patients agreed to the use of two forms of contraception during the treatment and for at least 3 months after the last dose of drug to administration of the compound, the examiner has interpreted that administration continued for as long as the patient is using contraception and that the subject is verified to be using contraception.
Regarding claims 64 and 70, Jagasia teaches belumosudil achieves response rates that are meaningful and consistent including in patients who have failed 2 or more prior therapies such as corticosteroids, tacrolimus and rituximab (page 1895 right col., Table A1).
The difference between the presently claimed methodology and Jagasia is that Jagasia does not specifically teach wherein said female or said male patient was advised of the potential risks to a fetus if the patient is treated with the graft-vs-host disease therapeutic. Nor does not specifically teach ceasing administration of the compound to the patient or the female partner of the patient when said patient is verified to be pregnant.
IBRUTINIB (prescribing information published 08/2017) is taught as an FDA approved treatment of chronic graft-vs-host disease. IBRUTINIB teaches that said graft-vs-host disease therapy comprises embryo fetal toxicity, wherein administration of said inhibitor can cause fetal harm when administered to pregnant patients (page 3). IBRUTINIB teaches to advise the risks of the fetus to the treated patient (page 3). IBRUTINIB also advices to said patients receiving the chronic graft-vs-host disease therapy to use contraceptives during treatment with IBRUTINIB and to continue to use contraceptives for one month after the last dose of IBRUTINIB (page 3). IBRUTINIB also advises males with female partners of reproductive potential to use effective contraception during the same time (page 3).
Zeiser (Clinical Advances in Hematology and Oncology Vol. 19 pages 1-24 published 02/2021) teaches ruxolitinib is effective at treating graft-vs-host disease in a subject in need (page 4-7, Figure 2). Zeiser teaches the graft-vs-host disease therapeutic regimen is not recommended for patients who are pregnant and should only be used if the potential benefit justifies the potential risk to the fetus (page 3). Zeiser also teaches lactation risks associated with the graft-vs-host disease therapeutic, as metabolites of the graft-vs-host disease therapeutic were found in the milk of lactating patients. Zeiser teaches that the potential for thrombocytopenia and anemia for patients of ruxolitinib, it is suggested to discontinue breast feeding during treatment with the graft-vs-host disease therapeutic and for 2 weeks after the final dose (page 3, page 5).
Duess (Toxicology and Applied Pharmacology Vol. 409 115277 pages 1-14. Published online 10/10/2020) teaches the ROCK-2 kinase inhibitor Y-27632 (abstract, page 1). Duess teaches that administration of Y-27632 in amounts that inhibit the ROCK pathway are teratogenic to fertilized chick embryos (abstract, page 7). Duess teaches that administration of Y-27632 produces gross malformations and morphological abnormalities in the later stages of embryogenesis (abstract, page 13).
Kono (Developmental Biology Vol. 354 pages 142-155 published 2014) teaches the ROCK-2 kinase inhibitors Y-27632 and Rho-1 (abstract). Kono teaches administration of Y-27632 in 20-100 mM to mammalian embryos yielded severe developmental defects including failures of cavitation and failure in compaction at the 8-cell stage (pages 12, 13 and 15). Kono also teaches that treatment of later stage embryos are still capable of being implanted, but are impaired in post-implantation development resulting in a significantly higher incidence of fetal loss (page 13).
Saadelin (Frontiers in Cell and Developmental Biology, published online 01/11/2021) teaches that ROCK kinase is required for early mammalian embryonic development, including pluripotent and embryonic stem cells, where it is implicated in proliferation, differentiation and survival (page 5 right col. through page 6). Saadelin further teaches that ROCK kinase targeting might be used for modulating early developmental stages to control pregnancy such as novel targeted contraceptive drugs (page 7 right col.).
Therefore, one of ordinary skill in the art of treating chronic graft-vs-host disease in female and male patients of reproductive potential comprising administering the ROCK2 inhibitor belumosudil in a dose of 200 mg as taught by Jagasia, said artisan would have found it prima facie obvious to (a) advise the patient the potential risks associated with getting pregnant while receiving treatment and continue administration of said ROCK2 inhibitor for as long as the patient is verified not to be pregnant, as well as (b) ceasing administration of the compound to the female patient or the female partner of the male patient when said patient is verified to be pregnant in view of the combined teachings of Ibrutinib, Zeiser, Duess, Kono and Saadelin, arriving at the instantly claimed methodology.
MPEP 2143 provides a rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art of Ibrutinib and Zeiser that agents FDA cleared to treat chronic graft-vs-host disease can cause fetal harm when administered to pregnant women. It was also known in the art of ibrutinib and Zeiser to advise female and male patients receiving agents FDA cleared to treat chronic graft-vs-host disease of the dangers to the fetus and to use contraceptives during drug administration and one month following cessation of treatment.
Secondly, rationale to make the patient aware of the risks of getting pregnant while being administered an art-recognized ROCK-2 kinase inhibitor to treat the graft-vs-host disease and to cease administering the compound to the female patient when said female patient is verified to be pregnant, or cease administering the compound to the male patient when the female partner of said male patient is verified to be pregnant additionally flows from the fact that it was known in the art that ROCK kinase is required for early mammalian embryonic development and that inhibition of ROCK kinase results in developmental defects in mammalian embryos.
Consistent with these teachings, said skilled artisan would have applied pregnancy risk advisory associated with graft-vs-host disease therapeutics and art-recognized ROCK-2 kinase inhibitors within the teachings of Zeiser, Ibrutinib, Duess, Kono and Saadelin to the female or male chronic graft-vs-host diseased patient of reproductive potential receiving belumosudil as taught by Jagasia above, arriving at the claimed methodology with a reasonable expectation of success.
Claim(s) 63 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Jagasia (Journal of Clinical Oncology Vol. 39 pages 1888-1898 published online 04/20/2021) as evidenced by Clinical Trial NCT02841995 (established 07/22/2016), IBRUTINIB (prescribing information published 08/2017), Zeiser (Clinical Advances in Hematology and Oncology Vol. 19 pages 1-24 published 02/2021), Duess (Toxicology and Applied Pharmacology Vol. 409 115277 pages 1-14. Published online 10/10/2020), Kono (Developmental Biology Vol. 354 pages 142-155 published 2014) and Saadelin (Frontiers in Cell and Developmental Biology, published online 01/11/2021) as applied to claims 62, 64-68, 70-73 above in view of Zanin-Zhorov (US2017/0112832 published 04/27/2017).
As disclosed above, the combination of Jagasia, IBRUTINIB, Zeiser, Duess, Kono and Saadelin render obvious treating chronic graft-vs-host disease in female and male patients of reproductive potential comprising administering the ROCK2 inhibitor belumosudil in a dose of 200 mg as taught by Jagasia, as well as (a) advising the female patient and the female partner of the male patient receiving belumosudil the potential risks to a fetus if the patient is treated with belumosudil, as such advising policies were known in the art to be performed to chronic graft-vs-host diseased patients of reproductive potential prior to receiving treatment for the immunological disorder coupled with the knowledge that ROCK kinase is required for early mammalian embryonic development and that inhibition of ROCK kinase results in developmental defects in mammalian embryos.
However, the combination of Jagasia, IBRUTINIB, Zeiser, Duess, Kono and Saadelin do not specifically teach wherein belumosudil is administered as the mesylate salt.
Zanin-Zhorov teaches treating chronic graft-vs-host disease in a subject in need comprising administering a therapeutically effective amount of SLX-2119 of a pharmaceutically acceptable salt thereof to said subject (claims 1, 2, 7).
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As evidenced by CAS Registry database, the aforementioned SLX-2119 corresponds to the claimed 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide and belumosudil of Jagasia. Zanin-Zhorov teaches that the mesylate salt is one of 20 suitable organic or inorganic acid salt forms of SLX-2119 to administer to the diseased patient ([0329]).
Therefore, one of ordinary skill in the art of treating chronic graft-vs-host disease in female and male patients of reproductive potential comprising administering the ROCK2 inhibitor belumosudil in a dose of 200 mg as taught by Jagasia, said artisan would have found it prima facie obvious to (a) advise the patient the potential risks associated with getting pregnant while receiving treatment and continue administration of said ROCK2 inhibitor for as long as the patient is verified not to be pregnant as taught by the combined teachings of Ibrutinib, Zeiser, Duess, Kono and Saadelin above, and administer said belumosudil as the mesylate salt in view of Zanin-Zhorov, arriving at the claimed methodology with a reasonable expectation of success.
MPEP 2143 provides rationale for a conclusion of obviousness including (E): "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
In the present case, Zanin-Zhorov teaches that the mesylate salt is one of 20 suitable organic or inorganic acid salt forms of SLX-2119 to administer to treat chronic graft-vs-host disease in a subject in need. Accordingly, said artisan would have readily predicted that belumosudil/SLX-2119, administered as the mesylate salt would have effectively treated chronic graft-vs-host disease in the afflicted patient.
Conclusion
In view of the rejections set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CLINTON A BROOKS can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GEORGE W KOSTURKO/ Primary Examiner, Art Unit 1621
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