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 .
Status of the Claims
Claims 1-18 are currently pending and under examination.
Priority
The instant application 18/843,599 filed on September 3, 2024 is a 371 of
PCT/IB2023/052010 filed on 03/3/2023, which claims priority to, and the benefits of U.S.
Provisional Application No. 63/316,623 filed on March 4, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/27/2024, 04/11/2025, 11/10/2025, 02/02/2026, 02/20/2026, 03/18/2026, 05/11/2026, 05/15/2026 and 06/17/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 5 ,7, 10, and 15-18 are objected to because of the following informalities:
Claim 1 is objected to because the abbreviation “b.i.d” in line 10 is used in the claim.
Claims 5 and 7 are objected to because the incorrect conjugation of the term “comprising” in line 15 and line 20. It should be wherein the method further comprises administering.
Claim 10 “following a corticosteroid d tapering regimen.” in line 26 should be following a corticosteroid tapering regimen.
Claims 15-18 are objected to because the acronyms “UPCR” and “eGFR” are used in the claims in line 12 and line 18. Appropriate language would appear to be urine protein to creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) at first use.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9, 10, 14, 16, and 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 9 and 10, the phrase “achieves a daily corticosteroid dose” renders the claims indefinite because it is unclear whether the recited dose refers to the amount of corticosteroid administered to the subject, or whether the recited dose refers to a corticosteroid dose achieved after tapering.
Regarding claim 14, the phrase “e.g. hydroxychloroquine” renders the claim indefinite because it is unclear whether hydroxychloroquine is merely exemplary of the recited antimalarial or is intended to be a required limitation of the claimed method. The phrase “e.g.” is similar to “such as” or “for example” language and make the claim scope unclear.
Regarding claim 16, the phrase “e.g., the UPCR value being measured by sampling from a first morning void or 24 hour urine collection” renders the claim indefinite because it is unclear whether the recited sampling method is merely exemplary or is required by the claim. The phrase “e.g.” is similar to “such as” or “for example” language and make the claim scope unclear. The phrase “compared to prior to administering” also renders the claim indefinite because it is not clear whether the comparison is made to a value measured before administration of iptacopan, or to another prior administration event. Appropriate language would appear to be “compared to the UPCR value measured before administration of iptacopan”.
Regarding claim 18, the phrase “e.g., no less than 85%” renders the claim indefinite because it is unclear whether the claimed eGFR value must be no less than 80%, no less than 85%, or whether the 85% value is merely exemplary. The phrase “e.g.” is similar to “such as” or “for example” language and make the claim scope unclear. The phrase “compared to prior to administering” also renders the claim indefinite because it is not clear whether the comparison is made to a value measured before administration of iptacopan, or to another prior administration event. Appropriate language would appear to be “compared to the eGFR measured before administration of iptacopan”.
Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-11 and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (WO2015009616A1) in view of Li et al. (J. Clin. Med. 2021, 10(4), 626), further in view of Wong et al. (Journal of the American Society of Nephrology 31(10S):p.55 SU-OR39).
Regarding claim 1, Adams et al. teaches piperidinyl indole derivatives as complement factor B inhibitors (see e.g., p. 1, line 1). Adams et al. specifically discloses Example 26d, 4-((2S,4S)-(4-ethoxy-1 -((5-methoxy-7-methyl-1 H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride, corresponding to iptacopan hydrochloride / LNP023 (see. e.g., p. 176, line 1). Adams et al. further teaches pharmaceutical compositions, including oral dosage forms such as tablets and capsules (see e.g., p. 46, line 14-23). Adams et al. also teaches that factor B inhibitors are useful for treating complement-mediated diseases, including systemic lupus erythematosus, SLE nephritis, proliferative nephritis, and glomerulonephritis among complement-related diseases/disorders (see e.g., p. 50, line 10).
Adams et al. does not expressly teach administering iptacopan at 50–200 mg twice daily for treating lupus nephritis.
Li et al. teaches that uncontrolled alternative complement pathway activity contributes to lupus nephritis (see e.g., p. 1, Abstract and introduction) and that lupus-prone mice deficient in factor B or factor D show delayed progression of glomerulonephritis (see e.g., p. 5, line 18). Li et al. further teaches that targeted reduction of circulating factor B prevented hypocomplementemia and reduced lupus-nephritis-like pathology, including reductions in proteinuria and glomerular C3 deposition (see e.g., p. 5, line 41). Li et al. therefore provide a lupus-nephritis-specific reason to target factor B/the alternative complement pathway. Li et al. teaches that lupus nephritis patients are commonly treated with background standard-of-care immunosuppression, including glucocorticoids, mycophenolate mofetil or related mycophenolic acid therapy, cyclophosphamide, calcineurin inhibitors, and B-cell-directed therapy (see e.g., p. 7, line 10). Li et al. teaches that corticosteroid/glucocorticoid therapy is commonly used in lupus nephritis. Corticosteroid tapering was also a conventional lupus nephritis management practice to reduce steroid-related toxicity after disease control (see e.g., p. 7, line 19). Li et al. teaches background immunosuppressive treatment for lupus nephritis, and steroid tapering/discontinuation was a known treatment-management goal to reduce corticosteroid exposure (see e.g., p. 7, line 8).
Adams and Li do not expressly teach the claimed twice-daily human dosing regimen. Wong teaches that LNP023/iptacopan is a highly selective oral low-molecular-weight inhibitor of complement factor B, a key alternative pathway protease.
Wong et al. teaches that LNP023/iptacopan is a highly selective oral low-molecular-weight inhibitor of complement factor B, a key alternative pathway protease. Wong et al. teaches clinical administration of oral LNP023/iptacopan in patients with C3 glomerulopathy, a complement-mediated renal disease involving dysregulation of the alternative complement pathway (see e.g., Background). Wong et al. further teaches that patients received 10-100 mg twice daily during weeks 1-3 and 200 mg twice daily during weeks 4-12, and that LNP023 200 mg twice daily resulted in alternative pathway blockade and reduced proteinuria in patients with C3G (see e.g., Methods). Wong et al. also teaches that UPCR fell from baseline, eGFR improved or stabilized, plasma C3 levels recovered, and maximal alternative pathway inhibition was obtained at 100 mg to 200 mg twice daily (see e.g., Results). Thus, Wong et al. teaches oral twice-daily LNP023/iptacopan dosing within the claimed dose range and renal efficacy endpoints relevant to lupus nephritis.
Regarding claims 2-4, Wong et al. teaches oral LNP023/iptacopan dosing at 100 mg twice daily and 200 mg twice daily in patients with complement-mediated renal disease, and teach that maximal alternative pathway inhibition was obtained at 100 mg to 200 mg twice daily. Therefore, the recited doses of about 50 mg twice daily, about 100 mg twice daily, and about 200 mg twice daily are taught or suggested by Wong, or would have been reached by routine clinical dose optimization of the known oral factor B inhibitor taught by Adams et al.
Regarding claims 5-6, as discussed above, Li et al. teaches conventional lupus nephritis background immunosuppressive therapy, including mycophenolate mofetil or related mycophenolic acid therapy, cyclophosphamide, calcineurin inhibitors, and B-cell-directed therapy. Therefore, administering iptacopan with an immunosuppressant, including mycophenolic acid, cyclophosphamide, an anti-B cell agent, or a calcineurin inhibitor, is taught or suggested by the combination of references.
Regarding claims 7-10, Li et al. teaches conventional lupus nephritis background therapy, including that corticosteroid/glucocorticoid. Corticosteroid tapering was also a conventional lupus nephritis management practice to reduce steroid-related toxicity after disease control. Therefore, administering a corticosteroid with iptacopan and using a corticosteroid tapering regimen, including achieving a reduced daily corticosteroid dose or 0 mg/day after tapering, is taught or suggested by Li and ordinary lupus nephritis treatment practice.
Regarding claim 11, Li et al. teaches background immunosuppressive treatment for lupus nephritis, and steroid tapering/discontinuation was a known treatment-management goal to reduce corticosteroid exposure. Therefore, administering an immunosuppressant without a corticosteroid, including after tapering or discontinuing corticosteroid therapy, is taught or suggested by the combination of references.
Regarding claims 15-18, Li et al. teaches that targeting factor B/the alternative pathway reduces proteinuria and lupus-nephritis-like renal pathology, including reductions in proteinuria and glomerular C3 deposition. Wong et al. teaches that oral LNP023/iptacopan reduced proteinuria as measured by UPCR and improved or stabilized renal function as measured by eGFR in complement-mediated renal disease. Therefore, to the extent the claims are definite, the recited renal-response limitations, including achieving UPCR below 0.5 g/g, reducing UPCR by at least 50%, achieving or preserving eGFR, and avoiding renal flare, would have been obvious clinical goals, endpoints, or expected results of treating lupus nephritis with the known oral factor B inhibitor iptacopan. A person of ordinary skill in the art would have been motivated to monitor and pursue these renal-response outcomes because reduction of proteinuria/UPCR and preservation of kidney function/eGFR were known measures of therapeutic success in proteinuric renal disease and lupus nephritis.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to orally administer iptacopan, or a pharmaceutically acceptable salt thereof, at about 50 mg to about 200 mg twice daily to treat lupus nephritis, including with the recited immunosuppressive/corticosteroid background therapy and renal-response endpoints, because Adams et al. teaches the same active compound as an oral factor B inhibitor and identifies SLE nephritis/proliferative nephritis as complement-mediated indications; Li et al. provides a lupus-nephritis-specific rationale for targeting factor B/the alternative pathway; and Wong et al. provides a complement-mediated renal-disease clinical dosing and efficacy framework for oral LNP023/iptacopan, including twice-daily dosing within the claimed range, reduction of UPCR/proteinuria, and improvement or stabilization of eGFR. Thus, a person of ordinary skill would have been motivated to use the known oral factor B inhibitor iptacopan to inhibit the alternative complement pathway in lupus nephritis, with a reasonable expectation of reducing proteinuria and preserving renal function. The claimed dose amounts and dosing frequency would have involved routine clinical optimization of dose, dosing frequency, efficacy, safety, and tolerability for a known oral factor B inhibitor in a complement-mediated renal indication.
Claims 1 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. in view of Li et al. and Wong et al., as applied to claim 1 above, and further in view of SOLIRIS (SOLIRIS labeling 2020).
Regarding claims 12-13, Adams et al., Li et al., and Wong et al. teach or suggest the method of treating lupus nephritis with oral iptacopan as discussed above. Adams et al., Li et al., and Wong et al. do not expressly teach vaccinating the subject against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administering iptacopan. SOLIRIS teaches that complement inhibition increases susceptibility to serious infections, particularly infections caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (see e.g., p. 8, line 2, p. 9, line 1). SOLIRIS further teaches vaccination precautions for patients receiving complement-inhibitor therapy, including meningococcal vaccination prior to complement-inhibitor treatment and vaccination for prevention of Streptococcus pneumoniae and Haemophilus influenzae type b infections according to ACIP guidance (See e.g., p. 1, WARNING). Accordingly, vaccinating a subject against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administering iptacopan is taught or suggested by the combination of references.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to vaccinate a subject receiving iptacopan against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before treatment because iptacopan is a complement-pathway inhibitor, Wong et al. teaches vaccination against encapsulated bacteria in LNP023/iptacopan-treated patients, and SOLIRIS teaches the known safety principle that complement inhibition increases susceptibility to serious encapsulated-bacterial infections and that vaccination precautions are used for complement-inhibitor therapy. Applying known complement-inhibitor vaccination precautions to iptacopan treatment would have been an obvious safety measure.
Claims 1-11 and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. in view of Li et al. and Wong et al., as applied to claim 1-11 and 15-18 above, and further in view of Hahn et al. (Arthritis care & research 2012, 64(6) 797-808).
Adams et al., Li et al., and Wong et al. teach or suggest the method of treating lupus nephritis with oral iptacopan as discussed above. Adams et al., Li et al., and Wong et al. do not expressly teach further treating the subject with supportive care selected from an antimalarial, hydroxychloroquine, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker.
Hahn et al. teaches adjunctive/background treatment for lupus nephritis, including hydroxychloroquine unless contraindicated and renin-angiotensin system blockade with an ACE inhibitor or ARB to reduce proteinuria and delay renal progression (see e.g., p. 802, III Adjunctive Treatments).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further treat the subject with supportive lupus nephritis care, including an antimalarial, hydroxychloroquine, an ACE inhibitor, or an angiotensin receptor blocker, because Hahn et al. teaches that such agents were conventional adjunctive/background therapies for lupus nephritis patients. Administering such supportive care together with iptacopan would have predictably combined conventional lupus nephritis supportive treatment with factor B inhibition directed to the alternative complement pathway component of renal injury.
Therefore, the claimed invention is obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
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/G.S./ Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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