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 Application
Claims 1-2, 4, and 6-21 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 03/18/2026 are acknowledged. Claims under consideration in the instant office action are claims 1-2, 4, and 6-21.
Applicants' arguments, filed 03/18/2026, have been fully considered and they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, 6, 9, 12-13, 15-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Schenk et al. (Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria, American Journal of Renal Physiology, 2018, 315, pp. F1777-F1786) in view of Miner et al. (Drug repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodiiate Airways, Frontiers in Pharmacology, 2019, 10, pp. 1-34, as disclosed in IDS).
Schenk et al. is drawn towards the role of the TMEM16A protein in kidney function (see abstract). Schenk et al. teaches that “TMEM16A is localized in the primary cilium of epithelial cells and can mediate cilia length and differentiation. It has been shown that TMEM16A promotes renal cyst growth via induction of chloride secretion and pro-proliferative effects on the cyst lining epithelium.” (pg. F1777, right column, first paragraph). Schenk et al. thus teaches that inhibition of the TMEM16A protein results can result in a reduction of renal cysts, which are characteristic in polycystic kidney disease, and one of ordinary skill in the art would immediately envision treating renal cysts present in PKD.
Schenk et al. does not teach administering niclosamide for the treatment of PKD. Schenk et al. does not teach co-administering an agent such as an antiinfective agent.
Miner et al. is drawn towards TMEM16 antagonist activity of niclosamide and nitazoxanide (see abstract). Miner et al. teaches “The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked away smooth muscle depolarization and contraction…For the first time we identify TMEM16A as a molecular target for these drugs” (see abstract).
It would have been obvious to one of ordinary skill in the art to administer niclosamide for the treatment of PKD, as suggested by Miner et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since niclosamide, as a potent TMEM16A antagonist as taught by Miner et al., can be administered to inhibit renal cyst growth in PKD via TMEM16A knockout as taught by Schenk et al., with a reasonable expectation of success absent evidence of criticality of the particular steps.
It would have been obvious to one of ordinary skill in the art to co-administer an agent such as an antiinfective agent, as suggested by Miner et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, it would have been prima facie obvious to combine niclosamide and nitazoxanide in a composition cojointly to treat PKD.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Schenk et al. (Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria, American Journal of Renal Physiology, 2018, 315, pp. F1777-F1786) and Miner et al. (Drug repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodiiate Airways, Frontiers in Pharmacology, 2019, 10, pp. 1-34, as disclosed in IDS) as applied to claims 1, 4, 6, 9, 12-13, 15-17, and 20 above, and further in view of Cnossen (Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management, Orphanet Journal of Rare Diseases 2014, 9:69, pp. 1-13).
The teachings of Schenk et al. and Miner et al. are presented above.
Schenk et al. and Miner et al. do not teach further treating polycystic liver disease (PLD). Cnossen teaches “Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications.” (see abstract).
It would have been obvious to one of ordinary skill in the art to further treat PLD, as suggested by Cnossen, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since the cyst formation that occurs in PLD can be targeted by niclosamide via TMEM16A knockout as taught by Schenk et al. and Miner et al., with a reasonable expectation of success absent evidence of criticality of the particular steps.
Claims 7-8, 10-11, 14, 18-19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Schenk et al. (Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria, American Journal of Renal Physiology, 2018, 315, pp. F1777-F1786) and Miner et al. (Drug repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodiiate Airways, Frontiers in Pharmacology, 2019, 10, pp. 1-34, as disclosed in IDS) as applied to claims 1, 3-6, 9, 12-3, 15-17, and 20 above, and further in view of Al-Hadiya (Niclosamide: Comprehensive Profile, Profiles of Drug Substances, Excipients and Related Methodology, 2005, 32, pp. 67-96).
The teachings of Schenk et al. and Miner et al. are presented above.
Schenk et al. and Miner et al. do not teach administering niclosamide, wherein said compound is administered in an amount of from 10 mg per day to 800 mg per day, or wherein said compound is administered once every 4-8 h, once daily, or once weekly.
Al-Hadiya is drawn towards a comprehensive profile of niclosamide. Al-Hadiya teaches that niclosamide can be administered orally as a single dose in an amount of 1-2 g (pg. 93, 6.4. Dosing Information). Al-Hadiya teaches that niclosamide was compatible with a majority of common tablet excipients (pg. 9, top paragraph).
It would have been obvious to one of ordinary skill in the art to administer niclosamide, wherein said compound is administered in an amount of from 10 mg per day to 800 mg per day, or wherein said compound is administered once every 4-8 h, once daily, or once weekly, as suggested by Al-Hadiya, and produce the instant invention.
With regards to the limitation claimed in instant claims 7 and 18, which claims a dosage of from 10 mg per day to 800 mg per day, Cnossen does not specifically teach the exact amounts claimed in instant claims 7 and 18. However, it would be within the skill of an ordinary artisan to be able to modify the dosage in order to obtain the desired bioavailability of niclosamide It is noted that “[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).
Response to Arguments
Applicant argues that “Schenk et al. neither study nor suggest that TMEM16A inhibition would confer any therapeutic benefit in pathological conditions characterized by cyst formation, such as ADPKD, ARPKD, and/or ADPLD. Schenk et al. merely teach a developmental biology model and do not evaluate cystogenesis in any disease-relevant model, including any form of PKD model.” The Examiner respectfully disagrees since although Schenk et al. does not disclose a particular model for cystogenesis, Schenk et al. does teach that “It has been shown that TMEM16A promotes renal cyst growth via induction of chloride secretion and pro-proliferative effects on the cyst lining epithelium” (pg. F1777, right column, 1st paragraph), and “TMEM16A-knockout mice showed reduced nephron numbers. However, cysts or metabolic disturbances could not be found.” (pp. F1784-F1785, bridging paragraph). One of ordinary skill in the art would thus be motivated to inhibit TMEM16A to provide therapeutic in cyst formation including in polycystic diseases.
Applicant also argues that “In view of Schenk et al., a skilled person would find it unexpected that ADPKD, ARPKD, and/or ADPLD may be treated or prevented using a TMEM16 inhibitor, such as benzbromarone, niclosamide, or pharmaceutically acceptable salts thereof. In contrast, the specification demonstrates the role of TMEM 16A in cyst expansion within a PKD1-deficient background, and unexpectedly shows that TMEM16 inhibitors, such as benzbromarone, niclosamide, and pharmaceutically acceptable salts thereat~ effectively suppress cyst growth in vivo (see, page 5, last paragraph, to page 6, first paragraph, Examples 4 and 6, and figures 4, 9 and 11 ). Only in this disease-relevant context does TMEI\1116A deletion result in a reduction of cyst burden, consistent with its role in chloride-driven fluid secretion.” The Examiner respectfully disagrees since it would have been expected that TMEM16 inhibition would suppress cyst growth, given that Schenk et al. does teach that “It has been shown that TMEM16A promotes renal cyst growth via induction of chloride secretion and pro-proliferative effects on the cyst lining epithelium” (pg. F1777, right column, 1st paragraph), and “TMEM16A-knockout mice showed reduced nephron numbers. However, cysts or metabolic disturbances could not be found.” (pp. F1784-F1785, bridging paragraph).
Applicant also argues that “Miner et al. teach the use of TMEM16A antagonists to bronchodilate airways in the context of asthma. Miner et al. do not teach or suggest the inhibition of cyst growth at all. Specifically, Miner et al. do not teach or suggest that ADPKD, ARPKD, and/or ADPLD may be treated or prevented using a TMEM16 inhibitor, such as benzbromarone, niclosamide, or pharmaceutically acceptable salts thereof. Thus, the Miner et al. reference does not cure the deficiency of the Schenk et al. reference.” The Examiner respectfully disagrees since Miner et al. is relied on for the teaching that niclosamide is a potent TMEM16A antagonist and given the teachings of Schenk et al. above, one of ordinary skill in the art would have been motivated to administer a TMEM16 inhibitor such as niclosamide to inhibit cyst growth in polycystic kidney disease.
Conclusion
Claims 1-2, 4, and 6-21 are rejected.
THIS ACTION IS MADE FINAL. 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 ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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