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 1, 3, 5, 7-15, 17, 19-25 filed October 10, 2025 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/10/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Amendment
Applicant’s amendments, filed 10/10/2023 are acknowledged. Claims 2, 4, 6, 16 and 18 have been canceled in their entirety. Amended claim 1 embraces the TLR7 inhibitor of original claim 2.
New claims 20-25 have been added, directed to a method of treating a patient having cutaneous lupus erythematosus, comprising administering to said patient a therapeutically effective dose of a TLR7 inhibitor or a pharmaceutically acceptable salt thereof, wherein the patient is receiving or has received a second agent selected from prednisolone and hydroxychloroquine, or a pharmaceutically acceptable salt thereof, and wherein said TLR7 inhibitor is
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or a pharmaceutically acceptable salt thereof.
Applicant's arguments, filed 10/10/2025 have been fully considered. Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103-Rejection(s) Maintained
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) 1, 3, 5, 7-8, 10-15, 17 rejected under 35 U.S.C. 103 as being unpatentable over the combination of Barrat (U.S. Patent 8,940,310 published 01/27/2015) and Dyckman (US2018/0000790 published 01/04/2018).
Barrat (U.S. Patent 8,940,310 published 01/27/2015) teaches the method of treating cutaneous lupus erythematosus in a subject in need comprising administering a therapeutically effective amount of an inhibitor of toll like receptor 7 and toll like receptor 9 (TLR7-TLR9) (abstract, col. 2 line 45- col. 3 line 20, claims 1, 9-15). As shown in Figures 29-30 in an animal model of cutaneous lupus erythematosus derived from tape-stripping of (NZBxNZW)F1 mice to create cutaneous lesions, Barrat teaches TLR7 signaling is required for cutaneous lesion formation in an afflicted patient and results in the upregulation of IFN regulated proinflammatory genes (col. 15 line 55 to col. 16 line 55, col. 126 to col. 130, Figures 29-30). These patients develop chronic skin lesions resembling human cutaneous lupus erythematosus after tape stripping. As shown in Example 22, and Figures 34A-C and 37A-C, administration of said therapeutically effective amount of the TLR7 inhibitor resulted in the reduction inflammatory responses such as IFT1and IL1A, IL1B and TNFa in the administered patient thereby effectively treated the afflicted patient (col. 16 line 10 to col 17 line 45, col. 128 to col. 133).
Administration of a corticosteroid or an anti-malarial compound in combination with the TLR7 inhibitor is embraced within the teachings of Barrat (claims 9, 11-13, 15). Embraced within the genus of corticosteroid is prednisolone (col. 103 line 50 to col. 105 line 40). Barrat teaches wherein the corticosteroid is administered in a dose of about 2 mg to about 20 mg per day, which reads on the amount embraced within claims 8, 15 and 18 (col. 104 lines 35-55). Simultaneous or sequential administration of the corticosteroid or antimalarial with the TLR7 inhibitor is embodied within the teachings of Barratt, which reads on the dosing cycle of claims 10-11 (col. 104 lines 55 to col. 105 line 40).
However Barrat does not specifically teach treating cutaneous lupus erythematosus in a subject comprising administering a therapeutically effective amount of a TLR7 inhibitor, wherein the TLR7 inhibitor is
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Dyckman (US2018/0000790 published 01/04/2018) teaches compounds of Formula (I) are potent inhibitor of toll like receptor 7-9 (TLR7-TLR9) (abstract, Table 27). Included within compounds of Formula (I) are compounds of Formula (I-6), which includes the TLR7 inhibitor #15, 2-(4-(2-(7,8-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide, which reads on the presently claimed TLR7 inhibitor ([0097], Table 27). Dyckman teaches that said TLR7 inhibitors are efficacious at treating cutaneous lupus in a human subject in need ([0148],[0153]). Dyckman teaches administration of said TLR7 inhibitor in doses of 0.001-100 mg/kg per day, and said compound is administered once through four times a day ([0184]). As evidenced by Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007), the average weight of a human is 60 kg (Table 1). Thus, the daily therapeutic range of the TLR7-9 inhibitor administered in Dyckman is 0.06 mg to 6,000 mg, which overlaps with the present claims. Applicant is reminded of MPEP 2144.05 wherein 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). Administration of said TLR7 inhibitor in combination with secondary therapeutic agents including prednisolone or hydroxychloroquine is embodied within the teachings of Dyckman ([0112], [0160]). Regarding claims 10-13, simultaneous administration of the TLR7 inhibitor with the secondary therapeutic agent is taught, as well as sequential administration of the TLR7 inhibitor with the secondary therapeutic agent. Administration of the secondary therapeutic agent either prior to or following the TLR7 inhibitor is also taught ([0161]).
Therefore, one of ordinary skill in the art of treating cutaneous lupus erythematosus in a subject in need knowing that administration of a therapeutically effective amount of an inhibitor of TLR7-TLR9 and either prednisolone or an anti-malarial is efficacious at treating the cutaneous disorder as taught by Barrat, said artisan would have readily predicted that substitution of the TLR7 inhibitor in the regimen of Barrat for another, such as TLR inhibitor #15 of Dyckman, the resulting combination of TLR7 inhibitor and prednisolone or ant-malarial would have effectively treated cutaneous lupus in the afflicted patient.
MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, the prior art of Barrat establishes that inhibition of TLR7 was taught as an effective therapeutic target to treat cutaneous lupus erythematosus in a subject in need, coupled with the knowledge that it is efficacious to include either the corticosteroid prednisolone or an antimalarial agent in said TLR7 inhibitor regimen. Considering Dyckman teaches that TLR7 inhibitor #15 is a potent inhibitor of TLR7 effective at treating cutaneous lupus and is suitable to combine with prednisolone or hydroxychloroquine to treat the immunological disorder, said skilled artisan would have readily predicted that the resulting combination of either prednisolone or hydroxychloroquine in combination with a TLR7 inhibitor, such as TLR inhibitor #15 of Dyckman, would have treated cutaneous lupus erythematosus in the afflicted patient.
Claim(s) 9 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Barrat (U.S. Patent 8,940,310 published 01/27/2015) and Dyckman (US2018/0000790 published 01/04/2018) as applied to claims 1, 3, 5, 7-8, 10-15, 17 above, in view of Zeldis (WO2006/127938 published 11/30/2006).
As disclosed above, the combination of Barrat and Dyckman render obvious the treatment of cutaneous lupus erythematosus in a subject in need comprising administering a therapeutically effective combination comprising a TLR7 inhibitor in combination with hydroxychloroquine. Sequential and simultaneous administration of the TLR7 inhibitor with hydroxychloroquine is taught. Administration of hydroxychloroquine either prior to or following the TLR7 inhibitor is also taught in the therapeutic regimen.
However, the combination of Barrat and Dyckman does not specifically teach administering the combination of the TLR7 inhibitor with hydroxychloroquine, wherein the therapeutically effective amount of hydroxychloroquine is from 1 to 20 mg.
Zeldis teaches treating cutaneous lupus erythematosus in a subject. Zeldis teaches that hydroxychloroquine is a suitable secondary agent to combine with cutaneous lupus treating regimens, and is administered in doses of 1-100 mg per day, which overlaps the amount embraced within the present claims ([0050]-[0057], [0063]). Applicant is reminded of MPEP 2144.05 wherein 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).
Therefore, one of ordinary skill in the art prior to the time of invention, knowing that administration of a combination comprising the TLR7 inhibitor #15 and hydroxychloroquine is efficacious at treating cutaneous lupus in a subject in need as taught by the combination of Barrat and Dyckman above, said artisan would have found it prima facie obvious to administer hydroxychloroquine in a dose of 1-20 mg per day in view of Zeldis.
MPEP 2143 provides 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 prior art of Zeldis that administration of hydroxychloroquine in overlapping doses of 1-1000 mg per day is efficacious at treating cutaneous lupus in a subject. Accordingly, said skilled artisan would have applied the hydroxychloroquine dosing methodology of Zeldis to the cutaneous lupus treating regimen of Barrat and Dyckman, arriving at the presently claimed with a reasonable expectation of success.
Applicant traverses. Applicant argues that the examiner does not establish why a person of ordinary skill in the art would select the TLR7-TLR9 inhibitor of Dyckman from the thousands of other compounds and substitute it for the TLR7-TLR9 cutaneous lupus erythematosus treating methodology of Barratt in order to arrive at the presently claimed methodology. Applicant further contends that the methodology of Barrat embraces the inhibition of TLR7 and TLR9 for treating cutaneous lupus erythematosus, while the compounds of Dyckman inhibit TLR7, TLR8 and TLR9, and a skilled artisan would not be motivated to select the TLR7-9 inhibitor of compound 15 of Dyckman for the regimen of Barrat in order to arrive at the presently claimed. Applicant additionally argues that the examiner does not establish why a person of ordinary skill in the art would select the secondary agents of prednisolone or hydroxychloroquine and combine them with the art-recognized TLR7 inhibitor in order to arrive at the claimed invention. Applicant further contends that Zeldis is immaterial to the selection of a TLR inhibitor as it is not directed to TLR inhibitors at all and instead related to TNF alpha inhibitors.
Response to Arguments
Applicant’s arguments, filed 10/10/2025 are acknowledged and have been carefully considered. Regarding Applicant’s contention that the examiner does not establish why a person of ordinary skill in the art would select the TLR7-TLR9 inhibitor of Dyckman from the thousands of other compounds and substitute it for the TLR7-TLR9 cutaneous lupus erythematosus treating methodology of Barratt in order to arrive at the presently claimed methodology, this argument is unavailing. Applicant is reminded that “[I]t is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).”
In the instant case, Dyckman teaches that said TLR7 inhibitors are efficacious at treating cutaneous lupus in a subject in need coupled with the knowledge that the TLR7 inhibitor #15, 2-(4-(2-(7,8-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide is a potent inhibitor of TLR7([0097], [0153], Table 27). Considering Barrat teaches the method of treating cutaneous lupus erythematosus in a subject in need comprising administering a therapeutically effective amount of an inhibitor of toll like receptor 7 and toll like receptor 9, said skilled artisan would have readily selected the art-recognized and potent TLR7-9 inhibitor #15 of Dyckman and readily predicted that administration of the art-recognized and potent TLR7-9 inhibitor #15 of Dyckman would have resulted in the disclosed effect of treating cutaneous lupus erythematosus in the afflicted patient. Furthermore, Applicant has not provided objective evidence that there is unpredictability in the field of treating cutaneous lupus erythematosus in a subject in need with the administration of a TLR7-9 inhibitor, or that there are unexpected results of the claimed TLR7-9 inhibitor in comparison to that of Barrat and Dyckman.
Secondly, regarding Applicant’s assertion that the methodology of Barrat embraces the inhibition of TLR7 and TLR9 for treating cutaneous lupus erythematosus, while the compounds of Dyckman inhibit TLR7, TLR8 and TLR9, and a skilled artisan would not be motivated to select the TLR7-9 inhibitor of compound 15 of Dyckman, this argument is unpersuasive. Applicant is reminded that “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references” In re Merck and Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In the present case, Barrat established that inhibition of TLR7 and TLR9 is an advantageous therapeutic target to effectively treat cutaneous lupus erythematosus in an afflicted patient, wherein as shown in Figures 29-30 in an animal model of cutaneous lupus erythematosus derived from tape-stripping of (NZBxNZW)F1 mice to create cutaneous lesions, Barrat teaches TLR7 signaling is required for cutaneous lesion formation in an afflicted patient and results in the upregulation of IFN regulated proinflammatory genes (col. 15 line 55 to col. 16 line 55, col. 126 to col. 130, Figures 29-30). These patients develop chronic skin lesions resembling human cutaneous lupus erythematosus after tape stripping. As shown in Example 22, and Figures 34A-C and 37A-C, administration of said therapeutically effective amount of the TLR7 inhibitor resulted in the reduction inflammatory responses such as IFT1and IL1A, IL1B and TNFa in the administered patient thereby effectively treated the afflicted patient (col. 16 line 10 to col 17 line 45, col. 128 to col. 133).
Considering Dyckman teaches that inhibitor #15, 2-(4-(2-(7,8-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide is a potent inhibitor of TLR7 and is taught to be efficacious at treating cutaneous lupus, said skilled artisan would have readily predicted that administration of the art-recognized and potent TLR7 inhibitor #15 of Dyckman would have resulted in the disclosed effect of treating cutaneous lupus erythematosus in the afflicted patient. Furthermore, Applicant has not provided objective evidence that there is unpredictability in the field of treating cutaneous lupus erythematosus in a subject in need with the administration of the TLR7, TLR8 and TLR9 inhibitory compounds of Dyckman, or that selective inhibition of one toll-like receptor over another is critical for treating cutaneous lupus erythematosus in the afflicted patient.
Thirdly, regarding Applicant’s contention that the examiner does not establish why a person of ordinary skill in the art would select the secondary agents of prednisolone or hydroxychloroquine and combine them with the art-recognized TLR7 inhibitor, Applicant is reminded of MPEP 2144.07 wherein the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). In the present case, Barrat teaches administration of a corticosteroid or an anti-malarial compound in combination with the TLR7 inhibitor to treat the cutaneous disorder, wherein prednisolone is embraced within the genus of corticosteroid (col. 103 line 50 to col. 105 line 40claims 9, 11-13, 15). Coupled with the knowledge that Dyckman teaches that prednisolone or hydroxychloroquine are suitable secondary therapeutic agents to combine with said TLR7 inhibitor therapy to treat the disclosed disorders ([0112], [0160]), said skilled artisan would have readily selected prednisolone or hydroxychloroquine and readily predicted that the administration of prednisolone or hydroxychloroquine in combination with the TLR7 inhibitor of Dyckman would have treated cutaneous lupus erythematosus in the afflicted patient. Moreover, Applicant has not provided objective evidence that there is unpredictability in the field of treating cutaneous lupus erythematosus in a subject in need with the administration of a TLR7 inhibitor with the claimed secondary therapeutic agents, nor that there are unexpected results in comparison to the combined teachings of Barrat or Dyckman.
Lastly, regarding Applicant’s contention that Zeldis is immaterial to the selection of a TLR inhibitor as it is not directed to TLR inhibitors at all and instead related to TNF alpha inhibitors, this argument is unpersuasive. Applicant is reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208, USPQ 871 (CCPA 1981) and MPEP 2145. As set forth above, the combination of Barrat and Dyckman render obvious the administration of a TLR7-9 inhibitor in combination with either prednisolone or hydroxychloroquine, wherein the TLR7-9 inhibitor is Example 15 of Dyckman, as it was known in the art that combinations of TLR7-9 inhibitors with hydroxychloroquine or prednisolone are efficacious at treating cutaneous lupus erythematosus in a subject in need (Barrat) and that compound 15 of Dyckman is a potent inhibitor of TLR7-9 and effective at treating cutaneous lupus (Dyckman). As Zeldis teaches that hydroxychloroquine is a suitable secondary agent to combine with cutaneous lupus treating regimens, and is administered in doses of 1-100 mg per day
which overlaps the amount embraced within the present claims ([0050]-[0057], [0063]), said skilled artisan would have found it prima facie obvious to administer hydroxychloroquine in the TLR7-9 inhibitor and hydroxychloroquine cutaneous lupus erythematosus treating regimen of Barrat and Dyckman a dose of 1-20 mg per day in view of Zeldis, arriving at the presently claimed regimen with a reasonable expectation of success.
Double Patenting-Rejection Maintained
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, 3, 5, 7-15, 17 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5 and 18 of U.S. Patent No. RE49,880E published 03/26/2024; referred to as Dyckman ‘880E) in view of the combination of Barratt (U.S. Patent 8,940,310 published 01/27/2015), Dyckman (US2018/0000790 published 01/04/2018; referred to as Dyckman ‘790) and Zeldis (WO2006/127938 published 11/30/2006).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following. Dyckman ‘880E claims the method of treating systemic lupus erythematosus in a subject in need comprising administering a therapeutically effective amount of the claimed toll-like-receptor 7 inhibitor embraced within the present claims (claims 1, 4-5, and 18).
The difference between the present claims and that of Dyckman ‘880E and that of the presently claimed methodology is that Dyckman ‘880E does not specifically teach treating cutaneous lupus erythematosus comprising administering the claimed TLR7 inhibitor, nor does Dyckman ‘880E teach administering the claimed TLR7 inhibitor in combination with either prednisolone or hydroxychloroquine to treat the afflicted patient.
Barratt (U.S. Patent 8,940,310 published 01/27/2015 teaches the method of treating cutaneous lupus erythematosus or systemic lupus erythematosus in a subject in need comprising administering a therapeutically effective amount of an inhibitor of toll like receptor 7 and toll like receptor 9 (TLR7-TLR9) (abstract, col. 2 line 45- col. 3 line 20, claims 1, 9-15). Administration of a corticosteroid or an anti-malarial compound in combination with the TLR7 inhibitor is embraced within the teachings of Barrat (claims 9, 11-13, 15). Embraced within the genus of corticosteroid is prednisolone (col. 103 line 50 to col. 105 line 40). Barrat teaches wherein the corticosteroid is administered in a dose of about 2 mg to about 20 mg per day, which reads on the amount embraced within claims 8, 15 and 18 (col. 104 lines 35-55). Simultaneous or sequential administration of the corticosteroid or antimalarial with the TLR7 inhibitor is embraced within the teachings of Barratt, which reads on the dosing cycle of claims 10-11 (col. 104 lines 55 to col. 105 line 40).
Dyckman ‘0790 teaches the claimed compound of Dyckman ‘880E as a potent inhibitor of TLR7 (abstract, [0097], table 27). Dyckman ‘0790 teaches that said TLR7 inhibitors are efficacious at treating cutaneous lupus in a subject in need ([0155]). Dyckman ‘0790 teaches administration of said TLR7 inhibitor in doses of 0.001-100 mg/kg per day, and said compound is administered once through four times a day ([0184]). Administration of said TLR7 inhibitor in combination with secondary therapeutic agents including prednisolone or hydroxychloroquine is embodied within the teachings of Dyckman‘0790 ([0112], [0160]). Regarding claims 10-13, simultaneous administration of the TLR7 inhibitor with the secondary therapeutic agent is taught, as well as sequential administration of the TLR7 inhibitor with the secondary therapeutic agent is embodied within the teachings of Dyckman ‘0790. Administration of the secondary therapeutic agent either prior to or following the TLR7 inhibitor is also taught ([0161]).
Zeldis (WO2006/127938 published 11/30/2006) teaches treating cutaneous lupus erythematosus in a subject. Zeldis teaches that hydroxychloroquine is a suitable secondary agent to combine with cutaneous lupus treating regimens, and is administered in doses of 1-100 mg per day, which overlaps the amount embraced within the present claims ([0050]-[0057], [0063]). Applicant is reminded of MPEP 2144.05 wherein 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).
Therefore, one of ordinary skill in the art knowing that administration of an inhibitor of TLR7 is efficacious at treating systemic lupus erythematosus in a subject in need as taught by Dyckman ‘880E, said skilled artisan would have found it prima facie obvious to administer said TRL7 inhibitor to treat cutaneous lupus erythematosus in a subject in view of Barrat and Dyckman ‘0790. Motivation to administer said TRL7 inhibitor of Dyckman ‘880E to treat cutaneous lupus erythematosus flows logically from the fact that Dyckman ‘0790 teaches that said compound is a potent inhibitor of TLR7 and TLR7 inhibitors were art-recognized at treating cutaneous lupus erythematosus in a subject in need, which in turn, raises a reasonable expectation of success that administering the TLR7 inhibitor of Dyckman ‘880E to said cutaneous lupus erythematosus patient would have treated the cutaneous immunological disorder.
Secondly, said skilled artisan would have found it prima facie obvious to combine either prednisolone or the antimalarial hydroxychloroquine to the cutaneous lupus erythematosus treating TLR7 inhibitor regimen of Dyckman ‘880E and Barrat in view of Barrat and Dyckman ‘790. Motivation to combine either prednisolone or the antimalarial hydroxychloroquine to the cutaneous lupus erythematosus treating TLR7 inhibitor regimen of Dyckman ‘880E flows logically from the fact that Barrat and Dyckman ‘790 each teach that prednisolone and hydroxychloroquine are suitable to combine with TLR7 inhibitors to treat said immunological disorders.
Thirdly, said skilled artisan would have found it prima facie obvious to administer prednisolone in the combination of the TLR7 inhibitor of Dyckman ‘880E and prednisolone, in a dose of 0.5-50 mg per day in view of Barrat as Barrat teaches that a 2-20 mg/day dose of prednisolone is therapeutically effective at treating the cutaneous immunological disorder.
Fourthly, said skilled artisan would have found it prima facie obvious to administer hydroxychloroquine in the combination of the TLR7 inhibitor and hydroxychloroquine of Dyckman ‘880E, Barrat and Dyckman ‘790, in a dose of 1-20 mg per day in view of Zeldis, as Zeldis teaches that administration of hydroxychloroquine in overlapping doses of 1-1000 mg per day is efficacious at treating cutaneous lupus in a subject.
Applicant traverses. Applicant asserts that the claims of ‘880 patent are directed to treating systemic lupus erythematosus which is a distinct indication from the claimed cutaneous lupus erythematosus and that the examiner has not justified why a person of ordinary skill in the art would be motivated to switch indications and use particular secondary agents with the claimed TLR7 inhibitor compound to arrive at the presently claimed methodology.
Response to Arguments
Applicant’s arguments, filed 10/10/2025 are acknowledged and have been carefully considered, but remain unpersuasive. Regarding Applicant’s contention that Dyckman ‘880 and Dyckman ‘0790 do not qualify as prior art, the Dyckman ‘880 patent is used not as prior art but rather to interpret the scope of the claim, namely the treatment of systemic lupus erythematosus with the same claimed TLR7 inhibitor. As recited in MPEP 804, even though the specification of the applied patent or copending application is not prior art, it may still be used to interpret the applied claims. See paragraph II.B.1, above. The analysis employed with regard to nonstatutory double patenting is "similar to, but not necessarily the same as that undertaken under 35 USC § 103." In re Braat, 937 F.2d 589, 592-93, 19 USPQ2d 1289, 1292 (Fed. Cir. 1991) (citing In re Longi, 759 F.2d 887, 892 n.4, 225 USPQ 645, 648 n.4 (Fed. Cir. 1985)); see also Geneva Pharmaceuticals, 349 F.3d at 1378 n.1, 68 USPQ2d at 1869 n.1 (Fed. Cir. 2003); In re Basell Poliolefine, 547 F.3d 1371, 1379, 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). In addition, regarding Dyckman ‘0790 as qualifying as prior art, as recited in MPEP 804, any secondary reference used to support an obviousness analysis for a nonstatutory double patenting rejection must be prior art under 35 U.S.C. 102 or pre-AIA 35 U.S.C. 102. See MPEP § 2120 et seq. for more information on determining if a reference is prior art and MPEP § 2141, subsection II.A, for determining the scope and content of the prior art. In the present case, priority for the instant application is made of the national stage entry of PCT/US2021/063740 filed 06/10/2021, which claims foreign priority to application 202011024586 filed 06/11/2020. Meanwhile, Dyckman ‘0790 is published in US2018/0000790 on 01/04/2018, and thus, qualifies as prior art under 35 U.S.C 102.
Regarding Applicant’s arguments that there is no justification why a skilled artisan would be motivated to switch indications and use a systemic lupus erythematous treating regimen to treat the claimed cutaneous lupus erythematosus, this argument is unpersuasive. TLR7 is required for the initiation and maintenance of both SLE and CLE as taught by Barrat above (col. 127-col.137). Further, Barrat teaches inhibitors of TLR7 and TLR9 are art-recognized as efficacious at treating both systemic and cutaneous lupus erythematosus (claims 1, 9, 15). Considering that Dyckman ‘0790 teaches that the claimed compound is a potent inhibitor of TLR7 and TLR7 inhibitors were art-recognized at treating both systemic and cutaneous lupus erythematosus in a subject in need, said artisan would have readily predicted that administering the systemic lupus treating TLR7 inhibitor of Dyckman ‘880E to a cutaneous lupus erythematosus patient would have also treated the claimed cutaneous immunological disorder.
Secondly, regarding Applicant’s contention that there is no justification why a skilled artisan would be motivated to use particular secondary agents with the claimed TLR7 inhibitor compound, this argument is also unavailing.
Applicant is reminded of MPEP 2144.07 wherein the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). In the present case, Barrat teaches administration of a corticosteroid or an anti-malarial compound in combination with the TLR7 inhibitor to treat the cutaneous disorder, wherein prednisolone is embraced within the genus of corticosteroid (col. 103 line 50 to col. 105 line 40 claims 9, 11-13, 15). Coupled with the knowledge that Dyckman teaches that prednisolone or hydroxychloroquine are suitable secondary therapeutic agents to combine with said TLR7 inhibitor therapy to treat the disclosed disorders ([0112], [0160]), said skilled artisan would have readily selected prednisolone or hydroxychloroquine and readily predicted that the administration of prednisolone or hydroxychloroquine in combination with the TLR7 inhibitor of Dyckman would have treated cutaneous lupus erythematosus in the afflicted patient.
NEW CLAIMS 20-25
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) 20-25 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Barrat (U.S. Patent 8,940,310 published 01/27/2015) and Dyckman (US2018/0000790 published 01/04/2018).
Barrat (U.S. Patent 8,940,310 published 01/27/2015) teaches the method of treating cutaneous lupus erythematosus in a subject in need comprising administering a therapeutically effective amount of an inhibitor of toll like receptor 7 and toll like receptor 9 (TLR7-TLR9) (abstract, col. 2 line 45- col. 3 line 20, claims 1, 9-15). As shown in Figures 29-30 in an animal model of cutaneous lupus erythematosus derived from tape-stripping of (NZBxNZW)F1 mice to create cutaneous lesions, Barrat teaches TLR7 signaling is required for cutaneous lesion formation in an afflicted patient and results in the upregulation of IFN regulated proinflammatory genes (col. 15 line 55 to col. 16 line 55, col. 126 to col. 130, Figures 29-30). These patients develop chronic skin lesions resembling human cutaneous lupus erythematosus after tape stripping. As shown in Example 22, and Figures 34A-C and 37A-C, administration of said therapeutically effective amount of the TLR7 inhibitor resulted in the reduction inflammatory responses such as IFT1and IL1A, IL1B and TNFa in the administered patient thereby effectively treated the afflicted patient (col. 16 line 10 to col 17 line 45, col. 128 to col. 133).
Administration of a corticosteroid or an anti-malarial compound in combination with the TLR7 inhibitor is embraced within the teachings of Barrat (claims 9, 11-13, 15). Embraced within the genus of corticosteroid is prednisolone (col. 103 line 50 to col. 105 line 40). Barrat teaches wherein the corticosteroid is administered in a dose of about 2 mg to about 20 mg per day (col. 104 lines 35-55). Regarding the claimed dosing cycle wherein the patient is receiving or has received a second agent selected from prednisolone and hydroxychloroquine, sequential administration of the corticosteroid or antimalarial with the TLR7 inhibitor is embodied within the teachings of Barratt. Said sequential administration reads on the claimed regimen of either the corticosteroid prednisolone first followed by the TLR7 inhibitor (e.g., having received prednisolone), or alternatively the anti-malarial first, followed by the TLR7 inhibitor (e.g., having received hydroxychloroquine) (col. 104 lines 55 to col. 105 line 40).
However Barrat does not specifically teach treating cutaneous lupus erythematosus in a subject comprising administering a therapeutically effective amount of a TLR7 inhibitor, wherein the TLR7 inhibitor is
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Dyckman (US2018/0000790 published 01/04/2018) teaches compounds of Formula (I) are potent inhibitor of toll like receptor 7-9 (TLR7-TLR9) (abstract, Table 27). Included within compounds of Formula (I) are compounds of Formula (I-6), which includes the TLR7 inhibitor #15, 2-(4-(2-(7,8-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide, which reads on the presently claimed TLR7 inhibitor ([0097], Table 27). Dyckman teaches that said TLR7 inhibitors are efficacious at treating cutaneous lupus in a human subject in need ([0148], [0153]). Dyckman teaches administration of said TLR7 inhibitor in doses of 0.001-100 mg/kg per day, and said compound is administered once through four times a day ([0184]). As evidenced by Reagan-Shaw (FASEBJ Vol. 22 pages 659-661 published 2007), the average weight of a human is 60 kg (Table 1). Thus, the therapeutic range of the TLR7-9 inhibitor administered in the methodology of Dyckman is 0.06 mg to 6,000 mg, which overlaps with the present claims. Applicant is reminded of MPEP 2144.05 wherein 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). Administration of said TLR7 inhibitor in combination with secondary therapeutic agents including prednisolone or hydroxychloroquine is embodied within the teachings of Dyckman ([0112], [0160]). Administration of the secondary therapeutic agent prior to the TLR7 inhibitor is also taught by Dyckman ([0161]).
Therefore, one of ordinary skill in the art of treating cutaneous lupus erythematosus in a subject in need knowing that administration of a therapeutically effective amount of an inhibitor of TLR7-TLR9 and either prednisolone or an anti-malarial is efficacious at treating the cutaneous disorder and that said prednisolone or an anti-malarial is administered prior to said TLR7 inhibitor as taught by Barrat , said artisan would have readily predicted that substitution of the TLR7 inhibitor in the regimen of Barrat for another, such as TLR inhibitor #15 of Dyckman, the resulting combination of TLR7 inhibitor and prednisolone or ant-malarial would have effectively treated cutaneous lupus in the afflicted patient. MPEP 2143 provides rationale for a conclusion of obviousness including (B): Simple substitution of one known element for another to obtain predictable results;
In the present case, the prior art of Barrat establishes that inhibition of TLR7 was taught as an effective therapeutic target to treat cutaneous lupus erythematosus in a subject in need, coupled with the knowledge that it is efficacious to include either the corticosteroid prednisolone or an antimalarial agent prior to in said TLR7 inhibitor regimen. Considering Dyckman teaches that TLR7 inhibitor #15 is a potent inhibitor of TLR7 effective at treating cutaneous lupus and is suitable to combine with prednisolone or hydroxychloroquine to treat the immunological disorder, said skilled artisan would have readily predicted that the resulting combination of either prednisolone or hydroxychloroquine in combination with a TLR7 inhibitor, such as TLR inhibitor #15 of Dyckman would have treated cutaneous lupus erythematosus in the afflicted patient.
Lastly, regarding the limitation wherein prednisolone or hydroxychloroquine is administered prior to the TLR7 inhibitor, Applicant is also reminded of MPEP 2144.04 wherein selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946).
Conclusion
In view of the rejections set forth above, no claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GEORGE W KOSTURKO/ Examiner, Art Unit 1621