Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a continuation of application 19/273,213, which claims priority to US provisional applications 63/717,634, 63/675,648, and 63/673,607. There is also a PCT/US25/38265 application.
The effective filing date is 07/19/2024.
Response to Arguments
Applicants’ claim amendments and Remarks of 5/18/2026 are acknowledged and have been considered.
Any rejection and/or objection not specifically addressed or modified below is herein withdrawn.
In regard to the correction of priority, Examiner has reviewed the corrected filing receipt. Priority is described above.
In regard to the 102 rejection, this rejection is maintained. Applicants remarks with Examiner’s reply are summarized below:
Applicants submit that limitations (ii) and (iii) are functional printed matter.
Limitation (ii) is NOT directed toward determining CYP2C9 genotype, but is merely instructions, as is "contraindication information," as such neither (ii) nor (iii) are active steps.
With regards to the ‘label’ and ‘instructions’, The MPEP states, “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed.). See also In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983)("Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability …. [T ]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate.").” (MPEP § 2112.01).
Further, this is a product claim, i.e., a composition in a kit; these limitations are directed as if claim 37 is written as a method of use.
Applicants also cite In re Gulack, which established that printed matter must be considered in a 35 USC 103 obviousness analysis if it has a functional relationship.
Examiner has reviewed the case law citation provided by Applicants. This is not persuasive. The printed matter limitation has been considered and these limitations are directed toward a method and not toward the product itself as argued by Applicant.
Applicants further argue unexpected results (Compound I is metabolized primarily by CYP2C9).
This is not persuasive for anticipatory rejections.
In regard to obviousness rejection, this rejection is maintained. Applicants remarks with Examiner’s reply are summarized below:
Applicants submit that the cited references fail to provide any rationale for the discontinuation of treatment with a CYP2C9 inhibitor before administering an effective amount of Compound I.
Examiner disagrees. Zhao is used to teach that an artisan would have been expected to avoid known adverse events associated with a high dose of Ruxolitnib (page 8 of the Nonfinal).
More generally, an artisan (i.e. health care practitioner, doctor, nurse, etc.) would have been motivated and expected to switch from an ineffective (or less effective) treatment to another more effective treatment (as evidenced by Heneghan).
Applicants submit that Compound (I) is primarily metabolized by CYP2C9 (not CYP3A4); while Ruxolitinib is primarily metabolized by CYP3A4. Applicants submit unexpected results (how Compound I is metabolized).
Examiner has reviewed the paragraph ([0053]) where Applicants say Compound (I) is unexpectedly metabolized primarily by CYP2C9. Paragraph [0053] states that Example 2 (paragraphs [00163-00164]) describes the methods for determining the drug-drug interaction for Compound (I) and Fluxonazole (a moderate CYP3A4/CYP2C9 inhibitor).
MPEP 716.02 states that unexpected results a) are greater than expected results, b) show superiority of a property shared with the prior art, c) exhibit the presence of an unexpected property, and/or d) exhibit the absence of an expected property. MPEP 716.02 additionally states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art.
Examiner is unsure how in the instant case how Compound (I) c) exhibits the presence of an unexpected property, and/or d) exhibit the absence of an expected property.
Though Applicant states that unexpected results have been achieved, the instant specification does not provide any unexpected or surprising results. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See MPEP 716.01(c).
Applicants submit that Zhao’s teachings of drug-drug interactions between Voriconazole and Ruxolitinib do not apply to the instant claims.
Zhao teaches drug-drug interactions between Ruxolitinib (metabolized primarily by CYP3A4) and Voriconazole (a strong CYP3A4 inhibitor).
Because the present claims have a different compound, which is metabolized differently (primarily by CYP2C9), Applicants submit that the effect of Voriconazole on Compound (I) would be unknown at the time of invention.
Examiner disagrees. Zhao teaches that there is drug-drug interaction (which causes issues adverse events; page 6 of the Nonfinal) because some of the metabolic pathways overlap between Ruxolitinib and Voriconazole (including cytochrome P450 (CYP) isozymes 3A4 and 2C9—Abstract’s Background; cited on page 6 of the Nonfinal).
An artisan would have been expected to avoid known adverse events (page 8 of the Nonfinal).
More generally, an artisan (i.e. health care practitioner, doctor, nurse, etc.) would have been motivated and expected to switch from an ineffective (or less effective) treatment to another more effective treatment (as evidenced by Heneghan).
Furthermore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. . .’The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious’”, See MPEP 2145(II).
The obviousness rejection over claims 1, 12-13, and 18-19 is maintained. This obviousness rejection is focused on the dosage of Deuruxolitinib, which are known. This rejection is maintained for the reasons above.
In regard to the double patenting rejections, these rejections are maintained for the reasons above. The typographical errors (for the second and third rejections) have been corrected.
Response to Amendment
Claim Rejections - 35 USC § 102
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) 37 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023).
Papierzewska anticipates a pharmaceutical composition of Deuruxolitinib, which is administered to human patients to treat Alopecia areata (abstract and results). Deuruxolitinib is the instant compound (I) of claim 1. Papierzewska teaches that Deuruxolitinib is a JAK inhibitor (abstract) and used to treat patients with alopecia areata (page 332).
The phrase “prescribing information for the use of said composition for the treatment of a JAK-inhibition-responsive condition” constitutes nonfunctional printed matter; nonfunctional printed matter does not distinguish claimed product from prior art. Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. See MPEP 2112.01(III). This anticipates claim 37.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1, 2-3, 12-13, 20-24 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (Zhao et al., “Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies, Drug Design, Development and Therapy, March 25, 2022), Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023), as evidenced by Chaundary (Chaundary et al., “LC-MS/MS: a powerful tool for modern analytical science: Fundamentals, techniques, applications, and innovations”, Journal of Liquid Chromatography and Related Technologies, April 16, 2025), and in view of KUSHNER (Kushner et al., “Pharmacological uses and perspectives of heavy water and deuterated compounds”, Can J Physio Pharmacol. Feb 1999).
Zhao teaches a method of treating a JAK inhibition responsive condition in a subject (Graft-versus-host disease is responsive to a treatment of JAK inhibitors; Abstract).
Zhao teaches co-administering (title) ruxolitinib (JAK inhibitor) and voriconazole (which can inhibit CYP2C9 weakly; page 818).
Zhao teaches drug–drug interaction (DDI) may occur between them because Ruxolitinib metabolic pathways overlap with voriconazole and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9 (background). This helps teach claim 22.
Zhao teaches that subjects receiving CYP2C9 inhibitor displayed increased Cmax and half life for JAK inhibitor, Ruxolitnib (page 821). This helps teach why an artisan would stop one medication before starting another (helps teach claim 1). Zhao also teaches that higher dose of Ruxolitinib have higher incidents of adverse events whereas the 5mg dosage of Ruxolitinib was not reported to have adverse events (pages 821 and 823).
Zhao also teaches that the maximum plasma concentration (Cmax), area under the curve from time zero to last (AUClast), and AUC from time zero to infinity (AUCinf) of plasma concentration-time are increased significantly when ruxolitinib was coadministered with fluconazole, a moderate CYP2C9 and CYP3A4 dual inhibitor, compared with ruxolitinib alone (page 818). This helps teach claims 20-22.
Zhao teaches that the CYP2C9 inhibitor is determined to be in the blood (page 819 sample collection) by chromatography (specifically LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry method; page 819 Drug Concentration detection). This teaches claim 38.
Chaudhary is relied upon for the beneficial teaching that LC-MS/MS is a high performance liquid chromatography, offering exceptional sensitivity, specificity, and the ability to detect multiple analytes simultaneously (abstract). This teaches claim 39.
Zhao (Figure 2 and page 819) as evidenced by Chaudhary teaches that drug amount and drug identity (via mass spectrometry). This helps teach claims 23-24.
Zhao does not disclose discontinuing treatment with a CYP2C9 inhibitor (in this case voriconazole) and does not teach administering the instantly claimed compound I (which is a deuterated version of Zhao’s Ruxolitinib).
Papierzewska teaches a pharmaceutical composition of Deuruxolitinib, which is administered to human patients to treat Alopecia areata, which is a JAK inhibitor responsive condition (abstract and results). Deuruxolitinib is the instant compound (I) of claim 1. Papierzewska teaches that Deuruxolitinib is a JAK inhibitor (abstract) and used to treat patients with alopecia areata (page 332). Other JAK inhibitors are also known to treat Alopecia areata (table 1). This helps teach claims 1 and 12-13.
Papierzewska does not teach discontinuing treatment with a CYP2C9 inhibitor.
KUSHNER teaches advantages of deuterated compounds: Most deuterated compounds are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 (CYP) systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity (abstract).
An artisan would have been motivated to have discontinued the treatment with a CYP2C9 inhibitor (voriconazole) and administer an effective amount of Ruxolitinib to the subject. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823). This helps teach claim 1.
The artisan would have been further motivated to use a deuterated compound in Zhao’s method of treating a JAK inhibition responsive condition (abstract) in order to use the benefits taught by Kushner (such as increased duration of action and lower toxicity; Abstract). Additionally, the artisan would have been motivated to substitute Deuruxolitinib for Ruxolitinib. The artisan would have expected Deuruxolitinib (the deuterated version of Zhao’s Ruxolitinib) to be effective as both compounds are JAK inhibitors (Papierzewska abstract; Zhao page 821). This teaches claim 1.
The artisan would have been motivated, in a course of normal dose tailoring, to select a time interval effective to provide the patient with an effective level of Deuruxolitinib. See MPEP 2144.05(II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there Is evidence indicating such concentration or temperature is critical”. Neither the specification nor the claims indicate the administration time is critical. This teaches claims 2-3.
The artisan would expect that a pharmaceutical composition of Deuruxolitinib would be effective in treating Alopecia areata after discontinuing treatment with a CYP2C9 inhibitor. The artisan would expect that because Alopecia areata is a JAK inhibitor responsive condition and Deuruxolitinib by itself is known to be effective in treating Alopecia areata (Papierzewska abstract and results). This teaches claims 12-13.
Furthermore, the artisan would have been motivated to discontinue any CYP2C9 inhibitor, including a strong, moderate, or weak CYP2C9 inhibitor. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823) especially since a moderate CYP2C9 and CYP3A4 dual inhibitor (fluconazole) impacted the pharmacokinetics of ruxolitinib so greatly (Zhao page 818). In order to avoid any drug-drug interactions, the artisan would be motivated to discontinue any CYP2C9 inhibitor. This teaches claims 20-22.
Because the purpose of LC-MS/MS is to identify both the drug amount and drug identity, the artisan would be expected when using Zhao’s LC-MS/MS to do both of these actions in order to determine if the exogenous CYP2C9 is a strong or moderate CYP2C9 inhibitor based on the identity of the compound (Zhao Figure 2 and page 819 as evidenced by Chaudhary abstract). This teaches claims 23-24.
Claim(s) 1, 12-13, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (Zhao et al., “Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies, Drug Design, Development and Therapy, March 25, 2022), Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023), Kushner (Kushner et al., “Pharmacological uses and perspectives of heavy water and deuterated compounds”, Can J Physio Pharmacol. Feb 1999) in view of KING (King et al., “Phase 2 Randomized, dose-ranging trial of CTP-542, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata” J Am Aca Dermatol, March 29, 2022).
Claims 1 and 12-13 are taught above.
Papierzewska confirms that CTP-543 (from King below) is Deuruxolitinib (table 1).
King teaches that Deuruxolitinib (referred to as CTP-543) is administered in a dosage from 8mg to 24 mg a day (4 mg, 8 mg, or 12 mg doses given twice a day) (methods).
The artisan would be motivated and expected to use a known dosage range in order to administer the same drug (Deuruxolitinib) for the same disease (alopecia areata). This teaches claims 18 and 19.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 1 is provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1 of copending Application No. 19/273,213 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
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, 2-3, 12-13, 20-24 and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 159 of copending Application No. 18/910,606 in view of Zhao (Zhao et al., “Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies, Drug Design, Development and Therapy, March 25, 2022), Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023), as evidenced by Chaundary (Chaundary et al., “LC-MS/MS: a powerful tool for modern analytical science: Fundamentals, techniques, applications, and innovations”, Journal of Liquid Chromatography and Related Technologies, April 16, 2025), and in view of KUSHNER (Kushner et al., “Pharmacological uses and perspectives of heavy water and deuterated compounds”, Can J Physio Pharmacol. Feb 1999).
The reference application teaches compound (I), the same as instant compound (I), used to treat alopecia areata in a subject (ref claim 159).
Zhao teaches a method of treating a JAK inhibition responsive condition in a subject (Graft-versus-host disease is responsive to a treatment of JAK inhibitors; Abstract).
Zhao teaches co-administering (title) ruxolitinib (JAK inhibitor) and voriconazole (which can inhibit CYP2C9 weakly; page 818).
Zhao teaches drug–drug interaction (DDI) may occur between them because Ruxolitinib metabolic pathways overlap with voriconazole and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9 (background). This helps teach claim 22.
Zhao teaches that subjects receiving CYP2C9 inhibitor displayed increased Cmax and half life for JAK inhibitor, Ruxolitnib (page 821). This helps teach why an artisan would stop one medication before starting another (helps teach claim 1). Zhao also teaches that higher dose of Ruxolitinib have higher incidents of adverse events whereas the 5mg dosage of Ruxolitinib was not reported to have adverse events (pages 821 and 823).
Zhao also teaches that the maximum plasma concentration (Cmax), area under the curve from time zero to last (AUClast), and AUC from time zero to infinity (AUCinf) of plasma concentration-time are increased significantly when ruxolitinib was coadministered with fluconazole, a moderate CYP2C9 and CYP3A4 dual inhibitor, compared with ruxolitinib alone (page 818). This helps teach claims 20-22.
Zhao teaches that the CYP2C9 inhibitor is determined to be in the blood (page 819 sample collection) by chromatography (specifically LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry method; page 819 Drug Concentration detection). This teaches claim 38.
Chaudhary is relied upon for the beneficial teaching that LC-MS/MS is a high performance liquid chromatography, offering exceptional sensitivity, specificity, and the ability to detect multiple analytes simultaneously (abstract). This teaches claim 39.
Zhao (Figure 2 and page 819) as evidenced by Chaudhary teaches that drug amount and drug identity (via mass spectrometry). This helps teach claims 23-24.
Zhao does not disclose discontinuing treatment with a CYP2C9 inhibitor (in this case voriconazole) and does not teach administering the instantly claimed compound I (which is a deuterated version of Zhao’s Ruxolitinib).
Papierzewska teaches a pharmaceutical composition of Deuruxolitinib, which is administered to human patients to treat Alopecia areata, which is a JAK inhibitor responsive condition (abstract and results). Deuruxolitinib is the instant compound (I) of claim 1. Papierzewska teaches that Deuruxolitinib is a JAK inhibitor (abstract) and used to treat patients with alopecia areata (page 332). Other JAK inhibitors are also known to treat Alopecia areata (table 1). This helps teach claims 1 and 12-13.
Papierzewska does not teach discontinuing treatment with a CYP2C9 inhibitor.
KUSHNER teaches advantages of deuterated compounds: Most deuterated compounds are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 (CYP) systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity (abstract).
An artisan would have been motivated to have discontinued the treatment with a CYP2C9 inhibitor (voriconazole) and administer an effective amount of Ruxolitinib to the subject. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823). This helps teach claim 1.
The artisan would have been further motivated to use a deuterated compound in Zhao’s method of treating a JAK inhibition responsive condition (abstract) in order to use the benefits taught by Kushner (such as increased duration of action and lower toxicity; Abstract). Additionally, the artisan would have been motivated to substitute Deuruxolitinib (the same as ref compound (I) from application 18/910,606) for Ruxolitinib. The artisan would have expected Deuruxolitinib (the deuterated version of Zhao’s Ruxolitinib) to be effective as both compounds are JAK inhibitors (Papierzewska abstract; Zhao page 821). This teaches claim 1.
The artisan would have been motivated, in a course of normal dose tailoring, to select a time interval effective to provide the patient with an effective level of Deuruxolitinib. See MPEP 2144.05(II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there Is evidence indicating such concentration or temperature is critical”. Neither the specification nor the claims indicate the administration time is critical. This teaches claims 2-3.
The artisan would expect that a pharmaceutical composition of Deuruxolitinib would be effective in treating Alopecia areata after discontinuing treatment with a CYP2C9 inhibitor. The artisan would expect that because Alopecia areata is a JAK inhibitor responsive condition and Deuruxolitinib by itself is known to be effective in treating Alopecia areata (Papierzewska abstract and results). This teaches claims 12-13.
Furthermore, the artisan would have been motivated to discontinue any CYP2C9 inhibitor, including a strong, moderate, or weak CYP2C9 inhibitor. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823) especially since a moderate CYP2C9 and CYP3A4 dual inhibitor (fluconazole) impacted the pharmacokinetics of ruxolitinib so greatly (Zhao page 818). In order to avoid any drug-drug interactions, the artisan would be motivated to discontinue any CYP2C9 inhibitor. This teaches claims 20-22.
Because the purpose of LC-MS/MS is to identify both the drug amount and drug identity, the artisan would be expected when using Zhao’s LC-MS/MS to do both of these actions in order to determine if the exogenous CYP2C9 is a strong or moderate CYP2C9 inhibitor based on the identity of the compound (Zhao Figure 2 and page 819 as evidenced by Chaudhary abstract). This teaches claims 23-24.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2-3, 12-13, 20-24 and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US Patent 12285432 in view of Zhao (Zhao et al., “Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies, Drug Design, Development and Therapy, March 25, 2022), Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023), as evidenced by Chaundary (Chaundary et al., “LC-MS/MS: a powerful tool for modern analytical science: Fundamentals, techniques, applications, and innovations”, Journal of Liquid Chromatography and Related Technologies, April 16, 2025), and in view of KUSHNER (Kushner et al., “Pharmacological uses and perspectives of heavy water and deuterated compounds”, Can J Physio Pharmacol. Feb 1999).
The reference application teaches compound (I), the same as instant compound (I), used to treat alopecia areata in a subject (ref claim 1). The instant claims use the open-ended language of “comprising”, which can include the additional agent included in the ref claim 1.
Zhao teaches a method of treating a JAK inhibition responsive condition in a subject (Graft-versus-host disease is responsive to a treatment of JAK inhibitors; Abstract).
Zhao teaches co-administering (title) ruxolitinib (JAK inhibitor) and voriconazole (which can inhibit CYP2C9 weakly; page 818).
Zhao teaches drug–drug interaction (DDI) may occur between them because Ruxolitinib metabolic pathways overlap with voriconazole and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9 (background). This helps teach claim 22.
Zhao teaches that subjects receiving CYP2C9 inhibitor displayed increased Cmax and half life for JAK inhibitor, Ruxolitnib (page 821). This helps teach why an artisan would stop one medication before starting another (helps teach claim 1). Zhao also teaches that higher dose of Ruxolitinib have higher incidents of adverse events whereas the 5mg dosage of Ruxolitinib was not reported to have adverse events (pages 821 and 823).
Zhao also teaches that the maximum plasma concentration (Cmax), area under the curve from time zero to last (AUClast), and AUC from time zero to infinity (AUCinf) of plasma concentration-time are increased significantly when ruxolitinib was coadministered with fluconazole, a moderate CYP2C9 and CYP3A4 dual inhibitor, compared with ruxolitinib alone (page 818). This helps teach claims 20-22.
Zhao teaches that the CYP2C9 inhibitor is determined to be in the blood (page 819 sample collection) by chromatography (specifically LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry method; page 819 Drug Concentration detection). This teaches claim 38.
Chaudhary is relied upon for the beneficial teaching that LC-MS/MS is a high performance liquid chromatography, offering exceptional sensitivity, specificity, and the ability to detect multiple analytes simultaneously (abstract). This teaches claim 39.
Zhao (Figure 2 and page 819) as evidenced by Chaudhary teaches that drug amount and drug identity (via mass spectrometry). This helps teach claims 23-24.
Zhao does not disclose discontinuing treatment with a CYP2C9 inhibitor (in this case voriconazole) and does not teach administering the instantly claimed compound I (which is a deuterated version of Zhao’s Ruxolitinib).
Papierzewska teaches a pharmaceutical composition of Deuruxolitinib, which is administered to human patients to treat Alopecia areata, which is a JAK inhibitor responsive condition (abstract and results). Deuruxolitinib is the instant compound (I) of claim 1. Papierzewska teaches that Deuruxolitinib is a JAK inhibitor (abstract) and used to treat patients with alopecia areata (page 332). Other JAK inhibitors are also known to treat Alopecia areata (table 1). This helps teach claims 1 and 12-13.
Papierzewska does not teach discontinuing treatment with a CYP2C9 inhibitor.
KUSHNER teaches advantages of deuterated compounds: Most deuterated compounds are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 (CYP) systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity (abstract).
An artisan would have been motivated to have discontinued the treatment with a CYP2C9 inhibitor (voriconazole) and administer an effective amount of Ruxolitinib to the subject. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823). This helps teach claim 1.
The artisan would have been further motivated to use a deuterated compound in Zhao’s method of treating a JAK inhibition responsive condition (abstract) in order to use the benefits taught by Kushner (such as increased duration of action and lower toxicity; Abstract). Additionally, the artisan would have been motivated to substitute Deuruxolitinib (the same as ref compound (I)) for Ruxolitinib. The artisan would have expected Deuruxolitinib (the deuterated version of Zhao’s Ruxolitinib) to be effective as both compounds are JAK inhibitors (Papierzewska abstract; Zhao page 821). This teaches claim 1.
The artisan would have been motivated, in a course of normal dose tailoring, to select a time interval effective to provide the patient with an effective level of Deuruxolitinib. See MPEP 2144.05(II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there Is evidence indicating such concentration or temperature is critical”. Neither the specification nor the claims indicate the administration time is critical. This teaches claims 2-3.
The artisan would expect that a pharmaceutical composition of Deuruxolitinib would be effective in treating Alopecia areata after discontinuing treatment with a CYP2C9 inhibitor. The artisan would expect that because Alopecia areata is a JAK inhibitor responsive condition and Deuruxolitinib by itself is known to be effective in treating Alopecia areata (Papierzewska abstract and results). This teaches claims 12-13.
Furthermore, the artisan would have been motivated to discontinue any CYP2C9 inhibitor, including a strong, moderate, or weak CYP2C9 inhibitor. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823) especially since a moderate CYP2C9 and CYP3A4 dual inhibitor (fluconazole) impacted the pharmacokinetics of ruxolitinib so greatly (Zhao page 818). In order to avoid any drug-drug interactions, the artisan would be motivated to discontinue any CYP2C9 inhibitor. This teaches claims 20-22.
Because the purpose of LC-MS/MS is to identify both the drug amount and drug identity, the artisan would be expected when using Zhao’s LC-MS/MS to do both of these actions in order to determine if the exogenous CYP2C9 is a strong or moderate CYP2C9 inhibitor based on the identity of the compound (Zhao Figure 2 and page 819 as evidenced by Chaudhary abstract). This teaches claims 23-24.
Claims 1, 2-3, 12-13, 20-24 and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 18/033,730 in view of Zhao (Zhao et al., “Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies, Drug Design, Development and Therapy, March 25, 2022), Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023), as evidenced by Chaundary (Chaundary et al., “LC-MS/MS: a powerful tool for modern analytical science: Fundamentals, techniques, applications, and innovations”, Journal of Liquid Chromatography and Related Technologies, April 16, 2025), and in view of KUSHNER (Kushner et al., “Pharmacological uses and perspectives of heavy water and deuterated compounds”, Can J Physio Pharmacol. Feb 1999).
The reference application teaches compound (I), the same as instant compound (I), used to treat alopecia areata in a subject (ref claims 1-2).
Zhao teaches a method of treating a JAK inhibition responsive condition in a subject (Graft-versus-host disease is responsive to a treatment of JAK inhibitors; Abstract).
Zhao teaches co-administering (title) ruxolitinib (JAK inhibitor) and voriconazole (which can inhibit CYP2C9 weakly; page 818).
Zhao teaches drug–drug interaction (DDI) may occur between them because Ruxolitinib metabolic pathways overlap with voriconazole and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9 (background). This helps teach claim 22.
Zhao teaches that subjects receiving CYP2C9 inhibitor displayed increased Cmax and half life for JAK inhibitor, Ruxolitnib (page 821). This helps teach why an artisan would stop one medication before starting another (helps teach claim 1). Zhao also teaches that higher dose of Ruxolitinib have higher incidents of adverse events whereas the 5mg dosage of Ruxolitinib was not reported to have adverse events (pages 821 and 823).
Zhao also teaches that the maximum plasma concentration (Cmax), area under the curve from time zero to last (AUClast), and AUC from time zero to infinity (AUCinf) of plasma concentration-time are increased significantly when ruxolitinib was coadministered with fluconazole, a moderate CYP2C9 and CYP3A4 dual inhibitor, compared with ruxolitinib alone (page 818). This helps teach claims 20-22.
Zhao teaches that the CYP2C9 inhibitor is determined to be in the blood (page 819 sample collection) by chromatography (specifically LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry method; page 819 Drug Concentration detection). This teaches claim 38.
Chaudhary is relied upon for the beneficial teaching that LC-MS/MS is a high performance liquid chromatography, offering exceptional sensitivity, specificity, and the ability to detect multiple analytes simultaneously (abstract). This teaches claim 39.
Zhao (Figure 2 and page 819) as evidenced by Chaudhary teaches that drug amount and drug identity (via mass spectrometry). This helps teach claims 23-24.
Zhao does not disclose discontinuing treatment with a CYP2C9 inhibitor (in this case voriconazole) and does not teach administering the instantly claimed compound I (which is a deuterated version of Zhao’s Ruxolitinib).
Papierzewska teaches a pharmaceutical composition of Deuruxolitinib, which is administered to human patients to treat Alopecia areata, which is a JAK inhibitor responsive condition (abstract and results). Deuruxolitinib is the instant compound (I) of claim 1. Papierzewska teaches that Deuruxolitinib is a JAK inhibitor (abstract) and used to treat patients with alopecia areata (page 332). Other JAK inhibitors are also known to treat Alopecia areata (table 1). This helps teach claims 1 and 12-13.
Papierzewska does not teach discontinuing treatment with a CYP2C9 inhibitor.
KUSHNER teaches advantages of deuterated compounds: Most deuterated compounds are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 (CYP) systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity (abstract).
An artisan would have been motivated to have discontinued the treatment with a CYP2C9 inhibitor (voriconazole) and administer an effective amount of Ruxolitinib to the subject. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823). This helps teach claim 1.
The artisan would have been further motivated to use a deuterated compound in Zhao’s method of treating a JAK inhibition responsive condition (abstract) in order to use the benefits taught by Kushner (such as increased duration of action and lower toxicity; Abstract). Additionally, the artisan would have been motivated to substitute Deuruxolitinib (the same as ref compound (I) from application 18/033,730) for Ruxolitinib. The artisan would have expected Deuruxolitinib (the deuterated version of Zhao’s Ruxolitinib) to be effective as both compounds are JAK inhibitors (Papierzewska abstract; Zhao page 821). This teaches claim 1.
The artisan would have been motivated, in a course of normal dose tailoring, to select a time interval effective to provide the patient with an effective level of Deuruxolitinib. See MPEP 2144.05(II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there Is evidence indicating such concentration or temperature is critical”. Neither the specification nor the claims indicate the administration time is critical. This teaches claims 2-3.
The artisan would expect that a pharmaceutical composition of Deuruxolitinib would be effective in treating Alopecia areata after discontinuing treatment with a CYP2C9 inhibitor. The artisan would expect that because Alopecia areata is a JAK inhibitor responsive condition and Deuruxolitinib by itself is known to be effective in treating Alopecia areata (Papierzewska abstract and results). This teaches claims 12-13.
Furthermore, the artisan would have been motivated to discontinue any CYP2C9 inhibitor, including a strong, moderate, or weak CYP2C9 inhibitor. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823) especially since a moderate CYP2C9 and CYP3A4 dual inhibitor (fluconazole) impacted the pharmacokinetics of ruxolitinib so greatly (Zhao page 818). In order to avoid any drug-drug interactions, the artisan would be motivated to discontinue any CYP2C9 inhibitor. This teaches claims 20-22.
Because the purpose of LC-MS/MS is to identify both the drug amount and drug identity, the artisan would be expected when using Zhao’s LC-MS/MS to do both of these actions in order to determine if the exogenous CYP2C9 is a strong or moderate CYP2C9 inhibitor based on the identity of the compound (Zhao Figure 2 and page 819 as evidenced by Chaudhary abstract). This teaches claims 23-24.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2-3, 12-13, 20-24 and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of US Patent 10561659 in view of Zhao (Zhao et al., “Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies, Drug Design, Development and Therapy, March 25, 2022), Papierzewska (Papierzewska et al., “Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review”, Clinical Drug Investigation, May 3, 2023), as evidenced by Chaundary (Chaundary et al., “LC-MS/MS: a powerful tool for modern analytical science: Fundamentals, techniques, applications, and innovations”, Journal of Liquid Chromatography and Related Technologies, April 16, 2025), and in view of KUSHNER (Kushner et al., “Pharmacological uses and perspectives of heavy water and deuterated compounds”, Can J Physio Pharmacol. Feb 1999).
The reference application teaches compound (I), the same as instant compound (I), used to treat alopecia areata in a subject (ref claim 1). The instant claims use the open-ended language of “comprising”, which can include the additional agent included in the ref claim 1.
Zhao teaches a method of treating a JAK inhibition responsive condition in a subject (Graft-versus-host disease is responsive to a treatment of JAK inhibitors; Abstract).
Zhao teaches co-administering (title) ruxolitinib (JAK inhibitor) and voriconazole (which can inhibit CYP2C9 weakly; page 818).
Zhao teaches drug–drug interaction (DDI) may occur between them because Ruxolitinib metabolic pathways overlap with voriconazole and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9 (background). This helps teach claim 22.
Zhao teaches that subjects receiving CYP2C9 inhibitor displayed increased Cmax and half life for JAK inhibitor, Ruxolitnib (page 821). This helps teach why an artisan would stop one medication before starting another (helps teach claim 1). Zhao also teaches that higher dose of Ruxolitinib have higher incidents of adverse events whereas the 5mg dosage of Ruxolitinib was not reported to have adverse events (pages 821 and 823).
Zhao also teaches that the maximum plasma concentration (Cmax), area under the curve from time zero to last (AUClast), and AUC from time zero to infinity (AUCinf) of plasma concentration-time are increased significantly when ruxolitinib was coadministered with fluconazole, a moderate CYP2C9 and CYP3A4 dual inhibitor, compared with ruxolitinib alone (page 818). This helps teach claims 20-22.
Zhao teaches that the CYP2C9 inhibitor is determined to be in the blood (page 819 sample collection) by chromatography (specifically LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry method; page 819 Drug Concentration detection). This teaches claim 38.
Chaudhary is relied upon for the beneficial teaching that LC-MS/MS is a high performance liquid chromatography, offering exceptional sensitivity, specificity, and the ability to detect multiple analytes simultaneously (abstract). This teaches claim 39.
Zhao (Figure 2 and page 819) as evidenced by Chaudhary teaches that drug amount and drug identity (via mass spectrometry). This helps teach claims 23-24.
Zhao does not disclose discontinuing treatment with a CYP2C9 inhibitor (in this case voriconazole) and does not teach administering the instantly claimed compound I (which is a deuterated version of Zhao’s Ruxolitinib).
Papierzewska teaches a pharmaceutical composition of Deuruxolitinib, which is administered to human patients to treat Alopecia areata, which is a JAK inhibitor responsive condition (abstract and results). Deuruxolitinib is the instant compound (I) of claim 1. Papierzewska teaches that Deuruxolitinib is a JAK inhibitor (abstract) and used to treat patients with alopecia areata (page 332). Other JAK inhibitors are also known to treat Alopecia areata (table 1). This helps teach claims 1 and 12-13.
Papierzewska does not teach discontinuing treatment with a CYP2C9 inhibitor.
KUSHNER teaches advantages of deuterated compounds: Most deuterated compounds are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 (CYP) systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity (abstract).
An artisan would have been motivated to have discontinued the treatment with a CYP2C9 inhibitor (voriconazole) and administer an effective amount of Ruxolitinib to the subject. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823). This helps teach claim 1.
The artisan would have been further motivated to use a deuterated compound in Zhao’s method of treating a JAK inhibition responsive condition (abstract) in order to use the benefits taught by Kushner (such as increased duration of action and lower toxicity; Abstract). Additionally, the artisan would have been motivated to substitute Deuruxolitinib (the same as ref compound (I)) for Ruxolitinib. The artisan would have expected Deuruxolitinib (the deuterated version of Zhao’s Ruxolitinib) to be effective as both compounds are JAK inhibitors (Papierzewska abstract; Zhao page 821). This teaches claim 1.
The artisan would have been motivated, in a course of normal dose tailoring, to select a time interval effective to provide the patient with an effective level of Deuruxolitinib. See MPEP 2144.05(II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there Is evidence indicating such concentration or temperature is critical”. Neither the specification nor the claims indicate the administration time is critical. This teaches claims 2-3.
The artisan would expect that a pharmaceutical composition of Deuruxolitinib would be effective in treating Alopecia areata after discontinuing treatment with a CYP2C9 inhibitor. The artisan would expect that because Alopecia areata is a JAK inhibitor responsive condition and Deuruxolitinib by itself is known to be effective in treating Alopecia areata (Papierzewska abstract and results). This teaches claims 12-13.
Furthermore, the artisan would have been motivated to discontinue any CYP2C9 inhibitor, including a strong, moderate, or weak CYP2C9 inhibitor. The artisan would have been expected to avoid known adverse events associated with high dose of Ruxolitinib (Zhao pages 821 and 823) especially since a moderate CYP2C9 and CYP3A4 dual inhibitor (fluconazole) impacted the pharmacokinetics of ruxolitinib so greatly (Zhao page 818). In order to avoid any drug-drug interactions, the artisan would be motivated to discontinue any CYP2C9 inhibitor. This teaches claims 20-22.
Because the purpose of LC-MS/MS is to identify both the drug amount and drug identity, the artisan would be expected when using Zhao’s LC-MS/MS to do both of these actions in order to determine if the exogenous CYP2C9 is a strong or moderate CYP2C9 inhibitor based on the identity of the compound (Zhao Figure 2 and page 819 as evidenced by Chaudhary abstract). This teaches claims 23-24.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/G.A.H./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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