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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 21 July 2026.
CLAIMS UNDER EXAMINATION
Claims 8-9 have been examined on their merits.
PRIORITY
The Applicant claims priority to KR10-2018-0109535 filed on 13 September 2018.
WITHDRAWN REJECTIONS
Claim 8 has been amended to recite a uremic toxin consisting of urea, creatinine, uric acid and indoxyl sulfate which increases reactive oxygen species production, promotes apoptosis and inhibits tube formation. The previous rejections have been withdrawn due to claim amendment.
REJECTIONS
New grounds of rejection have been necessitated by claim amendment.
Claim Rejections - 35 USC § 103
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 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu et al. (previously cited; High Uric Acid Ameliorates Indoxyl Sulfate-Induced Endothelial Dysfunction and Is Associated with Lower Mortality among Hemodialysis Patients. Toxins 2017, 9(1), 20: 1-113) in view of O’Loughlin et al. (Systems and methods related to degradation of uremic toxin. US20050123529A1), Xiao et al. (previously cited; Uremic levels of urea inhibit l-arginine transport in cultured endothelial cells. Am J Physiol Renal Physiol. 2001 Jun;280(6):F989-95), Lee et al. (Lack of modulatory effect of simvastatin on indoxyl sulfate-induced activation of cultured endothelial cells, Life Sciences, Volume 90, Issues 1–2, 2012, Pages 47-53) and Marchenko et al. (Creatinine Deiminase Adsorption onto Silicalite-Modified pH-FET for Creation of New Creatinine-Sensitive Biosensor. Nanoscale Res Lett 11, 173 (2016).
Hsu teaches an in vitro system to study the effect of toxins in a uremic environment (see page 5, first paragraph section 202). The system comprises endothelial cell. Cells are contacted with a mixture containing uric acid (0.125, 0.25 and 0.5 mM) and indoxyl sulfate (200 µM; see Figures 3C and 3F) for “uremic conditions” (See Figure 3, text).
The following is also taught:
Hsu teaches “a high concentration of uric acid (1 mM) or IS (500 µM)” decreased cell viability in the system, while a “low concentration” (0.5 mM uric acid and 200 µM) does not (see section 2.2 on page 5).
Hsu teaches uremic toxins in patients with end-stage renal disease induce oxidative stress (text of Figure 5). Indoxyl sulfate increases oxidative stress (page 2, second paragraph). Increased serum UA levels initiates oxidative stress (page 1, first paragraph of introduction).
The deficiencies of Hsu are:
The art does not teach the claimed amount of uric acid and indoxyl sulfate.
The art does not teach adding urea and creatinine to the toxin mixture.
O’Loughlin et al. teach a uremic test solution containing metabolites at levels comparable to those found in the blood of ESRD patients was prepared. The solution included urea, uric acid, and creatinine (Table 1). O’Loughlin teaches urea, uric acid and creatinine are commonly used as markers to monitor kidney dialysis and other similar treatments (See [0003]).
Xiao analyzes the effect of uremic conditions on endothelial cells. Xiao treats endothelial cells with “uremic” media containing 50 mM urea (F990, right column, first paragraph). Xiao teaches urea is a uremic marker ((F990, left column, last paragraph).
Lee teaches endothelial dysfunction is a common manifestation of chronic kidney disease (CKD). Human umbilical endothelial cells (HUVEC) were incubated using 1000 μM indoxyl sulfate (Abstract). 1000 μM is 1 mM (1000 μM divided by 1000). Lee teaches this concentration produces a two to three fold increase in inflammatory markers including ICAM-1, VCAM-1 and MCP-1 (see Figure 1).
Marchenko et al. teach patients with renal failure have a creatinine concentration which is about 1000 μM (see page 5, left column, first sentence of section titled “Optimization of Biosensor for Blood Serum Analysis”). 1000 μM is 1 mM (1000 μM divided by 1000) .
It would have been obvious to combine the teachings of Hsu and O’Loughlin by
using urea and creatinine in uremic toxin mixture. Hsu treats endothelial cells with indoxyl sulfate and uric acid to study the effect of toxins in a uremic environment. Hsu teaches uremic toxins in patients with end-stage renal disease leads to endothelial dysfunction. O’Loughlin teaches a uremic mixture comprising urea, uric acid and creatinine to represent end-stage renal disease. One would have been motivated to combine all four toxins to simulate a uremic environment in end stage renal disease. Applicants are referred to In re Kerkoven . This meets the “consists of” language recited in 8. One would have had a reasonable expectation of success since O’Loughlin teaches urea and creatinine are also present in uremic ESRD patients. One would have expected similar results since Hsu and O’Loughlin are both directed to uremic mixtures present in end stage renal disease.
It would have been obvious to use the claimed amounts of each toxin. Hsu treats endothelial cells with 1.0 mM uric acid. The art teaches cell viability is concentration dependent. One would optimize the amount of uric acid in Hsu to simulate uremic conditions with the desired cell viability. One would have had a reasonable expectation of success since Hsu teaches endothelial cells can be treated with different concentrations of uric acid in the disclosed system.
It would have been obvious to combine teachings of Hsu and Xiao by using 50 mM urea in a uremic toxin mixture. One would have been motivated to do so since Xiao teaches it is a uremic concentration. One would have had a reasonable expectation of success since Xiao teaches 50 mM urea can be used to treat endothelial cells. One would have expected similar results since Hsu and Xiao both teach in vitro systems with uremic conditions.
It would have been obvious to combine the teachings of the prior art by using 1mM creatinine. O’Loughlin teaches a uremic toxin mixture comprising creatine. One would have been motivated to use 1 mM since Marchenko et al. teach 1000 μM creatinine is the concentration present in patients with renal failure. It would have been obvious to use 1 mM indoxyl sulfate. One would have been motivated to do so since Lee teaches uses this concentration to simulate uremic toxin exposure in endothelial cells. One would have had a reasonable expectation of success since Lee teaches endothelial cells can be treated with this concentration of indoxyl sulfate. The skilled artisan would use toxin concentrations which are known to simulate uremic conditions. Because the mixture consisting of the claimed toxins is rendered obvious, it would be expected to induce endothelial dysfunction as recited in claim 8. Therefore claim 8 is rendered obvious.
Claim 9 recites the endothelial cells are “derived from induced pluripotent stem cells”. This is a product by process limitation that does not distinguish the claimed endothelial cells from those taught by the art. MPEP 2113 indicates that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. Therefore claim 9 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
37 CFR 1.132 Declaration
The examiner acknowledges receipt of the Declaration under 37 CFR 1.132 by Hye Ryoun Jang filed on 21 July 2026. The Declaration is insufficient to overcome the rejection of claims 8-9 based upon obviousness over Hsu et al. in view of O’Loughlin et al., Xiao et al, Lee et al. and Marchenko et al. as set forth in the rejections above because:
The Declaration states only treatment with UT-H (media supplemented with the claimed amounts of urea, uric acid, creatinine and indoxyl sulfate) and uric acid alone (0.8 mM) produce a significant increase in apoptosis at 4 hours (Exhibit 1).
In response: The Declaration also discloses UT-H, UT-I (the same media, without any uric acid) and urea alone also demonstrate significant apoptosis at 24 hours (Exhibit 2). Therefore the effect noted by the Declarant is time dependent. Claim 8 does not recite any limitations requiring 4 hours. The effect argued by the Applicant is not commensurate with the scope of the claims. It is also noted the data does not indicate criticality of the claimed toxin amounts.
Exhibit 3 analyzes reactive oxygen species over three days in 1) control, 2) a base mixture without uric acid, 3) base mixture+0.25 uric acid, 4) base mixture+ 0.5 mM, 5) base mixture + 0.8mM uric acid and 6) base mixture+ 1.0 mM uric acid. The Declaration discloses ROS levels are significantly elevated in the 0.8 mM and 1.0 mM uric acid groups (see section 12 of page 3). By day 3, the 1.0 mM group showed significantly higher ROS levels relative to lower concentrations. Therefore the concentration of uric acid does not appear to be critical.
The Declaration states Exhibits 4 demonstrates reduced tube formation, “including in the uric acid free group” (see section 14 on page 3 of Declaration). Therefore the Declaration discloses uric acid is not required for reduced tube formation. The tube formation parameters disclosed in Exhibit 5 and 6 do not appear to disclose a significant difference between 0.8 and 1.0 mM uric acid.
Affidavits or declarations are provided as evidence and must set forth facts, not merely conclusions. In re Pike and Morris, 84 USPQ 235 (CCPA 1949).
Upon consideration of the facts taught by the prior art and the information submitted by the Affiant, the balance of evidence indicates that the prior art teaches the instantly claimed inventions.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 21 July 2026 are acknowledged.
Argument: Claim 8 requires a mixture that induces endothelial dysfunction characterized by increased reactive oxygen species production, promoted apoptosis, and inhibition of tube formation. The Applicant argues Hsu teaches co-incubation of indoxyl sulfate (IS) with uric acid "partially reversed" indoxyl-sulfate- induced reductions in nitric oxide production and in the activated forms of Akt and eNOS
Response: Figures 3D-F of Hsu analyze oxidative stress of endothelial cells following incubation with uric acid and indoxyl sulfate (IS). Figure 3F demonstrates co-treatment of IS with UA reduces oxidative stress relative to IS alone. Examiner notes oxidative stress is still increased in IS+ uric acid treated cells relative to control cells. Therefore treatment with uric acid and indoxyl sulfate results in increased oxidative stress in endothelial cells relative to control. The argument is not persuasive.
Argument: The Applicant argues Hsu does not teach the claimed concentrations of
uric acid (0.8 mM) and indoxyl sulfate (1mM). The Applicant argues the specification demonstrates a sharp, concentration-dependent transition in the effect of uric acid within the claimed mixture: no effect on reactive oxygen species production or tube formation below 0.55 mM, and excessive/non-physiological damage above 1 mM, “with the claimed 0.8-1 mM range disclosed as the effective window” (Specification, p. 7-8; Examples 2-1 through 2-3, p. 18-21; Figures 5-9).
Response: The arguments refer to the “claimed 0.8-1 mM range” as the “effective window”. Claim 8 does not recite a range for uric acid. As set forth above, Hsu teaches a high concentration of uric acid (1 mM) decreases cell viability in the system. Therefore Hsu teaches a uric acid concentration identified by the Applicant as effective. The deficiency is Hsu does not use 0.8 mM uric acid as recited in claim 8.
Hsu treats endothelial cells with 1.0 mM uric acid. The art teaches this concentration decreases 24 hour cell viability. Hsu teaches a low concentration (0.5 mM) does not.
One would optimize the concentration to simulate uremic conditions with the desired cell viability.
Regarding the claimed concentration of indoxyl sulfate: Lee treats endothelial cells with 1000 μM (1 mM) indoxyl sulfate. One would use this concentration since Lee teaches it can be used to simulate uremic toxin exposure in endothelial cells.
The rejection is not solely based on the toxins taught in Hsu. The rejection is based on the combined teachings of the prior art. Hsu teaches a toxin mixture comprising uric acid and indoxyl sulfate. O’Loughlin teaches a uremic test solution containing urea, uric acid, and creatinine. The claimed concentrations are rendered obvious. Therefore the mixture would be expected to increase ROS production, promote apoptosis and inhibit tube formation absent evidence to the contrary.
Argument: The filed Declaration reports apoptosis at 4 hours was significantly
increased only in 1) the UT-H group and 2) a uric-acid-alone control, and not in a three-component mixture lacking uric acid (Declaration I 8, Exhibit 1).
Response: The Declaration also discloses at 24 hours, the mixture lacking uric acid has significantly elevated apoptosis. Claim 8 does not recite any limitations requiring 4 hours. Therefore the effect argued by the Applicant is not commensurate with the scope of the claims.
Argument: The filed Declaration reports a concentration-dependent increase in reactive oxygen species production and impairment of tube formation as uric acid
concentration is increased within the claimed mixture (Exhibits 3-5).
Response: Exhibit 3 indicates treatment with both 0.8 mM and 1.0mM uric acid significantly increases ROS production. Therefore the Exhibit does not demonstrate criticality of the claimed amount of uric acid (0.8 mM). Examiner reiterates Hsu teaches 1 mM uric acid decreases 24 hour cell viability. Hsu teaches a low concentration (0.5 mM) does not. One would optimize to produce uremic conditions that result in the desired cell viability in vitro. Exhibit 4 indicates 0.8 mM and 1.0 mM uric acid reduce tube formation. The Exhibit does not indicate a significant difference between 0.8 mM and 1.0 mM treatment.
CONCLUSION
No Claims Are 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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