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 .
Application Status
Claims 1-4, 12-14, 16, 22-29, 32-33 and 109-112 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous rejections of claim 30 are rendered moot by claim cancellation.
Previous rejection of claims 1-4, 12-14, 16, 22-29, 32-33 and 109 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-4, 16, 22-30, 32-33, and 109-112 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT01900431 (Phase II Study to Analyze Sarilumab in Non-Infectious Uveitis; IDS entered May 14, 2024), Lin et al. (IDS entered July 15, 2021), Huizinga et al. (Ann Rheum Dis 2014; 73: 1626-1634; IDS entered May 14, 2024), and Holm (Doc Ophthalmol, 2007, 114(3):117-24; cited in OA 05/27/2025) as evidenced by KEGG (KEGG Drug, Sarilumab/ D10161, No Date available; PTO-892).
Regarding claims 1-3, 16, 109, and 112, NCT01900431 teaches a method of treating non-infectious uveitis (NIU) wherein they will evaluate the change in macular edema (Brief summary; secondary objective) in a subject by administering Sarilumab and methotrexate (Arms and Interventions). NCT001900431 teaches that the subject received Sarilumab subcutaneously (Arms and Interventions).
Regarding the limitation of CRT greater than or equal to 300 μm prior to administration of the antibody, NCT01900431 teaches measurement of the percentage of patients with CRT less than 300 μm at 16 weeks (secondary outcome measures).
Regarding the limitation that the subject has been previously administered corticosteroid and MTX, NCT01900431 further teaches that the subject for treatment must have active disease at screening and receiving oral prednisone between 15-80 mg per day with no dosage change for at least 4 weeks prior to randomization visit as single immunosuppressive therapy or in combination with Methotrexate (MTX) (≤ 25 mg/week) (Eligibility; Criteria).
Regarding claims 1-3 and 110-112, as evidenced by KEGG D10161, the sequence for Sarilumab heavy chain has 100% sequence identity to the instant claimed SEQ ID NOs: 2 and 4 and the light chain has 100% sequence identity to the instant claimed SEQ ID NOs: 3 and 5.
Regarding claims 4 and 109, NCT010900431 further teaches that the study will evaluate the change in ocular inflammation and retinal vessel leakage (Study description; brief summary).
Regarding claims 22-24, NCT001900431 teaches that the subject achieves at least a 2-step reduction in the vitreous haze, or a change in the prednisone dose to less than 10 mg per day at time frame 16 weeks (Primary Outcome Measures).
Regarding claims 25-29, NCT001900431 teaches that the subject experiences improved BVCA, CRT, retinal vessel leakage, anterior chamber score and clinical assessment at the 16 week time point (Secondary Outcome Measures).
Further regarding claims 22-29, 109, and 112, the results of the claims naturally flow from performing the method steps of claim 1, because the method teaches all of the claimed active method steps.
NCT01900431 does not teach the dosing of Sarilumab from 150 to 200mg once every two weeks or about 150 mg or 200mg once every 2 weeks or a central retinal thickness of 300uM or greater prior to treatment.
Regarding claims 1, 16, 32, 33 and 109, Huizinga et al. teaches that dosing of Sarilumab at 150 and 200 mg every 2 weeks had a safety profile consistent with other anti-IL-6 therapies, as well as confirmation of efficacy in combination with 10-25 mg per week of methotrexate (Discussion; Table 3). Huizinga et al. further teaches that in light of the safety and efficacy data the 150mg and 200mg every other week dosing regimens are optimal for Sarilumab as well as more convenient for the patient (page 1633, column 1, paragraph 2).
Lin et al. teaches that both preclinical and clinical data support the importance of IL-6 in uveitis and that IL-6 levels are elevated in the serum of active uveitis patients as well (page 1698, column 2, paragraph 2). Lin et al. further teaches that while rheumatoid arthritis (RA) is not commonly associated with uveitis, IL-6 production is dysregulated and serum levels appear to correlate with disease activity (page 1699, column 1, paragraph 2). Lin et al. further teaches that tocilizumab, a monoclonal antibody against soluble and membrane bound IL-6 receptor that is approved for treatment of RA has been successful in treating various types of uveitis and cystoid macular edema (page 1699).
Holm et al. teaches that the diagnosis and management of macular oedema is defined from the results from stereoscopic fundus biomicroscopy, fluorescein angiography and lately OCT and that studies have shown a correlation between retinal thickness and visual acuity (discussion, para 1). Holm et al. further teaches that eyes with a macular thickness above 300 μm had lower visual acuity (page 123, col 2, para 4) and that a macular thickness level about 300 μm might be a critical point regarding retinal function (page 123, col 1, para 4). Holm et al. further teach that Best corrected visual acuity was inversely correlated with the central area macular thickness page 121, col 1, para 1; fig 1). The macula is located at the center of the retina so therefore central retinal thickness is the same as macular thickness as seen by the interchangeability of the terms in Holm (see 121, subsection comparison of eyes according to a retinal thickness above and under 300 μm wherein the paragraph uses the term macular thickness throughout).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treatment by administering Sarilumab in combination with Methotrexate used in treatment of macular edema as taught by NCT01900431 in a subject that is determined to have been previously administered corticosteroid and MTX, and who is determined to have a central retinal thickness (CRT) greater than or equal to 300 μm prior to administration of the antibody with the dosing at 150mg or 200mg every other week, as established by Huizinga et al. and Lin et al. The ordinary artisan would have been motivated to do so because as Huizinga et al. teaches the 150 mg or 200 mg every other week of Sarilumab has a good safety profile as well as efficacy in inflammatory disease and provides the advantage to the patient of increased convenience. Holm et al. teaches that CRT of 300 μm might be a critical point regarding retinal function therefore it would be a good threshold limitation to enroll patients for treatment. Lin et al. teaches that both RA and uveitis have elevated serum IL-6 levels associated with disease activity and that another monoclonal antibody to the IL-6 receptor, tocilizumab, has shown efficacy in both RA and uveitis.
Further one of ordinary skill in the art would recognize antibody concentration and formulation as result-effective variables and optimize them by routine experimentation. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). As set forth at 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.”
Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT01900431 (Phase II Study to Analyze Sarilumab in Non-Infectious Uveitis; IDS entered May 14, 2024), Lin et al. (IDS entered July 15, 2021), Huizinga et al. (Ann Rheum Dis 2014; 73: 1626-1634; IDS entered May 14, 2024), and Holm (Doc Ophthalmol, 2007, 114(3):117-24; cited in OA 05/27/2025) as evidenced by KEGG (KEGG Drug, Sarilumab/ D10161, No Date available; PTO-892) as applied to claims 1-4, 13-14, 16, 22-29, 32-33, and 109-112 above, and further in view of NCT01095809 (Record history March 2012; cited in OA 11/19/2024) as evidenced by Teper (J Clin Med. 2021 Sep 14;10(18):4133; cited in OA 11/19/2024).
The teachings of NCT01900431, Lin et al., Huizinga et al. and Holm et al. as evidenced by KEGG are detailed above.
NCT01900431, Lin et al., Huizinga et al, and Holm et al. do not teach wherein the subject has been previously administered the corticosteroid for at least 3 months.
Regarding claims 12-14, NCT01900431 further teaches that the subject for treatment must have active disease at screening and receiving oral prednisone between 15-80 mg per day with no dosage change for at least 4 weeks prior to randomization visit (Eligibility; Criteria). This indicates that the subject has been receiving corticosteroid for longer than 4 weeks.
Regarding claim 12, NCT01095809 teaches stable treatment with oral prednisone at least during 3 months, either oral cyclosporine or other immunomodulator to treat intraocular inflammatory disease (inclusion criteria) in a trial for an anti-VEGF antibody (bevacizumab) to treat uveitic macular edema (title).
Regarding claim 12, as evidenced by Teper, systemic steroids are very effective for treating uveitic cystoid macular edema but their use is limited due to their numerous systemic side effects and it is important to identify a personalized minimal effective dose—usually starting with 0.5–1 mg of prednisone/kg or an equivalent dose of other steroids (section 3.2.1.). Teper further teaches that discontinuation of medication often results in a recurrence of edema (section 3.2.1).
It would have been obvious to one of ordinary skill in the art to apply the time period of 3 months of previous treatment with corticosteroid as taught by NCT01095809 and evidenced by Teper to the method of treating macular edema in a subject that is determined to have been previously administered corticosteroid and MTX, and who is determined to have a central retinal thickness (CRT) greater than or equal to 300 m prior to administration of the antibody as taught by NCT01900431, Lin et al. and Huizinga et al. The ordinary artisan would have been motivated to do so as NCT01095809 teaches stable treatment with oral prednisone at least during 3 months in a trial to treat uveitic macular edema, and Teper teaches that it is important to identify a personalized minimal effective dose in order to avoid recurrence after discontinuation and to minimize side effects.
Response to Arguments
Applicant's arguments filed February 17, 2026 have been fully considered but they are not persuasive.
Applicant submits: The prima facie case fails because none of the cited references teaches or suggests "a subject is determined to have a central retinal thickness (CRT) greater than or equal to 300 µm prior to administration of the antibody." As the Office admits, NCT '431 does not teach CRT >300 µm. Instead, NCT '431 is relied on for reporting a secondary outcome measuring the percentage of patients with CRT <300 µm at 16 weeks-a post-treatment endpoint, not a pretreatment inclusion criterion.
Holm's discussion of an approximately 300 µm macular thickness threshold arises in the context of diabetic macular edema. Nothing in Holm or the other cited documents teaches or suggests the significance of 300 µm in diabetic subjects is clinically relevant in specific patients as recited in the present claims. Holm itself notes that age and diabetes may influence retinal outcomes, further limiting applicability to a defined prior treatment history (a subject who is determined to have been previously administered a corticosteroid and MTX).
In response: This argument was previously addressed in the OA 10/16/2025 an included here for convenience.
Holm specifically discusses the diagnosis and management of macular edema in the context of diabetic retinopathy. Holm is directed to methods of measuring macular oedema for determining functional changes and not methods of treatment. The previous treatment with corticosteroids and MTX is addressed by the clinical trial. Holm concludes that macular thickness of about 300 μM increases the risk for disturbed macular function which is not only applicable to diabetic patients. Further the clinical trial includes the secondary outcome measure of the percentage of patients with CRT less than 300 µm, which does in fact reasonably suggest that subjects with greater than or equal to 300 µm CRT will be identified and results will be determined on that population.
Applicant submits: The Office further relies on Huizinga for its rheumatoid arthritis (RA) dosing. The Office asserts that because sarilumab is an anti-IL-6 antibody that has demonstrated efficacy in RA via the same method of administration, RA dosing would apply to macular edema. This reasoning is flawed. Huizinga' s dosing is for RA-a systemic autoimmune disease, not for a localized ocular inflammation. Nothing in Huizinga teaches or suggests that systemic dosing for RA would be effective for a localized inflammatory eye disease where the blood-ocular barriers may be a consideration or challenge for drug delivery and efficacy.
In response: This argument was previously addressed in the OA 10/16/2025 an included here for convenience.
Huizinga teaches safety and efficacy data the 150mg and 200mg every other week dosing regimens are optimal for Sarilumab as well as more convenient for the patient and that the safety profile was consistent with other anti-IL-6 therapies. This provides a reasonable expectation of success as a starting point for dosing optimization for alternative disease treatments. Further as Lin, shows in Table 2 Tocilizumab which also targets membrane and soluble IL-6 receptor has the same dosing for RA and uveitis and has shown efficacy for both, as well as maintaining control of macular edema and improvement of central foveal thickness (page 1699, col 2, para 2). As the prior art teaches that the same dosing for an antibody that has the same target has been effective systemically for treating ocular disease there is therefore a reasonable expectation of success for sarilumab.
Applicant submits In fact, biologics approved for systemic autoimmune diseases have required dosing modifications to achieve efficacy in ocular indications: Toclizumab, Adalimumab, Etanercept.
Moreover, IL-6R inhibitors are not interchangeable. The Office relies on Lin to suggest tocilizumab efficacy in RA and uveitis, implying interchangeability among IL-6R antibodies. This assumption is incorrect. Although both antibodies target IL-6R, they differ in many aspects including, but not limited to, structure, route of administration, dosing, and clinical performance.
In polymyalgia rheumatica, sarilumab demonstrated sustained efficacy in the SAPHYR Phase 3 trial and received FDA approval. Tocilizumab, despite short-term benefit, lacks comparable data demonstrating that such improvement is sustainable. The FDA' s requirement for robust, long-term Phase 3 evidence was met by sarilumab-but not by tocilizumab-underscoring their non-interchangeability in both regulatory and clinical contexts.
In response: This argument was previously addressed in the advisory action sent 02/09/2025 an included here for convenience.
The evidence presented of other biologics that have required dosing modifications for ocular indications are all not prior art to the instant application, so while the ordinary artisan would see this in post hoc comparison that other antibodies have needed dosing adjustment for ocular treatment versus RA, by the same reasoning the ordinary artisan would also see that sarilumab was effective at a dose of 200mg every 2 weeks for 16 weeks subcutaneously (Heissigerová et al; Ophthalmology 126.3 (2019): 428-437; IDS entered 02/19/2025).
The established safe dosing used for RA for sarilumab is still a reasonable dosing strategy and has a reasonable expectation of success.
The examiner did not rely on Lin et al. to teach the dosing or interchangeability of antibodies but the concept that targeting IL-6 was a valid strategy in the treatment of both RA and uveitis.
Applicant submits: Finally, in response to the Office's assertion that "lack of success does not negate prior expectation of success as determined by etiology," Applicants submit that this misapplies the obviousness standard. The ALIGN study shows that IL-6 involvement does not guarantee efficacy in AS, which underscores unpredictability and confirms that pathway association alone does not create a reasonable expectation of success. In view of the unpredictability of the efficacy of a biologics on various indications and none of the cited references providing efficacy data for the methods as presently claimed, the Office's reasoning merely relies on impermissible hindsight based on the Applicants' present disclosure, contrary to KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007), and MPEP § 2142.
In response: In disease treatment with biologics there is never a guarantee of efficacy. The bar is a “reasonable expectation of success” that must be met, not a guarantee thereof.
This argument was addressed in the non-final rejection sent November 19, 2024 and repeated herein for compact prosecution. There was a reasonable expectation of success in treating ankylosing spondylitis with sarilumab to inhibit IL-6 otherwise a clinical trial would not have been done. Sieper et al. (Annals of the Rheumatic Diseases 2015; 74:1051-1057.; IDS entered October 1, 2024) discloses that because high levels of TNF-α and interleukin (IL)-6 have been found in biopsy specimens from sacroiliac joints of patients with AS, these cytokines were thought to at least partially mediate the inflammation in AS and thus, blockade of IL-6 is an appealing potential therapeutic option (introduction). Lack of success in treatment does not negate the prior expectation of success as determined by the etiology of the disease, that is hindsight reasoning.
Applicant submits: Specifically, independent claims 112 and 119 each recite a method in which "the subject achieves after at least 16 weeks of the treatment a reduction in the VH level on the Miami 9 point scale of at least 2 steps, and/or a reduction of corticosteroid dose to a dose that is equivalent to prednisone at a dose of less than 10 mg per day." Such specific level of efficacy outcomes would not be apparent from any of the cited references, taken alone or in combination.
In response: This was addressed in the advisory action sent 02/09/2026.
The addition of these claims raises a new issue of whether the step of “the subject achieves” is a valid limitation to the claim as an active method step. In the instant application the specification teaches in various embodiments that the subject achieves a particular clinical measure (page 5, line 31 – page 6, line 4; embodiments 26-33 and 64-71), however as seen in Tables 4-12 not all patients that received the treatment method achieved the desired clinical response. As a proportion of patients do not achieve the clinical metric, the instant method would have to be not applied after the administration of the full course of medication to the predetermined patient population and analysis to determine whether or not the method step of “achieving” had been met. As there is no active step for sorting the patient population before or after administration and result analysis, the ordinary artisan would not be able to determine if the active step of “achieving” had been met.
It is the administration of the antibody and the methotrexate that results in treatment of the patient and the results achieved therein are inherent to the method and furthermore not guaranteed to every patient that receives treatment.
Applicant submits: As for claim 109, Applicants respectfully disagree with the Advisory Action's position that the "subject achieves ... " clause constitutes an improper method step. The clause describes the therapeutic result that the recited administration can produce, which the specification clearly supports. Under MPEP §§ 2111.03, 2111.04, and 2173.05(g), such functional and result-of-treatment limitations, including "wherein" clauses, are permissible and must be given patentable weight. These MPEP sections confirm that describing the effect or outcome of a treatment does not convert the outcome into an affirmative step of the method. Nor does clinical variability render the limitation improper; variability does not transform a therapeutic outcome limitation into an action step.
Importantly, the "subject achieves ... " clause defines the scope of the claimed method by reference to the outcome achieved by subjects who exhibit a reduction as recited in the present claims. It therefore operates as a proper therapeutic result limitation that characterizes the claimed method. Accordingly, Applicant respectfully submits that the Advisory Action's objection to the "subject achieves ... " language is misplaced and should be withdrawn.
In response: MPEP §§ 2111.03 and 2111.04 are drawn to transitional phrases including comp[rising, consisting of, or consisting essentially of and whether that renders the claim open or closed. Therefore, these sections of the MPEP are not relevant to the discussion at hand.
MPEP § 2173.05(g) is drawn to functional limitations as to what a feature does rather than what it is. While functional language does not in and of itself render a claim improper…it is evaluated and considered for what it fairly conveys to a person of ordinary skill in the pertinent art. The MPEP further explains: Notwithstanding the permissible instances, the use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear.
Applicant’s submission that “The clause describes the therapeutic result that the recited administration can produce, which the specification clearly supports”; is exactly the issue. This is the results that CAN be achieved but is not a given patentable weight as a limitation of the instant claims as it can also not be achieved. The result is therefore an inherent result of the active steps of the method.
Applicant submits: The Office relies on NCT '809 for teaching an anti-VEGF antibody trial for uveitic macular edema that requires stable oral prednisone treatment for at least three months. The Office asserts that "the type of antibody is not the issue but the length of time to establish corticosteroid treatment for a particular disease prior to testing an additional therapy" is relevant.
But the Office has not provided a legally sufficient rationale for why one skilled in the art would have selected only NCT '809's corticosteroid timing criterion for an entirely different antibody (anti-VEGF) when designing an IL-6R antibody regimen for macular edema. Nothing in NCT '809 teaches or suggests that anti-VEGF and IL-6R therapies share dosing strategies, PK/PD considerations, or clinical endpoints that would make such borrowing logical less for a defined population with a prior treatment history (a subject who is determined to have been previously administered a corticosteroid and MTX). Under KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), and MPEP §2143, an obviousness rejection must identify a reasoned motivation to combine references, not merely assert that the combination teaches or suggests the limitations.
Applicant also notes the Advisory Action's reference to Jabs et (Am J. Ophthalmol, 200 Oct 130 ( 4):492-513) that was previously submitted in the IDS of record. Applicant respectfully maintains that no additional search results or arguments have been presented that would alter the positions already set forth in the last response. This newly cited reference does not teach or suggest the claim limitations at issue, nor does the Advisory Action identify any new rationale that would cure the deficiencies already addressed. Accordingly, Applicant's prior arguments and amendments fully traverse the rejection.
In response: This argument was already addressed in advisory action 02/09/2026.
The NCT ‘809 trial is relevant because it is a trial for the same disease to test an antibody with previous treatment of corticosteroids for a specific period of time. The motivation to combine was detailed in the actual rejection. The ordinary artisan would have been motivated to do so as NCT01095809 teaches stable treatment with oral prednisone at least during 3 months in a trial to treat uveitic macular edema, and Teper teaches that it is important to identify a personalized minimal effective dose in order to avoid recurrence after discontinuation and to minimize side effects.
The inclusion of Jabs ( Am J Ophthalmol. 2000 Oct;130(4):492-513; cited in OA 02/09/2026) was further evidence to establishing a specific dose of corticosteroids for a period of 3 months as standard therapy for ocular inflammation to get the best effect while avoiding adverse reactions, before adding an additional therapeutic.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643