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 .
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/16/2026 has been entered.
DETAILED ACTION
Claims 1-12 are pending in the Claim Set filed 1/16/2026.
Claim 9 has been amended.
Applicants’ elected Group III: claims 9-12, in the reply filed on 11/25/2024 is acknowledged. Applicants elected species: the patient has had TURBT for treatment.
Claims 1-8 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Herein, claims 9, 10 and 12 are for examination.
Withdrawn Rejections
The rejection of claims 9, 10 and 12 under 35 U.S.C. 103 as being unpatentable over Jelmyto (Treatment of adult patients with Low-grade Upper Tract Urothelial Cancer (LG-UTUC), April 2020) in view of Kokorovic et al (UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma, Therapeutic Advances in Medical Oncology p.1 July 2020), Holzer (USP 9,040,074, cited in IDS filed 7/25/2024) and Nargund et al (Seminars in Oncology, p.559, October 2012) and Sharma et al (UROTODAY, pgs.1-5, 2012, September) [Sharma] and Chong et al (Urology Journal, cold-cup biopsy, p,46, 2018, Feb) [Chong] is withdrawn in favor of the New Grounds of Rejection as set forth below.
New Grounds of Rejections
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention
Claims 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Jelmyto (Treatment of adult patients with Low-grade Upper Tract Urothelial Cancer (LG-UTUC), April 2020, of record) [Jelmyto] in view of Holzer (USP 9,040,074, cited in IDS filed 7/25/2024) [Holzer], Kokorovic et al (UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma, Therapeutic Advances in Medical Oncology p.1 July 2020, of record) [Kokorovic], Porta et al (an evaluation of UGN-101, a sustained-release hydrogel polymer-based formulation containing mitomycin-C, for the treatment of upper urothelial carcinomas; EXPERT OPINION ON PHARMACOTHERAPY, p.2199, Sep 2020) [Porta], Porten et al, (Intravesical chemotherapy in non‑muscle‑invasive bladder cancer, Indian Journal of Urology, p.297, Oct. 2015) [Porten], UroGen (UroGen Reports Positive Data from Two Important Studies: UGN-101 OLYMPUS Pivotal Trial in LG UTUC and UGN-102 Phase OPTIMA II Trial in LG Bladder Cancer, p.1, September, 2019) [UroGen] and Chevli et al (Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial, Joyrnal of Urology, p.61, January, 2022) [Chevli] as evidenced by Specification.
Regarding claims 9 and 12,
Jelmyto teaches administering a thermally gelling pharmaceutical composition comprising mitomycin, hydroxypropyl methylcellulose and poloxamer once every six weeks via ureteral catheter or nephrostomy tube for use to treat low-grade Upper Tract Urothelial Carcinoma (LG-UTUC) (i.e., a cancer that affects the inside lining (urothelium) of the kidney and ureter (page 8; 2.2. page 2; p.9; p.13-14). Jelmyto teaches that a complete response (CR) (i.e., complete absence of tumor lesions) was achieved by patients in need thereof at 12 months for about 50% of the patients receiving the Jelmyto formulation. The major efficacy outcome measures were CR and durability of CR at 12 months after determination of CR based on ureteroscopic and local pathology assessment. CR was defined as complete absence of tumor lesions at 3 months after initiation of JELMYTO by urine cytology and ureteroscopy (i.e., reads on at least 15 months post-treatment initiation) (See 14. Clinical Studies, pages 9-10; Table 3). Further, Jelmyto incorporates by reference, compositions comprising mitomycin as disclosed in U.S. Patent Nos. 9,040,074 and 9,950,069 to Holzer (See Jelmyto at page 12). As evidenced by the Specification at paragraph [0043], in some embodiments, the thermally gelling pharmaceutical composition is a gel as set forth in any of U.S. Patent No. 9,040,074 (Patent to Holzer USP 9,040,074 is described below) and U.S. Patent No. 9,950,069.
Firstly, Jelmyto teaches that the thermally gelling pharmaceutical composition comprises mitomycin, hydroxypropyl methylcellulose and poloxamer, however, Jelmyto differs from the claims in that the poloxamer is 407 poloxamer (recited in claim 9).
However, Holzer and Kokorovic, as a whole, cure the deficiency.
Holzer teaches a method for administering a therapeutic agent, e.g., mitomycin, to the internal surface of an internal body cavity, e.g., bladder, comprising administering a hydrophilic biocompatible sustained-release material comprising Pluronic F-127 (poloxamer 407) and HPMC (hydroxypropyl methylcellulose), PEG-400, and water that is injected into an internal body cavity via a tube inserted within a urinary catheter. Holzer teaches the material comprising mitomycin, Pluronic F-127 (poloxamer 407) and HPMC (hydroxypropyl methylcellulose) at body temperature exhibits a much higher viscosity and will stably adhere to the internal surface of a body cavity so that as the material dissolves, the therapeutic agent, mitomycin, is slowly released to the body cavity, while the sustained-release material itself is excreted from the body (Abstract; col.14, lns.24-31; col.14, lns.51-56; col.17, lns.50-67 to col.18, lns.1-10; col.21, lns.9-28 (method for administering a therapeutic agent to the internal surface of an internal body cavity); col.23, lns.4-13; col.23, lns.50-55; col.24, lns.1-35; col.25, lns.46-55; Figs,1-8; col.26, lns.44-49 (internal cavity, e.g., bladder); col.26, lns.58-67 to col.27, lns.17; col.35, line 24: delaying expelling of MMC from the bladder result in dramatic improvement of the drug efficacy)); col.28, line 14; col.30, lns.56-67 (release rate controlled by the gel composition comprising HPMC); col.31, lns.46-67 (poloxamer 407 (PF-127; also Tradename Pluronic F127). Further, Holzer teaches the gel preparation will form a solid artificial barrier and a sustained release depot wherein the hydrogel composition will adhere well to the wall of internal cavity (bladder) to allow the controlled release of the drug, mitomycin, and poloxamer 407 has been reported to be the least toxic of commercially available copolymers (col.32, lns.17-32; col.37, lns.49-67; col.42, lns.14-49); col.32, lns.33-35: col.35, lns.1-10; col.43, lns.1-26, See Examples 1-3, 5, 7, 9, 15 (See Table 6): Pluronic F127, HPMC, MMC (Active agent); claims 1-22; See entire document). Holzer teaches that the system increases bioavailability, reduces toxicity and improves treatment efficacy (col.27, lns.1-2; col.28, lns.57-62; col.29, lns.1-12); col.31, lns.46-67 (poloxamer 407 (PF-127)). Moreover, Holzer teaches poloxamer 407 possesses a gelling temperature which is above 10o C. but below the human body temperature, i.e., 37o C., so that the pharmaceutical composition containing mitomycin is injected or infused in liquid state into a bodily inner cavity (bladder) at a low temperature and, afterwards, as the composition warms, it solidifies into a gel, thus stabilizing upon the wall of the inner body cavity, wherein the prolonged exposure of cancer cells to an anticancer drug, e.g., mitomycin, released from the coating enhances the efficacy of the drug in killing cancer cells and, therefore, reduces the recurrence rate of cancer tumors (col.27, lns.52-61). Particularly, Holzer teaches Holzer following SBC is a highly-recurrent form of cancer. To lower recurrence, it is considered necessary to treat patients with a single intravesical chemotherapy instillation immediately after TUR-T and resection (i.e., TUR) patients receive chemotherapy installation after Tumor resection decreases the relative risk of recurrence treatments (col.5, lns.50-67 to col.6, lns.1-18). Notably, Instant Specification at paragraph [0043], in some embodiments, the thermally gelling pharmaceutical composition is a gel as set forth in U.S. Patent No. 9,950,069 (Patent to Holzer USP 9,040,074). Further, Holzer teaches the gel preparation will form a solid artificial barrier and a sustained release depot wherein the hydrogel composition will adhere well to the wall of internal cavity (bladder) to allow the controlled release of the drug, mitomycin and poloxamer 407, wherein poloxamer has been reported to be the least toxic of commercially available copolymers (col.32, lns.17-32; col.37, lns.49-67; col.42, lns.14-49); col.32, lns.33-35: col.35, lns.1-10; col.43, lns.1-26, See Examples 1-3, 5, 7, 9, 15 (See Table 6): Pluronic F127, HPMC, MMC (Active agent); claims 1-22; See entire document). Moreover, Holzer teaches that the system increases bioavailability, reduces toxicity and improves treatment efficacy (col.27, lns.1-2; col.28, lns.57-62; col.29, lns.1-12); col.31, lns.46-67 (poloxamer 407 (PF-127).
Kokorovic teaches UGN-101 (mitomycin gel) is a treatment for low-grade upper tract urothelial carcinoma (low grade UTUC) (Title). Kokorovic teaches UGN-101 (Jelmyto™ is tradename for UGN-101: described above) has been approved by the US Food and Drug Administration (FDA) as the first treatment for low-risk UTUC. Kokorovic teaches UGN-101 is a temperature sensitive, water-soluble gel preparation of MMC (mitomycin) composed of a unique combination of polymers (as described above Jelmyto: a thermally gelling pharmaceutical composition comprising mitomycin, hydroxypropyl methylcellulose and poloxamer). This hydrogel formulation is liquid at room temperature and converts to a gel at body temperature, thereby conforming to each patient’s distinct pelvicalyceal and ureteric anatomy, wherein dissolution of the formula through continuous urinary bathing results in slow-release, sustained drug delivery (mitomycin). Kokorovic teaches preliminary clinical trial results suggested a durable treatment response for patients with low-risk disease following therapy with UGN-101, of which was subsequently confirmed with longer follow up (p.2, middle left col.). Kokorovic teaches UGN-101 (i.e., Jelmyto) was developed using RTGel as a hydrogel polymer base combined with MMC (mitomycin), wherein the safety and feasibility of this formulation was tested in a preclinical setting using a Yorkshire swine model. Kokorovic teaches UGN-101 dwell time was significantly increased compared with MMC control. There was no evidence of renal insufficiency, obstruction, myelosuppression or significant systemic absorption in both the single and serial administration settings, however, data from intravesical MMC administration in human subjects suggest that hypersensitivity skin reactions may occur and that systemic toxicity is rare. In one study using UGN-101 in the upper tracts, only one patient developed pancytopenia. These pharmacologic results were confirmed in an animal study using retrograde instillation ofUGN-101 at once-weekly intervals for 6 consecutive weeks (p.2, bottom right col. to p.3, top left col.). Kokorovic teaches studies have shown that there is a clear correlation between exposure time and efficacious pharmacologic activity of mitomycin (p.2, top of right col.). Thus, one skilled in the art would have recognized the therapeutic appropriateness of UGN-101 (mitomycin gel) for treating low-grade upper tract urothelial carcinoma (low grade UTUC) in accordance with the teachings of Kokorovic.
Accordingly, it would have prima facie obvious to use poloxamer 407 as the poloxamer in the thermally gelling pharmaceutical composition as taught by Jelmyto (hereinafter ’Modified Jelmyto’). One skilled in the art would have been motivated to do so because a mitomycin gel comprising poloxamer 407 and hydroxypropyl methylcellulose at body temperature exhibits a higher viscosity and will stably adhere to the internal surface of a body cavity so that mitomycin (therapeutic drug) is slowly released to the body cavity to allow the controlled release of mitomycin. Moreover, one of ordinary skill in the art would have recognized the advantage of controlled release of Mitomycin because it has been established that there is a clear correlation between exposure time and efficacious pharmacologic activity of mitomycin, so that ’Modified Jelmyto’ (thermally gelling pharmaceutical composition comprising mitomycin, poloxamer 407 and hydroxypropyl methylcellulose) would be expected to enhance the efficacy of mitomycin in killing cancer cells and, therefore, reduces the recurrence rate of cancer tumors in view of the teachings of Holzer and Kokorovic, as a whole. Particularly, Holzer teaches following resection (i.e., TURBT) patients receive immediate chemotherapy treatments, so that it would have been prima facie obvious to administer the ’Modified Jelmyto’ composition to a patient after treatment of TURBT.
‘Modified Jelmyto’ composition (i.e., as taught by Jelmyto, Holzer and Kokorovic, as a whole) differs from the claims in that the documents do not teach a method of increasing probability of maintaining an achieved complete response for at least 15 months post-treatment initiation comprising the step of administering to a patient in need thereof nonsurgical primary chemoablation with a thermally gelling pharmaceutical composition once weekly for six weeks, wherein the patient has recurrent low-grade intermediate-risk non-muscle-invasive bladder cancer, wherein the patient had a previous episode of low-grade intermediate-risk non-muscle-invasive bladder cancer that was treated with transurethral resection of bladder cancer (TURB T), and wherein the probability is increased in comparison to a probability expected if the patient were instead to receive TURBT monotherapy as treatment, wherein the thermally gelling pharmaceutical composition comprises 75 mg of mitomycin.
However, Porta, Porten, UroGen and Chevli, as a whole, cure the deficiencies.
Porta teaches intravesical treatment of non-muscle-invasive bladder cancer (NMIBC) is another possible application for UGN-101, although the physical characteristics of UGN-101 perfectly fit the specific need of UTUC, a sustained and prolonged contact with the bladder mucosa after TURBT, achievable by means of the use of the RTGel™ technique could potentially improve the results achieved so far with standard intravesical treatments (p.2202). Furthermore, Porta teaches an evaluation of UGN-101, a sustained-release hydrogel polymer-based formulation containing mitomycin-C, for the treatment of upper urothelial carcinomas (Title; See entire document).
Thus, Porta suggests UGN-101 may be suitable for intravesical treatment of non-muscle-invasive bladder cancer (NMIBC) after a patient has had a previous episode of NIMIBC that was treated with TURBT.
Porten teaches intravesical chemotherapy has a critical role in the treatment paradigm of non-muscle-invasive bladder cancer (NMIBC). Porten teaches evidence supports the use of intravesical chemotherapy within 24 hours after TURBT using mitomycin (favorable toward MMC), of which is based on available data and expert opinion wherein intravesical chemotherapy is targeted for specific patients with intermediate‑risk disease (consisting of recurrent low‑grade) is an appropriate first‑line adjuvant therapy. (p.301, See Conclusions). Accordingly, Porten teaches intravesical chemotherapy within 24 hours after TURBT using mitomycin for the treatment of recurrent low‑grade intermediate‑risk non-muscle-invasive bladder cancer (LG IR NMIBC).
UroGen teaches UGN-101 (mitomycin gel) for instillation is an investigational drug formulation of mitomycin in Phase 3 development for the treatment of low-grade upper tract urothelial cancer (LG UTUC). Utilizing the RTGel™ technology platform, wherein the sustained release, hydrogel-based formulation, UGN-101 is designed to enable longer exposure of urinary tract tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-101 is delivered to patients using standard ureteral catheters (third para. up from bottom). Further, UroGen teaches UGN-102 (mitomycin gel) for instillation is an investigational drug formulation of mitomycin for the treatment of low-grade non-muscle invasive bladder cancer (LG NMIBC), wherein utilizing the RTGel™ technology platform, the sustained release, hydrogel-based formulation, UGN-102, is designed to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using standard intravesical catheters (last para. up from bottom). As evidenced by the Specification at paragraph [0043], in some embodiments, the thermally gelling pharmaceutical composition is UGN-102. Accordingly, one skilled in the art would have recognized that both UGN-101 and UGN -102 are similarly provided utilizing a RTGel™ technology platform, to provide sustained release, hydrogel-based formulations, wherein they are designed to enable longer exposure of urinary tract tissue to mitomycin and enable longer exposure of bladder tissue to mitomycin, respectively, according to UroGen.
One skilled in the art would have been motivated to provide intravesical chemotherapy comprising administering to a patient ‘Mitomycin Gel’ provided (e.g. UGN-102) after having a previous episode of low‑grade non-muscle-invasive bladder cancer (LG IR NMIBC) that was treated with TURBT, wherein the Mitomycin Gel composition is designed to enable longer exposure of bladder tissue to mitomycin and the Mitomycin Gel’ is used in method for treating of LG IR NMIBC having a reasonable expectation of success in view of the teachings of Porta, Porten and UroGen, as a whole.
Chevli teaches Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial (Title). Chevli teaches the standard of care for treatment of low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is transurethral resection of bladder tumor (TURBT), typically performed under general anesthesia. As LG IR NMIBC is a highly recurrent malignancy, patients often endure repeated surgeries that may be associated with significant postoperative and long-term morbidity. Chevli teaches to evaluate the efficacy and safety of a nonsurgical alternative for the treatment of LG IR NMIBC offered by UGN-102- a mitomycin-containing reverse thermal gel. Chevli teaches Primary chemoablation using UGN-102 (patients received 6 once-weekly intravesical instillations) resulted in complete eradication of disease in a substantial number of patients (65%) 3 months after treatment initiation, with sustained durability up to 12 months (estimated probability of durable response 12 months after treatment initiation was 73%) (i.e., reads CR for at least 15 months). Chevli teaches treatment with UGN-102 may provide an alternative to repetitive TURBT surgery for patients with LG IR NMIBC ((p.61 JU Insight; p.64).
Chevli teaches UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC (Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer) (See p.62, The Journal of Urology). Chevli teaches a total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received >1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis (p.63, See Results). Chevli teaches Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC (p.63, See Conclusions). Chevli teaches UGN-102 is an agent designed for primary nonsurgical treatment of LG IR NMIBC, and to potentially obviate the need for repetitive TURBTs. UGN-102 consists of mitomycin and a reverse thermal hydrogel. Chevli teaches the reverse thermal properties of UGN-102 allow for local administration of mitomycin as a liquid in a cooled state, with subsequent conversion to a semi-solid gel depot at body temperature following instillation. The gel slowly disintegrates and is excreted by normal urine flow, allowing for sustained release of mitomycin over a period of 4 to 6 hours. The prolonged exposure of tumor cells to mitomycin is expected to improve chemoablation compared with aqueous preparations of the drug (p.63, lower left col. to top right col.). Chevli teaches that patients received 6 once-weekly intravesical instillations of UGN-102 (75 mg mitomycin in 56 ml admixture with reverse thermal hydrogel to equal 1.33 mg/mL (p.65). Chevli teaches patients with CR at 3 months of which CR was further provided at 12 months (Results, p.65; See Fig 1). Chevli teaches a total of 49 patients (78%) had recurrent LG NMIBC and 28 (44%) had a previous episode within 1 year of the current diagnosis. Patients with recurrence underwent prior TURBTs. (p.65, left col. to top right col.). The probability of durable response 9 months after CR (12 months after treatment initiation) estimated by the Kaplan-Meier method was 72.5% (p.65, See Fig. 2 on p.66-67). Chevli teaches due to the recurrent nature of the disease patients with LG IR NMIBC often undergo repeated TURBT, a surgical procedure with well-defined risks that include failure to cure, bleeding requiring unplanned hospital admission and bladder perforation. In addition, repetitive TURBT is independently associated with an increased mortality risk. Finally, the repeated use of general anesthesia in the elderly may predispose to cognitive decline (p.67, left col.). Chevli teaches UGN-102 is a formulation of mitomycin comprising a mixture of polymers designed to prolong dwell and contact time of mitomycin with the surface of the bladder cavity, potentially leading to improved chemoablation compared with aqueous preparations of mitomycin (p.67, right col.). Chevli teaches nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 results in a clinically significant treatment response with demonstrated durability. UGN-102 may provide an alternative to repetitive TURBT surgery for patients with LG IR NMIBC (p.67, Conclusions).
Thus, one skilled in the art would have recognized the benefit of using a Mitomycin Gel (e.g., URN-102) to provide a method for treating LG IR NMIBC, wherein a patient received 6 once-weekly intravesical instillations of a therapeutic effective amount of 75 mitomycin., wherein there is complete eradication of disease in 3 months after treatment initiation with sustained durability up to 12 months (CR for at least 15 months) in view of Chevli.
It would have been prima facie to provide a method of maintaining an achieved complete response (CR) for at least 15 months post-treatment initiation comprising the step of administering to a patient in need thereof nonsurgical primary chemoablation with ‘Modified Jelmyto’ comprising a thermally gelling pharmaceutical composition comprising 75 mg mitomycin, hydroxypropyl methylcellulose and poloxamer 407, once weekly for six weeks, wherein the patient has recurrent low-grade intermediate-risk non-muscle-invasive bladder cancer (LG IR NMIBC), wherein the patient had a previous episode of low-grade intermediate-risk nonmuscle-invasive bladder cancer that was previously treated with transurethral resection of bladder cancer (TURB T) having a reasonable expectation of success in view of the teachings of Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen and Chevli, as a whole.
Furthermore, there is no unobvious distinction between the structural and functional characteristics of the claimed composition and the ‘Mitomycin Gel’ composition of the prior art; thus, it would necessarily follow that ‘Mitomycin Gel’ of the cited prior art would provide a method of increasing probability of maintaining an achieved complete response (CR) for at least 15 months post-treatment initiation, wherein the probability is increased in comparison to a probability expected if the patient were instead to receive TURBT monotherapy as treatment. This property would be the natural result of the combination of the prior art elements. Inherency is appropriate in an obviousness analysis "when the limitation at issue is the 'natural result' of the combination of prior art elements." PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (quoting In re Oelrich, 666 F.2d 578,581 (CCPA 1981)). Lack of recognition of the inherency by those skilled in the art is thus not dispositive.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to provide instantly claimed invention and one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the claimed invention as a whole would have been obvious to one of ordinary skill as evidenced by Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen and Chevli, as a whole.
Claim 10 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Jelmyto (Treatment of adult patients with Low-grade Upper Tract Urothelial Cancer (LG-UTUC), April 2020, of record) [Jelmyto] in view of Holzer (USP 9,040,074, cited in IDS filed 7/25/2024) [Holzer], Kokorovic et al (UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma, Therapeutic Advances in Medical Oncology p.1 July 2020, of record) [Kokorovic], Porta et al (an evaluation of UGN-101, a sustained-release hydrogel polymer-based formulation containing mitomycin-C, for the treatment of upper urothelial carcinomas; EXPERT OPINION ON PHARMACOTHERAPY, p.2199, Sep 2020) [Porta], Porten et al, (Intravesical chemotherapy in non‑muscle‑invasive bladder cancer, Indian Journal of Urology, p.297, Oct. 2015) [Porten], UroGen (UroGen Reports Positive Data from Two Important Studies: UGN-101 OLYMPUS Pivotal Trial in LG UTUC and UGN-102 Phase OPTIMA II Trial in LG Bladder Cancer, p.1, September, 2019) [UroGen] and Chevli et al (Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial, Joyrnal of Urology, p.61, January, 2022) [Chevli] as evidenced by Specification as applied to claims 9 and 12 above and further in view of Chong et al (Urology Journal, cold-cup biopsy, p,46, 2018, Feb) [Chong].
The teachings of Jelmyto, Kokorovic, Porta, Chevli and Holzer, as a whole, are described above.
Jelmyto, Kokorovic, Porta, Chevli and Holzer fail to teach that the recurrent low-grade intermediate-risk non-muscle-invasive bladder cancer is diagnosed using cold cup biopsy.
However, Chong cures the deficiency.
Chong teaches using cold-cup biopsy is necessary at the end of transurethral resection of bladder tumors. Chong teaches that cold cup biopsy of the base of the tumor is a routinely practiced step at the end of tumor resection. Thus, it would have been obvious to use a well-established method of analyzing bladder diseases using cold-cup biopsy to diagnose of recurrent low grade non-muscle invasive bladder cancer in view of the teachings of Chong having a reasonable expectation of success (See entire document).
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to provide instantly claimed invention and one of ordinary skill would have had a reasonable expectation of success in producing the claimed invention. Therefore, in the absence of evidence to the contrary, the claimed invention as a whole would have been obvious to one of ordinary skill as evidenced by Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen, Chevli and Chong, as a whole.
Response to Arguments
Applicants argue that they take issue with the Examiner's allegation that "one of ordinary skill in the art before the effective filing date of the claimed invention would have recognized the problematic issues with using TURBT either as an initial treatment or a second treatment to treat patients comprising low-grade intermediate-risk non-muscle invasive bladder cancer (LG NMIBC), wherein one skilled in the art would have looked at Jelmyto, Kokorovic, Holzer and Nargund, as an alternative means of treating LG NMIBC in an attempt to avoid the adverse effects associated with using TURBT as taught by Sharma and would have instead used the thermally gelling composition comprising mitomycin, hydroxypropyl methylcellulose and poloxamer alone as taught by the cited prior art wherein the composition is administered as nonsurgical primary chemoablation, i.e., by itself with TURBT, to a patient in need thereof while having a reasonable expectation of success. Applicants argue that such an allegation is based on impermissible hindsight from knowledge of the invention itself rather than having a basis in the cited prior art. Using an Applicant's disclosure as a blueprint to reconstruct the claimed invention from isolated pieces of the prior art contravenes the statutory mandate of §103 which requires judging obviousness at the point in time when the invention was made
Applicants’ arguments directed to Nargund and Sharma are moot, because the teachings of Nargund and Sharma are not used in the above New Grounds of Rejection.
Regarding allegations of hindsight, Applicant argues that the examiner's conclusion of obviousness is based on improper hindsight picking and choosing in the references. However, any judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from appellant's disclosure, such a reconstruction is proper." In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). All the claimed elements are known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art. The examiner would like to point out that the cited prior art teachings of Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen, Chevli and Chong was available to those skilled in the art before the effective filing date of the claimed invention.
Applicants argue that nothing in any of the cited prior art in any way teaches the administration of an MMC-containing composition as nonsurgical primary chemoablation alone without TURBT for the treatment of recurrent LG NMIBC. To the contrary, the cited prior art consistently teaches the necessity of TURB T for the treatment of recurrent NMIBC. For example, Holzer teaches SBC is a highly-recurrent form of cancer. To lower recurrence, it is considered necessary to treat patients with a single intravesical chemotherapy instillation immediately after TUR-T'. Likewise, the Examiner notes that "Nargund teaches vesical cytotoxic chemotherapy as a single immediate installation after TURBT and also as 6-12 weekly prophylactic courses for intermediate-risk tumors, wherein intravesical instillation is usually done within 6-24 hours of TURBT'. Nargund at 565. Lastly, Chong notes that TURBT is now the accepted modality for treating most forms of superficial bladder tumors.
Applicants’ arguments directed to Nargund and Chong are moot, because the teachings of Nargund and Chong are not used in the above New Grounds of Rejection.
Applicant’s arguments have been fully considered but they are not persuasive, because the administration of an MMC-containing composition as nonsurgical primary chemoablation alone without TURBT for the treatment of recurrent LG NMIBC would have been prima facie obvious in view of administering the composition as taught by Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen, and Chevli, as a whole. For instance, Porten teaches the use of intravesical chemotherapy within 24 hours after TURBT using mitomycin (favorable toward MMC), of which is based on available data and expert opinion wherein intravesical chemotherapy is targeted for specific patients with intermediate‑risk disease (consisting of recurrent low‑grade) is an appropriate first‑line adjuvant therapy. (p.301, See Conclusions). Accordingly, the teachings of Porten makes prima facie obvious providing intravesical chemotherapy within 24 hours after TURBT using mitomycin for the treatment of recurrent low‑grade intermediate‑risk non-muscle-invasive bladder cancer (LG IR NMIBC). Furthermore, Holzer teaches following SBC is a highly-recurrent form of cancer. To lower recurrence, it is considered necessary to treat patients with a single intravesical chemotherapy instillation immediately after TUR-T, wherein resection (TUR) patients receive chemotherapy installation after Tumor resection decreases the relative risk of recurrence treatments (col.5, lns.57-67 to col.6, lns.1-18). Along these lines, Chevli teaches UGN-102 is an agent designed for primary nonsurgical treatment of LG IR NMIBC, wherein UGN-102 is an agent designed for primary nonsurgical treatment of LG IR NMIBC and to potentially obviate the need for repetitive TURBTs.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981
Applicant is reminded that obviousness does not require absolute predictability, In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976).
Applicants argue as to reasonable expectation of success, the Examiner notes that "Holzer teaches to lower recurrence SBC (NMIBC) it is necessary to treat patients with a single intravesical chemotherapy (e.g., mitomycin) instillation immediately after Tumor resection, of which decreases the relative risk of recurrence. Thus, it would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention that the risk is reduced in comparison to a risk expected if the patient were instead to receive TURBT monotherapy as treatment." Applicant argue that this is not the proper comparison by which to judge reasonable expectation of success. The Examiner is comparing risk of recurrence with MMC instillation "immediately after [TURBT]" with TURBT alone. Applicants argue the proper inquiry here should be TURBT monotherapy versus the nonsurgical primary chemoablation monotherapy according to the presently claimed method. For that inquiry, there is nothing in the prior art that could provide a reasonable expectation of success, as there is no teaching or suggestion of nonsurgical primary chemoablation without concomitant TURBT at all. Further, Applicants argue that the Examiner also relies on the "improved treatment efficacy" of Jelmyto. However, the improved treatment efficacy noted in Holzer is in relation to the administration of solutions of MMC in the context of the treatment of low-grade upper tract urinary cancer of the renal pelvis where TURBT is not even applicable.
Applicant’s arguments have been fully considered but they are not persuasive, because it would prima facie obvious that the administration of the composition as taught by Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen, and Chevli, as a whole, would be effective at treating LG-IR-NMIBC alone, i.e., by itself. Since TURBT is the standard treatment of LG-IR-NMIBC, of which has many limitations, as discussed above, one skilled in the art would recognize the benefit of subsequent treatment of LG-IR-NMIBC with Modified Jelmyto composition that provides CR for at least 15 months having a reasonable expectation of success. For instance, Chevli explicitly teaches UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic method to treat patients with LG IR NMIBC (Low-Grade Intermediate-Risk Non-muscle-Invasive Bladder Cancer) (See p.62, The Journal of Urology). Moreover, there is no unobvious distinction between the structural and functional characteristics of the claimed composition and the ‘Modified Jelmyto’ composition of the prior art; thus, it would necessarily follow that this composition would provide a method of increasing probability of maintaining an achieved complete response (CR) for at least 15 months post-treatment initiation, wherein the probability is increased in comparison to a probability expected if the patient were instead to receive TURBT monotherapy as treatment. This property would be the natural result of the combination of the prior art elements. Inherency is appropriate in an obviousness analysis "when the limitation at issue is the 'natural result' of the combination of prior art elements." PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (quoting In re Oelrich, 666 F.2d 578,581 (CCPA 1981)). Lack of recognition of the inherency by those skilled in the art is thus not dispositive
Applicants argue, in the Declaration of Sunil Raju Under 37 CFR 1.132 ("the Declaration") submitted previously, Applicant's sponsored ATLAS and ENVISION clinical studies provided the first indication that primary chemoablation with UGN-102 according to the claimed methods could provide a superior treatment method as compared to TURBT surgery, especially in the more difficult-to-treat recurrent patient population. Declaration at Paragraph 12. Applicants argue, thus, one of ordinary skill in the art at the time of the invention could not have reasonably expected that primary chemoablation in patients with recurrent LG-IR-NMIBC using the recited thermally gelling pharmaceutical composition would increase the probability of maintaining an achieved complete response for at least 15 months post-treatment initiation in comparison to a probability expected if the patient were instead to receive TURBT monotherapy as treatment. Without such a reasonable expectation of success, there would have been no motivation for a person of ordinary skill in the art to practice the claimed methods, as that would risk disease progression. Therefore, one of ordinary skill in the art would not have been motivated to provide such a specific treatment as presently claimed to the specifically claimed patient, let alone with the requisite intent.
Applicant’s arguments have been fully considered but they are not persuasive, because one of ordinary skill in the art would have expected that the Modified Jelmyto composition would be very effective at treating LG-IR-NMIBC alone. Most remarkedly, Chevli explicitly teaches UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic method to treat patients with LG IR NMIBC (Low-Grade Intermediate-Risk Non-muscle-Invasive Bladder Cancer. Moreover, Chevli teaches nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 results in a clinically significant treatment response with demonstrated durability. UGN-102 may provide an alternative to repetitive TURBT surgery for patients with LG IR NMIBC (p.67, Conclusions). The examiner would like to point out that the cited prior art teachings of Jelmyto, Holzer, Kokorovic Porta, Porten, UroGen, Chevli and Chong was available to those skilled in the art before the effective filing date of the claimed invention.
Applicants argue that nothing would have motivated a person of skill in the art to modify a key component (i.e., industry standard treatment with TURBT first prior to chemotherapy as taught by at least Holzer, Nargund, and Chong in the treatment methods of the cited art as would be required, among other modifications, to arrive at the present invention. In fact, if a proposed modification would render the prior art being modified unsatisfactory for its intended purpose, then there is no suggestion or motivation to make the proposed modification. ("A proposed modification is inappropriate for an obviousness inquiry when the modification renders the prior art reference inoperable for its intended purpose."). In re Ratti, 270 F .2d 810, 813 (CCP A 1959) (holding the suggested combination of references improper under § 103 because it "would require a substantial reconstruction and redesign of the elements shown in [a prior art reference] as well as a change in the basic principles under which [that reference's] construction was designed to operate"). As discussed above, the cited art is clear that TURBT is required for the treatment of recurrent LG-IR-NMIBC according to the industry standard.
Applicant’s arguments are moot regarding Nargund because the new grounds of rejection do not rely on the teachings of Nargund for any teaching or matter specifically challenged in the argument.
Furthermore, Applicant’s arguments have been fully considered but they are not persuasive, because the New Grounds of Rejection are directed to the modification of the teachings of Jelmyto in view of the teachings of Kokorovic, Porta, Chevli and Holzer, wherein one skilled in the art would have recognize the benefit of the providing an improved composition comprising 75 mg mitomycin, Pluronic F-127 (poloxamer 407) and HPMC (hydroxypropyl methylcellulose) that would be expected to provide a much higher viscosity a at body temperature exhibits that would stably adhere to the internal surface of a body cavity so that as the material dissolves, the therapeutic agent, e.g., mitomycin, that is slowly released to the body cavity, while the sustained-release material itself is excreted from the body as disclosed by Holzer. Whereas, the teachings of Chong are directed to using cold-cup biopsy, such that cold cup biopsy of the base of the tumor is a routinely practiced step at the end of tumor resection.
Applicants argue that the Examiner also states that "the composition as taught by Jelmyto and Holzer, as a whole, is indistinguishable from the claimed composition ... Accordingly, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to provide the thermally gelling composition in a method of treating recurrent low-grade intermediate-risk non-muscle invasive bladder cancer, where there is no unobvious distinction between the structural and functional characteristics of the claimed composition used in the method and the composition of the prior art, so that it would necessarily follow that when the thermally gelling composition is used in a method of treating recurrent LG NMIBC it would increase the probability of maintaining an achieved complete response for at least 15 months post-treatment. This property or properties would be the natural result of the combination of the prior art elements. Inherency is appropriate in an obviousness analysis 'when the limitation at issue is the 'natural result' of the combination of prior art elements. Applicants argue that the present claims are not directed to compositions, but rather to a method of treating using a specific therapy for specific patients for a particular purpose provided for by the preamble, as the claims recite that the treatment be administered "to a patient in need thereof. Although a new use of a known composition does not render the composition itself patentable, a nonobvious new use of that composition may be patentable when claimed as a method of use or treatment, particularly where the prior art did not teach or suggest the claimed use or provide a reasonable expectation of success. Here, the cited prior art fails to disclose or suggest the claimed methods; none of the cited prior art discloses or suggests "a method of increasing probability of maintaining an achieved complete response for at least 15 months post-treatment initiation" by administering the claimed composition to a patient with recurrent LG NMIBC without concomitant use of TURBT. Applicants argue, thus, contrary to the Examiner's assertion, all of the claimed elements were not known in the prior art and, therefore, an inherency analysis here is inappropriate.
Applicant’s arguments have been fully considered but they are not persuasive, because Chevli teaches Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial (Title). Chevli teaches the standard of care for treatment of low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is transurethral resection of bladder tumor (TURBT), typically performed under general anesthesia. As LG IR NMIBC is a highly recurrent malignancy, patients often endure repeated surgeries that may be associated with significant postoperative and long-term morbidity. Chevli teaches to evaluate the efficacy and safety of a nonsurgical alternative for the treatment of LG IR NMIBC offered by UGN-102- a mitomycin-containing reverse thermal gel - which can be administered on an outpatient basis in an office setting. Chevli teaches Primary chemoablation using UGN-102 resulted in complete eradication of disease in a substantial number of patients (65%) 3 months after treatment initiation, with sustained durability up to 12 months (estimated probability of durable response 12 months after treatment initiation was 73%), i.e., CR at least 15 months.
Applicants argue that Applicant maintains that the previously advanced arguments regarding unexpected results as discussed in the Declaration of Sunil Raju Under 37 CFR 1.132 are commensurate in scope with the instant claims. As discussed in that declaration, in UroGen's sponsored ATLAS study, starting on Day 1, patients randomized to the UGN-102 arm received UGN-102 (75 mg mitomycin) once weekly via intravesical instillation for 6 weeks, and patients randomized to the TURBT arm underwent TURBT. All patients returned to the clinic approximately 3 months after the start of treatment for a disease assessment visit. Patients confirmed to have a complete response received no further treatment and entered the Follow-up Period of the study. Declaration at paragraphs 7-9. The clinical endpoints for determining efficacy included durable complete response (DCR) rate at scheduled disease assessment time points (e.g., 12 months after determination of a complete response at the 3 month visit or, said another way, 15 months post-treatment initiation). The claims have been amended herein to clarify that "post-treatment" refers to post-treatment initiation as opposed completion of the six week treatment or determination of complete response.
Applicant’s arguments have been fully considered but they are not persuasive, because instant claim 9 fails to recite that mitomycin is provided at 75 mg. Moreover, Instant Claim 9 further fails to set limitations on the percent by weight of the poloxamer contained in the thermal gelling composition and the percent by weight of the amount of hydroxypropylmethylcellulose (HMPC) or the molecular weight range of HMPC thereof.
MPEP 716.02(d) Unexpected Results Commensurate in Scope with Claimed Invention [R-08.2012]
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Thus, in the instant case, the unexpected results are not commensurate in scope with what is instantly claimed, because the scope of Instant Claim 9 encompasses a thermal gelling pharmaceutical composition that is broadly claimed. That is, the method of increasing the probability of maintaining an achieved complete response (CR) that generated said alleged unexpected results are not commensurate in scope with the method of increasing the probability of maintaining an achieved complete response (CR) which is presently claimed.
MPEP 716.02(d) II. DEMONSTRATING CRITICALITY OF A CLAIMED RANGE
To 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). Applicants have not presented results demonstrating that the unexpected results lie inside the entire scope of the claimed invention compared to results that fall outside the claimed range.
Applicants bear the burden to establish that the results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). See MPEP 716.02(b).
Conclusions
No claim is allowed.
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/T.W./ Examiner, Art Unit 1619
/SARAH ALAWADI/ Primary Examiner, Art Unit 1619