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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 22 December 2025 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 22 December 2025.
CLAIMS UNDER EXAMINATION
Claims 8-9 and 21 have been examined on their merits.
PRIORITY
The Applicant claims priority to KR10-2018-0109535 filed on 13 September 2018.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
REJECTIONS
New rejections 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 Gao et al. (previously cited; Thrombotic Role of Blood and Endothelial. Cells in Uremia through Phosphatidylserine exposure and Microparticle Release. PLoS OE 10(11) 16 November 2015) in view of Vanholder et al. (previously cited; Review on uremic toxins: Classification, concentration and interindividual variability (Kidney International, Vol. 63: 1934-1943. 2003).
Gao incubates endothelial cells (EC) in a medium that mimics the in vivo conditions in uremic patients (page 2, fourth paragraph). Gao teaches a preparation of “mixed toxins” comprising urea (1200 µg/ml), creatinine (60 µg/ml), indoxyl sulfate (IS; 25 µg/ml), and uric acid (UA; 80 µg/ml) (see page 5, third paragraph and last paragraph). The art teaches these are median concentrations observed in uremic patients (see page 5, last paragraph).
Claim 8 has been amended to recite “consisting essentially of”. In addition to the toxins recited in claim 8, the Instant specification discloses the uremic toxin mixture can include advanced glycation end products (page 1, line 10). The specification states a “uremic toxin mixture” refers to a uremic mixture containing urea and uric acid, “among various uremic toxins” (see page 7, lines 18-19). The uremic toxin mixture can include AGEs, “and the types of uremic toxin that may be included are not limited thereto” (see page 8, lines 13-15). The specification does not clearly indicate the components that materially affect the basic and novel characteristic of the invention. For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, "consisting essentially of" will be construed as equivalent to "comprising” See MPEP 2111.03. Therefore the mixture of toxins disclosed in Gao read on claim 8.
The molecular weights of the toxins are well known in the art:
Urea = 60 g/mol
Creatinine = 113 g/mol
Uric acid = 168 g/mol
Indoxyl sulfate = 213 g/mol
Therefore the concentrations taught by Gao are:
Urea= (divide 1200 ug/ml by molecular weight of 60 = 20 mmol/L)
Creatinine= (divide 60 ug/ml by molecular weight of 113 =.53 mmol/L)
uric acid =(divide 80 ug/ml by molecular weight of 168 = 0.47 mmol)
indoxyl sulfate (divide 25 ug/ml by molecular weight of 213 = 0.11 mmol)
Gao treats endothelial cells with a uremic toxin mixture comprising urea, creatinine, uric acid and indoxyl sulfate. Gao teaches the median (hence, midpoint) concentration of each toxin found in patients. The deficiency of Gao is that it does not teach the claimed concentrations of components.
Vanholder teaches the choice of the correct concentration of potential uremic toxins for in vitro and ex vivo experiments is a concern (first paragraph page 1934). The art discloses a list of uremic retention solutes, containing their normal (CN), highest mean/median uremic concentration (CU) and the highest concentration ever reported (CMAX) (second paragraph page 1934). The art teaches the data is collected from patients at various stages of dialysis (page 1935, left column, last full paragraph). Vanholder teaches concentrations of retention solutes in uremia vary over a broad range (page 1934, left column, Conclusion paragraph).
Vanholder discloses the following at Table 1 and 2
Urea (g/L): CU 2.3 ± 1.1; CMAX 4.6
Creatinine (mg/L): CU 136.0 ± 46.0; CMAX 240
Uric acid (mg/L): CU 83.4 ± 44.5; CMAX 146.7
Indoxyl sulfate (mg/L): CU 53.0 ± 91.5; CMAX 236
The ranges disclosed by Vanholder encompass the claimed concentrations.
It would have been obvious to optimize the concentrations of the uremic toxins taught by Gao. Gao uses the median uremic concentrations found in patients and Vanholder teaches the concentrations of uremic toxins taught in Gao varies by the disease stage of the patient. The skilled artisan would optimize the uremic concentrations taught by Gao based on the uremic, in vivo conditions being mimicked. One would have had a reasonable expectation of success since Gao teaches uremic concentrations and Vanholder teaches the concentrations of uremic toxins vary. One would have expected similar results since both references are directed to uremic conditions. See MPEP 2133.03 and MPEP 2144.05. 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.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 03 December 2023 are acknowledged.
Argument 1: The arguments state claim 8 has been amended to recite the transitional phrase “consisting essentially of”. The Applicant argues the UT-H composition of the claimed invention exhibits a level of tube formation inhibition similar to that observed with actual patient serum. The Applicant argues the present invention only employs four toxins: urea, creatinine, uric acid and indoxyl sulfate. The argument state additional toxins would materially affect the basic and novel characteristics of the invention recited in claim 8.
Response to Argument 1: Claim 8 has been amended to recite “consisting essentially of”. The specification does not clearly indicate components that materially affect the basic and novel characteristic. In addition to the toxins recited in claim 8, the Applicant’s specification discloses the uremic toxin mixture can include advanced glycation end products (page 1, line 10). The specification states a “uremic toxin mixture” refers to a uremic mixture containing urea and uric acid, “among various uremic toxins (see page 7, lines 18-19). The uremic toxin mixture can include AGEs, “and the types of uremic toxin that may be included are not limited thereto (see page 8, lines 13-15). The specification does not clearly indicate the materials that are excluded
by the recitation of "consisting essentially of”. For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, "consisting essentially of" will be construed as equivalent to "comprising. Therefore the mixture of toxins disclosed in Gao read on claim 8.
Argument 2: The Applicant argues Vanholder does not teach which components to use for in vitro design.
Response to Argument 2:
Vanholder is not relied upon to teach which components are used for in vitro design. Gao teaches an in vitro endothelial cell system. Gao treats endothelial cells with a uremic toxin mixture comprising urea, creatinine, uric acid and indoxyl sulfate. Gao teaches the median patient concentrations is used each toxin. The deficiency of Gao is it does not teach the claimed concentrations. Vanholder is relied upon because it teaches the range of concentrations for urea, creatinine, uric acid and indoxyl sulfate found in uremic patients. The claimed concentrations are obvious for the reasons stated above. The Applicant provides arguments, but no evidence demonstrating criticality of the claimed concentrations. The arguments are not persuasive.
Claims 8-9 and 21 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 Xiao et al. (Uremic levels of urea inhibit l-arginine transport in cultured endothelial cells. Am J Physiol Renal Physiol. 2001 Jun;280(6):F989-95) and Vanholder et al.
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 and indoxyl sulfate. See Figure 3.
Hsu teaches cells are treated with 200 µM Indoxyl sulfate for uremic conditions and different concentrations of uric acid (see text of Figure 3, also see 3C, F, G). Cells are also treated with 0.125, 0.25 and 0.5 mM uric acid (see Figure 3C).
It is of note the art also contacts cells with 50-500 µM Indoxyl sulfate (0.05mM -0.5 mM) (Figure 3B). Hsu teaches a high concentration of uric acid (1 mM) decreased cell viability in the system (see section 2.2 on page 5). The art teaches a lower concentration of uric acid (0.5 mM) does not affect endothelial cell viability (see section 2,2 on page 5).
Hsu also teaches the following:
Nitric oxide (NO) is produced by endothelial cells and is fundamental to cardiovascular homeostasis (page 5, last paragraph). Diminished intrinsic NO production and subsequent endothelial dysfunction is a critical problem in uremic patients (page 9, second paragraph). Indoxyl sulfate causes endothelial dysfunction by reducing nitric oxide production and increasing oxidative stress (page 2, second paragraph). Increased serum UA levels lead to endothelial dysfunction and vascular stiffness because high serum UA initiates oxidative stress and reduces nitric oxide synthesis (page 1, first paragraph of introduction).
Hsu teaches:
an in vitro model to study endothelial dysfunction.
The model comprises endothelial cells contacted with uric acid and indoxyl sulfate.
The deficiencies of Hsu are:
The art does not teach the claimed amount of uric acid.
The art does not teach the amount of indoxyl sulfate as claimed.
The art is silent regarding urea and creatinine in a toxin mixture.
Xiao teaches a lack of nitric oxide in dialysis patients (Abstract). The art teaches end stage renal patients have a deficiency of the nitric oxide synthase substrate L-arginine (F989, left column, first paragraph).
Xiao treats endothelial cells with high (uremic) urea concentration of 50 mM (see page F990, right column, see first full paragraph). L-arginine transport is decreased at these levels (F989, left column, second paragraph). Xiao also teaches creatinine (10 ng/100 ml) also inhibits L-arginine transport when incubated with endothelial cells (F993, right column, second paragraph).
The teachings of Vanholder as set forth above are reiterated.
It would have been obvious to combine the teachings of the prior art by using urea and creatinine in the mixture taught by Hsu. Hsu treats endothelial cells with uremic toxins that reduce nitric oxide are Xiao teaches urea and creatinine are uremic toxins which reduce nitric oxide in endothelial cells. One would have been motivated to use the claimed toxins together since each toxin is taught by the prior art to induce endothelial cell dysfunction by reducing nitric oxide. Applicants are referred to In re Kerkoven. The prior art teaches each of the claimed toxins can be used for the same purpose. Barring unexpected results, one would reasonably expect enhanced activity to be observed by combining the compositions or materials. The combination of toxins reads on the transitional phrase “consisting essentially of” recited in claim 8.
It would have been obvious to use 0.8 mM uric acid. Hsu treats endothelial cells with 0.5-1.0 mM uric acid. The art teaches cell viability is concentration dependent. One would optimize to produce uremic concentration that results in the desired cell viability in vitro. It would have been obvious to optimize the concentrations of creatinine and indoxyl sulfate. Hsu and Xiao teach in vitro endothelial systems for studying uremic toxins. Vanholder teaches concentrations of toxins in uremia vary between uremic patients. The skilled artisan would optimize the concentrations of creatinine and indoxyl sulfate based on the uremic conditions being mimicked. One would have had a reasonable expectation of success since Vanholder teaches the uremic concentrations of creatinine and indoxyl sulfate vary across patients. One would have expected similar results since the references are directed to uremic conditions. See MPEP 2133.03 and MPEP 2144.05. 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.
Regarding claim 21: Hsu treats endothelial cells with uric acid and indoxyl sulfate. Xiao treats endothelial cells with uric acid. Xiao treats endothelial cells with creatinine. It would have been obvious to treat endothelial cells with a mixture consisting of the claimed toxins for the reasons set forth in the rejection of claim 21. This meets the “consists of” language recited in claim 21. Therefore claim 21 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
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) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653