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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/26/2025 has been entered.
Claim Status
Claims 1-4 and 8-13 are pending and under examination. Independent claims were amended to incorporate mechanistic limitations (e.g. increasing expression levels of genes).
Priority
This application claims benefit to Provisional Application No. 63/510,587, filed 6/27/2023.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s recent response.
Claim Rejections - 35 USC § 103
Rejection maintained
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.
Claims 1-4 and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over
Yang et al. (“VE-Cadherin Is Required for Lymphatic Valve Formation and Maintenance.” Cell Rep. 2019 August 27; 28(9): 2397–2412.e4. doi:10.1016/j.celrep.2019.07.072) in view of
Niimi et al. (“FOXO1 represses lymphatic valve formation and maintenance via PRDM1.” Cell Reports (November 2021); 37(9): 110048. https://doi.org/10.1016/j.celrep.2021.110048),
Inserm (WO 2020/169707A1), and
Grayburn et al. (US PG-PUB 2016/0263017).
Claimed invention
Claim 1 and Claim 10 are drawn to a method for treating congenital lymphedema in a subject in need thereof comprising increasing the expression level of valve-forming genes (e.g., FOXC2) by administering to the subject an effective amount of the FOXO1 inhibitor, AS1842856, at a dose of about 8 mg/kg (Claim 1) or a dose of between about 0.05 mg/kg and about 0.5 mg/kg (Claim 10).
Prior art
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Since lymphatic vessels transport fluid from the tissues to the bloodstream against an increasing hydrostatic pressure, lymphatic valves (LVs) serve to prevent retrograde lymph flow and edema (lymphedema). See Yang, p. 2397. Yang describes the critical role of VE-cadherin in the formation and maintenance of LVs. Loss of VE-cadherin in vivo prevents valve formation in the embryo and causes postnatal regression of nearly all LVs, which leads to lymphedema. See Yang, p. 2397. This indicates that defects in LVs lead to congenital lymphedema. See Yang, p. 2397. Yang found that VE-cadherin is required for β-catenin and AKT signaling that regulate nuclear PROX1 and FOXC2 expression factors that are involved in the proper formation of LVs and the loss of VE-cadherin causes deficits in both PROX1 and the major transcription factor, FOXC2. See Yang, figure and text on first page and further pp. 2397,2404. Therefore, Yang suggests postnatal congenital lymphedema results from loss of embryonic VE-cadherin, subsequent deficiencies in FOXC2 and consequent loss of adequate and stable LVs. Yang, therefore, concluded that VE-cadherin-dependent signaling is required for lymphatic valve formation and maintenance and suggests therapies to augment downstream pathways (e.g., FOXC2) as potential treatments for lymphedema in patients. See ‘Summary’, p. 2397.
While Yang teaches that 1) loss of VE-cadherin in the embryo leads to deficiencies of major transcription factor, FOXC2, defective valve formation/maintenance and, consequently, congenital lymphedema and 2) suggests the use of therapies to augment pathways downstream from VE-cadherin (e.g., FOXC2) as potential treatments for lymphedema, Yang does not expressly teach administration of the FOXO 1 inhibitor, AS1842856, or its dose amount of between about 0.05-0.5 mg/kg or about 8 mg/kg.
However, it would have been obvious to administer a FOXO1 inhibitor such as AS1842856 to treat congenital lymphedema because it was already known that FOXO1 inhibition increases FOXC2 expression, and it was known that FOXC2 deficiency is involved in impaired valve formation and lymphedema such as lymphedema distichiasis. For example, Niimi teaches that a loss-of-function mutation of FOXC2 in humans produces severe edema in limbs, a condition which is known as lymphedema distichiasis syndrome. See Niimi, p. 1. Niimi states that FOXO1 inhibition upregulates FOXC2 and promotes lymphatic valve formation and maintenance. See Niimi, p. 11 and Figure 7H. These results indicate that FOXO1 is a potential therapeutic target for LV-loss-related pathologies including lymphedema distichiasis. Id. Additionally, AS1842856 was already discovered to have FOXO1-inhibiting efficacy and this feature of this compound was used therapeutically before by administering AS1842856 to provide FOXO1 inhibition in the treatment of others. For example, Inserm describes an invention that uses agents that inhibit FOXO1 for the treatment of a viral infection. See Inserm, abstract. In a particular embodiment, Inserm teaches AS1842856 is the FOXO1 inhibitor. See Inserm, p. 4. Further corroborating AS1842856 as a FOXO1 inhibitor, Grayburn teaches AS1842856 is a FOXO1 inhibitor that can be used pharmaceutically at doses of 4mg/kg/ip 6 times over 2 weeks (that is, every other day). See Grayburn, 0255.
Therefore, one of ordinary skill in the art (POSA) would have found it obvious to use AS1842856 in known dose amounts for inhibiting FOXO1 in a method for increasing lymphatic valve formation or treating congenital lymphedema because Yang and Niimi suggests the use of a FOXO1 inhibitor for increasing lymphatic valve formation and treating congenital lymphedema while both Inserm and Grayburn teach AS1842856 as a potent FOXO1 inhibitor that is useful for therapeutic use. The artisan would have sought to take advantage of the potent FOXO1-inhibiting activity of AS1842856 in patients in need of increasing lymphatic valve formation and treatment of congenital lymphedema since FOXO1 inhibition is suggested by Yang and Niimi as effective for increasing lymphatic valve formation and treating congenital lymphedema.
With specific regard to the claimed doses of about 8 mg/kg (Claim 1) and 0.05-0.5mg/kg (Claim 10) and wherein the AS1842856 is administered at about every other day (Claim 8).
Grayburn teaches AS1842856 is a FOXO1 inhibitor that can be used pharmaceutically at doses of 4mg/kg/ip 6 times over 2 weeks (that is, every other day). See Grayburn, 0255. This meets the limitations recited of Claim 1 and Claim 8. Furthermore, Inserm teaches the term “therapeutically effective amount” or “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount of a FOXO1 inhibitor of the present invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody of the present invention to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the combination of a FOXO1 inhibitor of the present invention are outweighed by the therapeutically beneficial effects. The efficient dosages and dosage regimens for the combination of a FOXO1 inhibitor of the present invention depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the oligomers of the present invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable dose of a composition of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above. For example, a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease. Typically, the ability of a compound to inhibit FOXO1 may, for example, be evaluated in an animal model system predictive of efficacy to reverse latency for HIV-1 cure (e.g. simian immunodeficiency virus (SIV)/macaque model). Alternatively, this property of a composition may be evaluated by examining the ability of the compound to induce cytotoxicity by in vitro assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound may decrease latent reservoirs, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected. An exemplary, non-limiting range for a therapeutically effective amount of an antibody of the present invention is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg. An exemplary, non-limiting range for a therapeutically effective amount of an antibody of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg. Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target. See Inserm, p. 11-13. If desired, an effective daily dose of a pharmaceutical composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day. See p. 13. Thus, clearly the dose of AS1842856 can be adjusted based on several factors such as disease state, age, sex, and weight of the individual, wherein the dose is in an amount such as about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about 0.3 (which “about 0.3 mg/kg” and “0.5 mg/kg” meet the limitation recited in Claim 10), about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg (which meets the limitation recited in Claim 1). See Inserm, p. 12. Therefore, the POSA would have found it obvious to adjust the dose and regimen of AS1842856 in order to adjust the efficacy of the drug to inhibit FOXO1 and treat the condition at issue based on different factors such as the subject's size, the severity of the subject's symptoms disease state, age, sex, and weight of the individual.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 2 limits claim 1, wherein the subject has lymphedema-distichiasis syndrome. Niimi teaches FOXO1 and PRDM1 are potential therapeutic targets for lymphatic valve-loss-related pathologies such as lymphedema distichiasis because inhibition of FOXO1 and its downstream target PRDM1 upregulates FOXC2 and GJA4 and promotes lymphatic valve formation and maintenance. Therefore, the POSA would have found it obvious to administer a FOMO1 inhibitor to upregulate FOXC2 and promote lymphatic valve formation and maintenance to treat postnatal lymphedema patients presenting with lymphedema distichiasis. This also meets the limitation of Claim 12.
Claim 3 limits claim 1, wherein the subject is between about 0 and about 60 months old. Given that embryos with decreased VE-cadherin have decreased FOMC2 and, consequently, impaired lymphatic valve formation can present with postnatal lymphedema, the POSA would have found it obvious to treat a postnatal infant less than a year old and through adulthood with the FOXO1 inhibitor in order to ameliorate the lymphedema as it occurs.
Claim 4 limits claim 1, wherein the FOXO1 inhibitor is administered intraperitoneally. Intraperitoneal injections were conducted by Yang to increase the Akt pathway, resulting in increase in activity of downstream pathways. Therefore, the POSA would have found it obvious to administer a FOXO1 inhibitor to increase the expression of FOXC2 intraperitoneally as a suitable route of administration for a therapeutic agent. This also meets the limitation of Claim 11.
Claim 9 limits claim 1, wherein the subject is a human or a non-human mammal. Both reference teach treatment of mice. See Yang, p. 2410; see also Niimi, first page. This meets the limitation of Claim 13.
Response to arguments
As an initial matter, it is noted that Applicant’s amendments add mechanistic limitations that, upon administration of effective amounts of AS1842856, expression levels of specific lymphatic valve-forming genes (FOXC2, GATA2, KLF4, ITGA9, GJA4) are increased. This amendment does not overcome the prior art because Niimi expressly teaches that FOXO1 inhibition upregulates FOXC2 and promotes lymphatic valve formation and maintenance. Niimi, Fig. 7H and corresponding caption, demonstrate that suppression of FOXO1 leads to increased valve gene expression, including FOXC2 and its downstream targets involved in lymphatic valve development. Therefore, the newly added language merely recites the expected result of FOXO1 inhibition as described by Niimi and does not distinguish the claimed invention from the prior art.
Applicant contends that Niimi’s mechanism via PRDM1 is obscure and uncertain. This argument is not persuasive because Niimi clearly identifies FOXO1 inhibition as the upstream “event” resulting in upregulation of FOX2C and lymphatic valve-forming genes. The presence of intermediate modulating factors such as PRDM1 does not negate the explicit teaching that FOXO1 inhibition increases expression of FOXC2 and related genes. Thus, a POSA would have reasonably expected AS1842856, a known FOXO1 inhibitor, to produce the same biological mechanistic effects described in Niimi.
Applicant cites Ogunsina (Front. Cell Dev. Biol., Jan 2023) to support the claimed mechanism. However, as acknowledged by Applicant, Ogunsina is not prior art under 35 USC § 102(b)(1)(A), as acknowledged by Applicant, and therefore cannot be relied upon as such. Moreover, the same biological relationship between FOXO1 inhibition and valve gene expression was already established by Niimi (2018), rendering the claimed mechanisms obvious.
Further with regard to the newly added limitations, Inserm and Grayburn remain relevant for the dosage and mode-of-administration aspects of the claims. Inserm discloses therapeutically effective doses of FOXO1 inhibitors within the range of 0.1-100 mg/kg, while Grayburn teaches in vivo administration of AS1842856 at 4 mg/kg every other day, overlapping the claimed ranges and regimen. Therefore, even when combined with the mechanistic language, the claimed invention scope remains obvious in view of Yang, Niimi, Inserm, and Grayburn.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622