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 1-2, 4-10 filed January 20, 2026 are currently pending.
Response to Amendment
Applicant’s amendments, filed 01/20/2026 are acknowledged. Claim 3 is canceled in its entirety. Claim 1 is amended as follows: An application method of an ion channel blocker, comprising: administering a therapeutically effective amount of the ion channel blocker to a subject to treat and prevent hepatic fibrosis; wherein the ion channel blocker is gliclazide, and the therapeutically effective amount of the gliclazide is 500 micromoles per liter.
Withdrawn Rejection(s)
In view of Applicant’s amendments, the pending 35 U.S.C 102(a)(1) rejection of claims 1-3, 5-10 by Ren is withdrawn as Ren does not specifically teach administration of gliclazide in a dose of 500 mM. Next, the pending 35 U.S.C 102(a)(1) rejection of claims 1-2 by Paka is withdrawn as claim 1 now requires the ion channel blocker gliclazide and a dose of 500 mM, which is not taught by Paka. Thirdly, the pending 35 U.S.C 102(a)(1) rejection of claims 1-2 by Kim as claim 1 now requires the ion channel blocker gliclazide and a dose of 500 mM which is not taught by Kim. Fourthly, the pending 35 U.S.C 103 rejection in view of the combined teachings of Kim and Hinz is withdrawn as neither Kim nor Hinz teach or suggest the administration of gliclazide to treat or prevent hepatic fibrosis in a subject in a dose of 500 mM. Lastly, the double patenting rejection of record with copending Application 18348332 is withdrawn as the copending claims are not directed to the treatment of hepatic fibrosis with gliclazide.
Applicant's arguments, filed 01/20/2026 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 Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.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.
NEW REJECTIONS NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 112-Paragraph D
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 is directed to administering a therapeutically effective amount of the distinct ion channel blocker gliclazide in a dose of 500 mM to treat and prevent hepatic fibrosis in a subject in need. Claim 2 fails to further limit the scope of claim 1 as claim 2 broadens the genus of ion channel inhibitor to “a potassium ion channel inhibitor”, while amended claim 1 is directed to the distinct species of ion channel inhibitor gliclazide.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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) 1-2 and 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Ren (Molecules Vol. 27 pages 727-741. Published 2022) and Liu (CN111467354 published 07/31/2020; machine translation provided).
Claim interpretation is as follows: Claim 1 is directed to the method of an ion channel blocker, comprising: administering a therapeutically effective amount of the ion channel blocker to a subject to treat and prevent hepatic fibrosis; wherein the ion channel blocker is gliclazide, and the therapeutically effective amount of the gliclazide is 500 mM.
Ren (Molecules Vo. 27 pages 727-741. Published 2022) teaches the method of treating hepatic fibrosis in a high-fat induced fibrosis subject comprising administering a therapeutically effective amount of the potassium channel inhibitor gliclazide (abstract, page 11). Ren teaches inducing fibrosis in the subject with a high-fat diet. As shown in Figures 5-6, patients fed a high fat diet comprise hepatic fibrosis as evidenced by crosslinked collagen and Sirius red staining. See Paka (World Journal of Gastroenterology Vol. 23 pages 4181-4190. Published 2017; pages 4181-4183) for inducing hepatic fibrosis with high-fat diet and identification of fibrosis by Sirius staining.
Ren teaches oral administration of 2 mg gliclazide per day (0.040 mg/kg in a 20 g mouse), which corresponds to a dose of 6 mmole (MW of gliclazide is 323.41 grams/mole; page 10 of Ren). Ren teaches the administered therapeutically effective amount of gliclazide had a moderate inhibitory effect of collagen-1 protein induction into the liver of the patient compared to either control high-fat diet patients or high-fat diet patients treated with sitagliptin (page 5 Figure 6D, 6d and 6N). Ren also teaches that said therapeutically effective amount of gliclazide inhibits fibrosis marker TGFb in the induced hepatic fibrosis patient compared to control hepatic fibrosis patients (page 5 Figure 5F). Regarding claims 5 and 9, as shown in Figures 8B, 8D and 8E, Ren teaches that the administered gliclazide inhibits the autophagy pathway compared to control high fat diet patients as well as downregulates LC3 of hepatocytes compared to control high fat diet patients (page 7).
The difference between the present claims and the methodology taught by Ren is that Ren does not specifically teach adjusting the dose of gliclazide to wherein the dose of gliclazide is 500 mM.
Liu (CN111467354 published 07/31/2020; machine translation provided) teaches the anti-fibrotic effects of gliclazide. Liu teaches that doses of 40 mg/kg-100 mg/kg of gliclazide are efficacious at inhibiting fibrotic disorders in a subject in need, wherein said therapeutically effective dose reduces the expression of the collagen in the desired therapeutic tissue (Figure 4)
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to adjust the hepatic fibrosis treating dose of gliclazide in the therapeutic regimen of Ren from 2 mg per day to a dose of 40-100 mg/kg in view of Liu in order to arrive at the presently claimed methodology.
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 Liu that gliclazide in doses of 40-100 mg/kg are efficacious at treating fibrosis disorders and inhibiting collagen in the targeted tissue. Accordingly, said skilled artisan would have readily predicted that adjusting the therapeutically effective 2 mg dose of gliclazide in the hepatic fibrosis treating regimen of Ren to a dose of 40-100 mg/kg would have resulted in a gliclazide dose effective to treat hepatic fibrosis in the afflicted subject.
MPEP 2144.05 teaches that “[A] range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004). The patent claim at issue was directed to a weight plate having 3 elongated openings that served as handles for transporting the weight plate. Multiple prior art patents each disclosed weight plates having 1, 2 or 4 elongated openings. 392 F.3d at 1319, 73 USPQ2d at 1226. The court stated that the claimed weight plate having 3 elongated openings fell within the "range" of the prior art and was thus presumed obvious. 392 F.3d at 1322, 73 USPQ2d at 1228. The court stated that the "range" disclosed in multiple prior art patents is "a distinction without a difference" from previous range cases which involved a range disclosed in a single patent since the "prior art suggested that a larger number of elongated grips in the weight plates was beneficial... thus plainly suggesting that one skilled in the art look to the range appearing in the prior art." The court further stated that “[Nonetheless, where there is a range disclosed in the prior art, and the claimed invention falls within that range, there is a presumption of obviousness. But the presumption will be rebutted if it can be shown: (1) That the prior art taught away from the claimed invention, In re Geisler, 116 F.3d 1465, 1471 [43 USPQ2d 13621 (Fed. Cir. 1997); or (2) that there are new and unexpected results relative to the prior art, In re Woodruff, 919 F.2d 1575, 1578 M6 USPQ2d 19341 (Fed. Cir. 1990). In the instant case, there is no teaching away of adjusting the dose of gliclazide to the hepatic fibrosis patient as disclosed by the combination of Ren and Liu. As discussed below, the unexpected results have not demonstrated the criticality of the claimed concentration of gliclazide in the therapeutic regimen relative to the prior art teachings of Ren and Liu.
Regarding the limitation wherein the administered dose of gliclazide to the hepatic fibrosis patient is 500 mM, the optimum dose of gliclazide to the hepatic fibrosis patient would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles of the combined regimen, as well as the age, weight, sex, diet and severity of the medical condition of the patient. Thus, the dose of gliclazide to the hepatic fibrosis patient that would have been employed would have varied widely and, in the absence of evidence to the contrary, the current claimed specific administration regimen is not seen to be inconsistent with one that would have been determined by the skilled artisan. Furthermore, absent and evidence demonstrating a patentable difference between the compositions administered and the criticality of the claimed gliclazide, the determination of the optimum dose given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(”[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the workable ranges by routine experimentation.”)
Thirdly, regarding limitations wherein the therapeutically effective amount of gliclazide inhibits proliferation of T6-hepatic stellate cells or downregulates alpha-smooth muscle actin, or upregulates sequestrome 1 (p62) of hepatocytes in the treated hepatic fibrosis patient (claims 6-8, 10), properties that accrue from a process step of administering a therapeutically effective amount of gliclazide to a hepatic fibrosis patient as taught by Ren and Liu above are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case, Applicant is required to provide objective evidence that the administered therapeutically effective dose of gliclazide to the hepatic fibrosis patient taught by Ren above does not inhibit proliferation of T6-hepatic stellate cells nor does not downregulate alpha-smooth muscle actin nor does not upregulates sequestrome 1 (p62) of hepatocytes in the treated hepatic fibrosis patient.
Applicant traverses. Applicant argues that Ren does not specifically teach administration of gliclazide in a dose of 500 mM but rather 2 mg per day and this dose is not comparable to the claimed 500 mM concentration as a therapeutically effective amount of gliclazide for treating hepatic fibrosis. Applicant asserts that the activation of HSCs is inhibited and thereby, the carbon tetrachloride induced hepatic fibrosis is efficiently treated yielding unpredictable results.
Response to Arguments
Applicant’s arguments, filed 01/20/2026 are acknowledged and have been carefully considered. Regarding Applicant’s contention that the unexpected results within the instant specification and drawings are sufficient to overcome a prima facie case of obviousness, the examiner is unpersuaded. As shown in MPEP 716.02 (E); An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960).
In the instant case, the closest prior art is Ren (Molecules Vo. 27 pages 727-741. Published 2022) who teaches the method of treating hepatic fibrosis in a high-fat induced fibrosis subject comprising administering a therapeutically effective amount of the potassium channel inhibitor gliclazide (2 mg/day), wherein said gliclazide therapy inhibits fibrosis marker TGFb in the induced hepatic fibrosis patient compared to control hepatic fibrosis patients, inhibits the autophagy pathway compared to control high fat diet patients as well as downregulates LC3 of hepatocytes compared to control high fat diet patients ((page 5 Figure 5F, page 7 Figures 8B, 8D and 8E).
Applicants have provided no comparative data to the closest prior art of record to show that 1) the 500 mM gliclazide dose in the presently claimed methodology results in improved efficacy than the 2 mg/day gliclazide therapeutic regimen taught by Ren above. In essence, there is no positive control experiment between the instantly claimed solid dispersion composition and the composition of Ren. Data must be provided that demonstrates that the instantly claimed hepatic fibrosis treating regimen with 500 mM of gliclazide performs better than the prior art of Ren in order to demonstrate that the claimed regimen possesses a property not shared with the closest prior art. Applicant must also show that the different results of the between the instantly claimed and those of the prior art are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP 716.02(B) and Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Because Applicant has not done so, said unexpected results lack any statistical or practical significance.
Applicant is additionally reminded of MPEP 716.02(D) wherein “[T]o establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). In the present case, Applicant has not shown criticality of the claimed 500 mM dose of gliclazide in comparison to the 2 mg/day gliclazide treatment regimen of Ren, nor that doses outside the claimed range to show criticality of the therapeutically effective dose. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Ren (Molecules Vol. 27 pages 727-741. Published 2022) and Liu (CN111467354 published 07/31/2020; machine translation provided) as applied to claims 1-2 and 5-10 above, in view of Hinz (Methods in Molecular Biology: Myofibroblasts Methods and Protocols; pages 339-356, Published 2021).
As disclosed above, the combination of Ren and Liu render obvious the treatment of hepatic fibrosis in a subject in need comprising administering a therapeutically effective amount of gliclazide. As shown in Ren, administration of a therapeutically effective amount of gliclazide (2 mg/day; 6mmole) inhibits fibrosis marker TGFb in the choline-deficient high fat diet-induced hepatic fibrosis patient compared to control hepatic fibrosis patients, inhibits the autophagy pathway compared to control high fat diet patients as well as downregulates LC3 of hepatocytes compared to control high fat diet patients (page 5 Figure 5F, page 7 Figures 8B, 8D-8E), coupled with the knowledge that doses of 40-100 mg/kg gliclazide are also efficacious at inhibiting pathogenesis of fibrosis-mediated disorders in a subject in need.
The difference between the presently claimed methodology embodied within Ren and Liu is that neither Ren nor Liu teach treating hepatic fibrosis in the subject, wherein the hepatic fibrosis was induced by carbon tetrachloride.
Hinz (Methods in Molecular Biology: Myofibroblasts Methods and Protocols; Published 2021) teaches animal models for hepatic fibrosis. Hinz teaches that each model yields hepatic fibrosis with differing phenotypes. Hinz teaches that induction of hepatic fibrosis via a choline deficient high-fat diet as employed in Ren above more closely resembles human pathophysiology but drawbacks include a considerably slower onset of hepatic fibrosis compared to carbon tetrachloride induced fibrosis and mild histological fibrosis and hepatic stellate cell activation (pages 340, pages 345-347). In addition, Hinz teaches that carbon tetrachloride induced hepatic fibrosis induces rapid and robust liver fibrosis, within weeks compared to months with other induction methods. Hinz teaches that the carbon tetrachloride method has a high ease of use, high robustness and high reproducibility (pages 340-341; Figure 1).
Therefore, one of ordinary skill in the art of treating hepatic fibrosis in a subject in need, knowing that administration of a therapeutically effective amount of gliclazide is efficacious at inhibiting hepatic fibrosis in a patient comprising hepatic fibrosis induced by a choline deficient high-fat diet as taught by Ren and Liu above, said skilled artisan would have readily predicted that substituting the choline deficient high-fat diet animal model to induce hepatic fibrosis for an alternative model, such as carbon tetrachloride in view of Hinz, would have resulted in the reduction of hepatic fibrosis in the afflicted subject.
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, considering Hinz teaches that carbon tetrachloride induced hepatic fibrosis induces rapid and robust liver fibrosis within weeks compared to the slow onset and mild fibrosis observed with the choline deficient high-fat diet induction method of Ren, said artisan would have applied the carbon tetrachloride hepatic fibrosis model to the hepatic fibrosis treating methodology of Ren with a reasonable expectation that the administered therapeutically effective amount of gliclazide would have inhibited hepatic fibrosis within weeks in the carbon-tetrachloride model compared to months in the choline deficient high-fat diet induction model.
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/Primary Examiner, Art Unit 1621
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