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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 22nd, 2025 has been entered.
Response to Arguments
Applicant's arguments filed November 22nd, 2025 have been fully considered but they are not persuasive.
Regarding claim 1 Applicant argues that Farha’s disclosure of low uptake (~15%) for MOF-808 (a BTC-based zirconium MOF) would have discouraged the use of BTC linkers and therefore rendered the claimed ≥60 wt.% binding non-obvious. However, Farha does not attribute low uptake solely to the BTC linker. Rather, Farha indicates that the limited adsorption may be due to insufficient π-conjugation and/or lack of hydroxyl functionality. The disclosure does not criticize, discredit, or otherwise discourage BTC linkers per se. Instead, it identifies multiple structural factors that may influence adsorption performance. Such language does not rise to the level of a teaching away. Further, MOF-808 (Zr-based) is structurally and chemically distinct from MIL-100(Fe) (Fe-based). Differences in metal center chemistry are well known to influence adsorption behavior. Accordingly, Farha’s data regarding MOF-808 would not have discouraged a person of ordinary skill from evaluating iron-based BTC MOFs.
Applicant argues that the claimed invention would not have been obvious based on the prior art and that Yang is directed only to the adsorption capacity of creatinine on MIL-100(Fe). However, Yang (RSC Av. 2014) expressly teaches MIL-100(Fe) as a sorbent for removal of a uremic toxin under physiological conditions, demonstrating rapid kinetics and high adsorption capacity at 37°C. Yang further analyzes pore size compatibility and Lewis acid-base coordination between Fe sites and the toxin. Thus, Yang teaches that MIL-100(Fe) is suitable for artificial kidney/dialysis contexts and effectively adsorbs uremic toxins and adsorption occurs via predictable pore size and coordination interactions. In view of this teaching, a person of ordinary skill would have had reason to expect that MIL-100(Fe) could similarly adsorb other uremic toxins, including p-cresyl sulfate. The fact that creatinine and p-cresyl sulfate different structurally does not negate the reasonable expectation of adsorption behavior in a porous Fe-MOF system designed for uremic-toxin removal. Further Liu (ACS Appl. Mater. Interfaces 2021, 13, 9643−9655) establishes that iron-based MOFs exhibit lower cytotoxicity and favorable biocompatibility compared to other metal centers. In biomedical and dialysis applications, biocompatibility is a primary design consideration.
Regarding claim 11 Applicant argues that Farha uses Langmuir/Freundlich isotherm models and does not disclose multivariate linear regression. However, the rejection does not rely on Farha alone for this limitation. Rao (RJC Vol. 9 | No. 2 |254 - 277 | April - June | 2016) teaches regression analysis for evaluating adsorption systems and correlating adsorption capacity with system variables. Applying multivariate regression to adsorption data (mass, concentration, volume) constitutes the use of a known statistical tool to analyze known adsorption parameters. The substitution of one known modeling technique (regression analysis) for another (isotherm fitting) in order to analyze adsorption performance would have been an obvious analytical choice for a person of ordinary skill. No evidence of unexpected results attributable to the regression technique itself has been presented.
For at least the reasons stated above the rejections of the claims have been maintained.
Claims 1-2, 4-5, 7 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Farha (WO-2020086496-Al) in further view of Liu ("Iron-Based Metal-organic Frameworks in Drug Delivery") and Yang ("Metal–organic framework MIL-100(Fe) for artificial kidney application"). The combination of these with be referred to hereafter as "modified Farha".
Regarding claim 1, Farha discloses a method removing uremic toxins from blood, the method comprising: exposing blood to metal-organic frameworks (Farha claim 1); allowing the metal-organic frameworks to bind at least one uremic toxin in the blood (Farha, "uremic toxins are adsorbed by the metal-organic framework" claim 1); and separating the metal-organic frameworks from the blood after the metal-organic frameworks binds to the at least one uremic toxin (Farha par. [0033]), wherein after allowing the metal-organic frameworks to bind the at least one uremic toxin, at least 60 wt.% of p-cresyl sulfate is present in a bound state (Farha par. [0041] teaches adsorption of uremic toxins by MOFs and quantifies adsorption performance).
Farha does not disclose that the metal-organic frameworks are iron-based frameworks having benzenetricarboxylate (BTC) linkers.
Yang discloses a method for removing uremic toxins from blood, the method comprising: exposing blood to iron-based metal-organic frameworks having benzenetricarboxylate (BTC) linkers (Yang p. 40824 left col. par. 1 “MIL-100(Fe)” which is an iron-based metal-organic framework having benzenetricarboxylate (BTC) linkers); allowing the iron-based metal-organic frameworks to bind at least one uremic toxin (Yang p. 40824 left col. par. 1 “creatinine”) in the blood (Yang p. 40824 rt. col. par. 5).
Liu discloses the use of iron-based metal-organic frameworks in biomedicine detailing a review of historical uses of various metal-based metal-organic frameworks (MOFs) used for delivery in human blood. According to Liu "many groups have synthesized thousands of MOFs and deposited them in the Cambridge Structural Database. Among all the metals used in MOFs, Fe is the least toxic. This metal, widely distributed in nature and the fourth most abundant in the earth's crust, is an essential trace element for humans, who contain about 4 g."(Liu p. 9643 left column 1st par.) Additionally, Liu references a study which investigated the cytotoxicity of MOFs containing Fe, Zn or Zr and "MOFs containing Fe, Zn, or Zr as central metals against a human cervical carcinoma cell line (Hela) and a murine macrophage cell line (J774).12 Fe-MOFs were less cytotoxic than Zn-MOFs and Zr-MOFs"(Liu p. 9645 left col. section "4" second paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to employ an iron-based benzene-1,3,5-tricarboxylate (BTC) metal-organic framework, such as MIL-100(Fe), in the uremic toxin adsorption system of Farha for removal of p-cresyl sulfate, because Farha teaches MOF adsorption of uremic toxins in dialysis contexts, Liu teaches that iron-based MOFs exhibit improved biocompatibility and reduced cytotoxicity relative to other metal centers for biomedical applications, and Yang teaches that MIL-100(Fe), a BTC-linked Fe-MOF, is suitable for artificial kidney applications and demonstrates high adsorption capacity and rapid adsorption kinetics for uremic toxins under physiological conditions. In view of these teachings, a person of ordinary skill in the art would have been motivated to substitute an iron-based BTC MOF for other MOFs disclosed in Farha in order to improve biocompatibility while maintaining toxin adsorption functionality, with a reasonable expectation of success given Yang’s demonstration that MIL-100(Fe) effectively binds uremic toxins through predictable pore-size compatibility and Lewis acid-base coordination interactions. Furthermore, the degree of toxin binding (expressed as wt.%) constitutes a result-effective variable dependent upon known adsorption parameters such as concentration, mass loading, contact time, and temperature, such that achieving at least 60 wt.% binding would have involved routine optimization within the ordinary skill in the art absent any evidence of criticality or unexpected results.
Regarding claim 2, Farha discloses the method of claim 1, wherein after allowing the metal-organic frameworks to bind the at least one uremic toxin, at least 70 wt.% of p- cresyl sulfate is present in a bound state (Farha par. [0041] teaches adsorption of uremic toxins by MOFs and quantifies adsorption performance, furthermore, the degree of toxin binding (expressed as wt.%) constitutes a result-effective variable dependent upon known adsorption parameters such as concentration, mass loading, contact time, and temperature, such that achieving at least 70 wt.% binding would have involved routine optimization within the ordinary skill in the art absent any evidence of criticality or unexpected results).
Regarding claim 4, modified Farha discloses the method of claim 1, wherein the iron-based metal-organic frameworks include Iron 1,3,5-benzenetricarboxylate (MIL-100(Fe)) (Yang p. 40824 left col. par. 1).
Regarding claim 5, modified Farha discloses the method of claim 1, wherein the iron-based metal-organic frameworks are Iron 1,3,5-benzenetricarboxylate (MIL-100(Fe)) (Yang p. 40824 left col. par. 1).
Regarding claim 7, modified Farha discloses the method of claim 1, wherein the blood is exposed to about 700 milligrams (mg) to about 800 mg of the iron-based metal-organic frameworks.
While modified Farha does not disclose this mass range for every case, the adsorption capacity of the adsorbent was calculated (par. [0061]) using absorption isotherms so an understanding of the volume of solution and mass of the adsorbent was available. The point of saturation and reduction in efficiency was also known as was the predicted removal fraction (Farha par. [0049]) for a given amount of human serum albumin (HSA). As the optimum range was found to be 20mg per 50mg HSA, 700 mg would be added to blood containing 1750mg HSA. It would have been obvious to one of ordinary skill in the art and a matter of routine optimization to provide the mass needed fora given amount of human serum albumin to remove an acceptable portion of uremic toxins from the target solution.
Regarding claim 9, modified Farha discloses the method of claim 1, wherein the uremic toxin includes p-cresyl sulfate (Farha par. [0036]).
Regarding claim 10, modified Farha discloses the method of claim 1, wherein the method is performed until the p-cresyl sulfate concentration of the blood is equal to or less than 10 uM. (Farha [0049] 20μg p-cresyl sulfate in 1ml solution with a 93% reduction in p-cresyl sulfate after performing the method which would relate to a final concentration of 7.44μM).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Farha (WO- 2020086496-Al) in view of Rao ("Experimental Investigation on Adsorption of Lead From Aqueous Solution Using Activated Carbon From the waste Rubber Tire: Optimization of Process Parameters Using Central Composite Design").
Regarding claim 11, Farha discloses a method for predicting adsorptive capacity of a metal-organic framework for a uremic toxin, the method comprising: measuring uptake of the uremic toxin by the metal-organic framework (Farha par. [0061] “by using an Agilent HPLC 1100”) while varying the concentration of the uremic toxin in the solution and holding constant the mass of the metal-organic frameworks and the volume of the solution to determine uptake of the uremic toxin by the metal- organic framework as a function of the concentration of the uremic toxin in the solution (Farha Eq. 6 par. [0061]).
Farha does not disclose the method comprising: measuring uptake of the uremic toxin by the metal-organic framework while varying mass of metal-organic frameworks and holding constant a concentration of the uremic toxin in a solution and a volume of the solution to determine uptake of the uremic toxin by the metal-organic framework as a function of the mass of the metal-organic frameworks; measuring uptake of the uremic toxin by the metal-organic framework while varying the solution volume and holding constant the mass of the metal- organic frameworks and the concentration of the uremic toxin of the solution to determine uptake of the uremic toxin by the metal- organic framework as a function of the solution volume; while performing multivariate linear regression to produce an uptake function as an effect of the solution volume, uremic toxin content and metal-organic framework mass; and predicting the adsorptive capacity of the metal-organic framework using the uptake function produced from the multivariate linear regression.
Rao teaches the use of multivariate statistical modeling techniques, including linear regression analysis, to evaluate and optimize adsorption systems by correlating adsorption performance with multiple independent variables such as adsorbent mass, solute concentration, and solution volume (Rao-p. 258 and Fig. 2-6). Rao explains that regression modeling enables quantitative assessment of how these variables collectively influence adsorption capacity and system efficiency, thereby permitting optimization of adsorption processes. In particular Rao demonstrates that adsorption data collected across varying operational parameters can be subjected to multivariate linear regression to generate models that describe system behavior and guide optimization of adsorbent performance. Thus, Rao teaches the analytical step of applying multivariate linear regression to adsorption datasets involving mass, concentration, and volume parameters.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multivariate linear regression techniques taught by Rao to the MOF-based adsorption system of Farha, because Farha teaches measuring adsorption performance of uremic toxins as a function of system variables, and Rao teaches that multivariate regression is a known statistical tool for analyzing and optimizing adsorption systems based on variables such as adsorbent mass, solute concentration, and solution volume. A person of ordinary skill in the art seeking to quantitatively model and optimize MOF adsorption performance would have been motivated to employ Rao’s regression techniques to analyze collected adsorption data in order to predict system behavior and improve removal efficiency.
Claims 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Farha (WO-2020086496-Al) in further view of Liu ("Iron-Based Metal-organic Frameworks in Drug Delivery") and Yang ("Metal–organic framework MIL-100(Fe) for artificial kidney application"). The combination of these with be referred to hereafter as "modified Farha" as applied to claim 1 above.
Regarding claim 12, modified Farha discloses the method of claim 1 further comprising: prior to exposing the blood to the iron-based metal-organic frameworks, removing the blood from a patient (Farha par. [0026] “hemodialysis of blood samples taken from patients”); and after separating the blood from the iron-based metal-organic frameworks, returning the blood to the patient (Farha par. [0026] hemodialysis is a process by which blood is treated extra-corporeally and then after treatment the blood is returned to the body).
Regarding claim 13, modified Farha discloses the method of claim 12, wherein exposing the blood to the iron-based metal- organic frameworks includes exposing the blood to the iron-based metal-organic frameworks within a machine external to the patient (Farha par. [0026] hemodialysis is a process that uses an extracorporeal apparatus (cited from Wiktionary.org)).
Regarding claim 14, modified Farha discloses the method of claim 13, wherein the machine external to the patient includes a dialysis machine (Farha par. [0026] “hemodialysis”).
Regarding claim 15, modified Farha discloses the method of claim 12, wherein exposing the blood to the iron-based metal- organic frameworks includes contacting the blood and the iron-based metal-organic frameworks for at least ten seconds and less than 30 minutes (Farha par. [0037]).
Regarding claim 16, modified Farha discloses the method of claim 1, and further comprising: removing the blood from a patient (Farha par. [0026] “hemodialysis of blood samples taken from patients”) prior to exposing the blood to the iron-based metal-organic frameworks; and returning the blood to the patient after separating the blood from the iron-based metal-organic frameworks (Farha par. [0026] hemodialysis is a process by which blood is treated extra-corporeally and then after treatment the blood is returned to the body), wherein exposing the blood to the iron-based metal-organic frameworks consists of exposing the blood to the iron-based metal-organic frameworks within a dialysis machine (Farha par. [0026] “hemodialysis”); and wherein the iron-based metal-organic frameworks are Iron 1,3,5- benzenetricarboxylate (MIL-100(Fe)) (Yang p. 40824 left col. par. 1 “MIL-100(Fe)”) and the uremic toxin includes p- cresyl sulfate (Farha par. [0041]).
Conclusion
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/W.A.G./Examiner, Art Unit 1779
/Bobby Ramdhanie/Supervisory Patent Examiner, Art Unit 1779