DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/28/2026 has been entered.
Response to Amendment
The amendments received 01/28/2026 have been entered. Claims 1, 48-58, 60-66, and 68-70 are pending. Any objection or rejection as set forth in the Office Action mailed 07/28/2025 not maintained herein has been overcome and is withdrawn.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 49-54 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 49 and 53 depend on claim 2. However, claim 2 has been cancelled. Claims 49 and 53, and dependent claims 50-52 and 54, therefore lack antecedent basis. Correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 48-58, 60-66, and 68-70 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a method of treating urothelial carcinoma comprising administering erdafitinib or a pharmaceutically acceptable salt thereof to a patient, followed by co-administering a P-glycoprotein (P-gp) substrate, wherein the erdafitinib is administered at least 6 hours before or after the P-gp substrate.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claims indicates that these claims are drawn to a generic genus, i.e., generic formula for compounds.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. Per MPEP 2163(II)(3)(a)(ii), “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021).”
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 48 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (48 USPQe2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
The instantly claimed P-gp substrate encompasses a potentially indefinite number of possible compounds, as Applicant has failed to describe any representative species of P-gp substrates, nor has Applicant provided an adequate description of the physical or chemical properties of a P-gp substrate such that one of ordinary skill in the art could envisage the species which are intended by “P-gp substrate”. Therefore, each of these potential species of P-gp substrate could vary greatly in their mechanism, structure, or function, yet all of these properties are unclear. Moreover, Applicant provides no specific examples wherein erdafitinib has been combined with any particular P-gp substrate, as such one of ordinary skill in the art could not possibly discern what the combination of erdafitinib administered 6 hours before or after a P-gp substrate is intended to accomplish or what unexpected effect is intended to arise.
Generally, the lack of exemplified guidance establishes a reasonable level of doubt that would suggest that the Applicant was not in possession of the various species claimed and thus has not met the written description requirement. Although Applicants describe the compounds of Formula I generally and describe the exemplified embodied substituents, Applicant’s disclosure is silent regarding a number of functionality modifications to the claimed invention thus introducing uncertainty. Applicant does not provide a description that reasonably overcomes the factual understanding that is indicative of the state of the art and that shows that the given possible species, or any related synthon have yet to be established. One of skill in the art would find these factors important in considering the practical application of generating the proposed instantly claimed species. Thus, the claimed P-gp substrates are neither within Applicant's possession nor reasonably supported by Applicant’s disclosure. While Applicant recites this broad genus, Applicant provides no evidence of record that any of the species of this genus are in possession.
In the absence of sufficient guidance, the specification does not provide adequate written description of the claimed genus of P-gp substrate, which is a generic genus of compounds. One of ordinary skill in the art would not recognize from the disclosure that the Applicant was in possession of the genus. The specification does not clearly allow persons of ordinary skill in the art to recognize that they have invented what is claimed (see Vas-Cath at page 1116).
Claims 1, 48-58, 60-66, and 68-70 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ameliorating or alleviating urothelial carcinoma, does not reasonably provide enablement for curing or preventing urothelial carcinoma. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01 (a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level.
The nature of the invention claims a method of treating urothelial carcinoma, a form of cancer. The specification defines “treat” and “treatment” as “treatment of a patient inflicted with a pathological condition… and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included.”
Cancer, in the current state of the art, is considered incurable and non-preventable There is virtually no predictability in the art regarding curing or preventing cancer, despite the high level of skill in the art.
The state of the art, with regards to cancer, is that cancer prevention remains nearly impossible through the use of medicaments. Risk factors and causative agents of cancer are highly variable, such as genetic and environmental factors (Meyskens et al.; p. 2, col. 1) of which the present invention cannot mitigate. Additionally, lifestyle-oriented preventive measures can be cancer-specific, and it is impossible to predict which individuals will develop a certain form of cancer (Meyskens et al.; p. 2, col. 2). Current methods of prevention do not include use of medicaments, and instead focus on lifestyle changes and surgical intervention (Meyskens et al.; p. 2, col. 1). As such, there is little evidence in the current state of the art that the instant invention can be administered as a preventative means for cancer. Moreover, regarding curing cancer, even when cancer is undetectable or in remission, when or if the cancer will relapse is entirely unpredictable.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] …anti-cancer treatment." In re Application of Hozumi et al., 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
It is maintained by the examiner that applicant has not enabled the instant claims in view of the current state of the art, as the applicant fails in the specification to demonstrate the ability of the claimed invention to prevent or cure urothelial carcinoma. Furthermore, said disease has no reasonable expectation to be curable or preventable.
The breadth of the claims
The claims are very broad insofar as the instant claims recite a method of treating urothelial carcinoma comprising administering erdafitinib and a generic P-gp substrate. The specification defines “treat” and “treatment” as “treatment of a patient inflicted with a pathological condition… and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included.”
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for preventing or curing urothelial carcinoma. Notably, the only working examples set forth in the instant specification describe treating (ameliorating or alleviating) urothelial carcinoma comprising administering erdafitinib, but describes no examples wherein the erdafitinib is administered with a P-gp substrate.
The quantity of experimentation necessary
Due to the known unpredictability in the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instant invention would be capable of curing or preventing urothelial carcinoma, and the amount of experimentation required would most certainly be undue.
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claim(s) 1, 48, 60-62, 65-66, and 68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Soria et al. (Annals of Oncology; IDS filed 11/09/2021) as evidenced by NCT01703481 (ClinicalTrials.gov; 2012; earliest version), further in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), and Mahato et al. (CRC Press; 2018).
Soria et al. discloses the treatment of advanced urothelial carcinoma in patients with FGFR mutations, comprising administering to the patients erdafitinib at a dose of 9 mg continuously or 10 mg intermittently (Methods). Soria et al. teaches that this study was part of a first-in-human phase 1 study, NCT01703481. As evidenced by the earliest version of NCT01703481, erdafitinib was administered orally as a liquid (p. 12).
Soria et al. does not teach that the erdafitinib is co-administered with a P-glycoprotein (P-gp) substrate and that the administration of erdafitinib is separated by at least 6 hours before or after administration of the P-gp substrate. However, these limitations are obvious over Chang et al., Xiao-peng et al., Nishina et al., and Yacyshyn et al.
Chang et al. teaches that early use of rapamycin reduces tumor grade and occurrence in rat models of urothelial carcinoma (Abstract).
Xiao-peng et al. teaches that rapamycin reduced tumor recurrence in patients treated with post-renal transplantation and intravesical instillation chemotherapy (Abstract).
Yacyshyn et al. teaches that rapamycin is a P-gp substrate (Abstract).
Nishina et al. teaches a study evaluating the pharmacokinetics and pharmacodynamics of erdafitinib. Nishina et al. teaches that erdafitinib reaches peak plasma concentrations at median tmax of 2 to 3 hours after a single dose and 2 to 6 hours after multiple doses (p. 427-428 bridging paragraph).
Leucuta et al. teaches that P-gp is a major transporter protein that plays an important role in systemic disposition of hormones, drugs, and xenobiotics (p. 10). Leucuta et al. additionally teaches that drug-drug interactions can occur at the sites of transporters and affect plasma concentration-time profiles (p. 9).
Zimmerman et al. teaches that rapamycin (sirolimus) is known to have various drug interactions, such as CYP3A and P-gp substrates (p. 8). Zimmerman et al. teaches the co-administration of rapamycin with cyclosporine wherein the rapamycin is administered 4 hours after cyclosporine or 2 hours before or after cyclosporine to reduce blood rapamycin exposure (p. 8).
Mahato et al. teaches that tablet dosage forms are preferred due to patient convenience and acceptance (p. 479).
It would have been prima facie obvious for one of ordinary skill in the art to combine erdafitinib with rapamycin, wherein the erdafitinib is administered 6 hours before or after the erdafitinib. One would have been motivated to combine the two agents, with reasonable expectation of success, as rapamycin has been shown to be effective in treating urothelial carcinoma. One would have been motivated to arrive at administering the erdafitinib 6 hours before or after rapamycin via routine optimization, wherein one of ordinary skill in the art would be apprised of potential drug interactions that may occur and affect plasma concentrations of the agents, wherein erdafitinib reaches a tmax at up to 6 hours. Thus, it would be reasonable for one to avoid administering the two drugs within 6 hours of each other and would be particularly advantageous for a P-gp inhibitor with a narrow therapeutic index to avoid potential toxicity. Moreover, it would have been prima facie obvious to administer erdafitinib in a solid tablet form, rather than a liquid, due to its preference by patients.
Claim(s) 1, 48-51, 52-58, 60-64, and 68-70 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
Tabernero et al. teaches a method of treating urothelial carcinoma in patients with advanced solid tumors comprising administering to patients escalating continuous doses from 0.5 to 12 mg daily or intermittent doses of 10 or 12 mg JNJ-42756493 (erdafitinib, see instant specification page 12). Tabanero et al. further discloses that the patients wherein standard treatment was ineffective and had been previously treated with chemotherapy, including adjuvant chemotherapy (Table 1). Tabanero et al. additionally discloses that the patients have FGFR2 and FGFR3 mutations, as determined by blood sample assays (p. 3402) and particular patients had the mutation FGFR3-TACC3, FGFR2-BICC1 and FGFR2-CASP7 (p. 3406). Tabernero et al. additionally teaches that administration of 9 mg daily typically resulted in serum phosphate levels increasing to more than the safety threshold of 7 mg/dL within 1 to 3 weeks of the first dose (p. 3404). Tabernero et al. also teaches that the intermittent 7 days on/7 days off schedule at 10 mg/day resulted in more favorable serum phosphate levels, decreasing to less than 5.5 mg/dL with no grade 3 drug related toxicity (p. 3405).
Tabernero et al. does not teach that the erdafitinib is co-administered with a P-glycoprotein (P-gp) substrate and that the administration of erdafitinib is separated by at least 6 hours before or after administration of the P-gp substrate. However, these limitations are obvious over Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, and Leucuta et al.
Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, and Leucuta et al. teach as above.
Knowles teaches that FGFR3 mutations common in urothelial carcinomas include R248C and S249C (p. 582).
Sridhar teaches that common immunotherapy treatments for urothelial carcinoma include anti PD-1 and PD-L1 checkpoint inhibitors (p. 312).
It would have been prima facie obvious for one of ordinary skill in the art to arrive at a dose of erdafitinib increased from 8 mg to 9 mg at 14 to 21 days after initiating treatment, if the serum phosphate level is less than or equal to about 5.5 mg/dL or 9 mg/dL and no grade 2 or greater adverse reaction has occurred. Based on the teachings of Tabernero, one would have been apprised that lowering the starting dose of continuous erdafitinib (from 9 mg) would be advantageous in order to reduce serum phosphate levels and drug-related toxicities and to evaluate patient tolerance before increasing the dose. One would have been motivated to arrive at 5.5 mg/dL or 9 mg/dL at 14 to 21 days via routine optimization, and would have had reasonable expectation of success, as Tabernero et al. teaches that a serum phosphate level of 5.5 mg/dL with no drug-related toxicity above grade 3 is particularly favorable when evaluating for the safety of erdafitinib, when compared to serum phosphate levels over 7 mg/dL reached within 1 to 3 weeks of initial dosing.
It would have been prima facie obvious to administer the erdafitinib to a patient with a FGFR3 mutation at R248C or S249C. One would have been motivated to do so, with reasonable expectation of success, as Tabernero et al. teaches administering erdafitinib to patients with FGFR3 mutations, of which R248C or S249C are found in patients with urothelial carcinomas.
It would have been prima facie obvious for one of ordinary skill in the art to administer erdafitinib to a patient that had previously been treated with immunotherapy such as anti PD-1/PD-L1. One would have been motivated to do so, with reasonable expectation of success, as anti PD-1/PD-L1 treatment is a common immunotherapeutic treatment for urothelial carcinoma.
For the same reasons as in the above 103 rejection, it would have been prima facie obvious for one of ordinary skill in the art to combine erdafitinib with rapamycin, wherein the erdafitinib is administered 6 hours before or after the erdafitinib.
Claim(s) 1, 48, 55-58, 60-64, and 68-70 is/are rejected under 35 U.S.C. 103 as being unpatentable over Siefker-Radtke et al. (Journal of Clinical Oncology; 2018) in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021), Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), and Leucuta et al. (Current Clinical Pharmacology; 2006).
Siefker-Radtke et al. teaches a method of treating metastatic urothelial carcinoma with FGFR alterations in patients who experienced progression after at least one line of neoadjuvant chemotherapy and optionally immunotherapy, comprising administering to the patients 8 mg/day continuous JNJ-42756493 (erdafitinib, see instant specification page 12) with uptitration to 9 mg/day if target serum phosphate level was not reached and no significant treatment-related adverse events occurred.
Siefker-Radtke et al. does not teach that the patient exhibits a serum phosphate level less than or equal to about 5.5 mg/dL or 9 mg/dL at 14-21 days after initiating treatment. Siefker-Radtke et al. does not teach that the erdafitinib is co-administered with a P-glycoprotein (P-gp) substrate and that the administration of erdafitinib is separated by at least 6 hours before or after administration of the P-gp substrate. However, these limitations are obvious over Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, and Leucuta et al.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, and Leucuta et al. teach as above.
It would have been prima facie obvious for one of ordinary skill in the art to increase the dose of erdafitinib from 8 mg to 9 mg at 14 to 21 days after initiating treatment, if the serum phosphate level is less than or equal to about 5.5 mg/dL or 9 mg/dL and no grade 2 or greater adverse reaction has occurred. One would have been motivated to arrive at 5.5 mg/dL or 9 mg/dL at 14 to 21 days via routine optimization, and would have had reasonable expectation of success, as Tabernero et al. teaches that a serum phosphate level of 5.5 mg/dL with no drug-related toxicity above grade 3 is particularly favorable when evaluating for the safety of erdafitinib, when compared to serum phosphate levels over 7 mg/dL reached within 1 to 3 weeks of initial dosing.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to combine erdafitinib with rapamycin, wherein the erdafitinib is administered 6 hours before or after the erdafitinib.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 48-58, 60-64, and 68-70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 13-14 of U.S. Patent No. 11,077,106 B2 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
The claims of the ‘106 patent are directed to a method of treating urothelial carcinoma, comprising administering to a patient 8 mg/day of erdafitinib, and increasing the dose to 9 mg/day if certain thresholds in serum phosphate levels are reached.
The claims are not directed toward additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
Claims 1, 48-58, 60-64, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 20, and 26-30 of copending Application No. 17/360,618 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
The claims of the ‘618 application are directed to a method of treating urothelial carcinoma, comprising administering to a patient 8 mg/day of erdafitinib, and increasing the dose to 9 mg/day if certain thresholds in serum phosphate levels are reached.
The claims are not directed toward additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 48-58, 60-64, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19 and 37 of copending Application No. 17/430,025 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
The claims of the ‘025 application are directed to a method of treating urothelial carcinoma, comprising administering to a patient 8 mg/day of erdafitinib, and increasing the dose to 9 mg/day if certain thresholds in serum phosphate levels are reached.
The claims are not directed toward additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 48-58, 60-66, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 17-24 of copending Application No. 17/904,139 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
The claims of the ‘139 application are directed to a method of treating urothelial carcinoma, comprising administering to a patient 8 mg/day of erdafitinib, and increasing the dose to 9 mg/day if certain thresholds in serum phosphate levels are reached.
The claims are not directed toward additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 48-58, 60-64, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 14-26 of copending Application No. 17/904,129 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
The claims of the ‘129 application are directed to a method of treating urothelial carcinoma, comprising administering to a patient 8 mg/day of erdafitinib, and increasing the dose to 9 mg/day if certain thresholds in serum phosphate levels are reached.
The claims are not directed toward additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 48-58, 60-64, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-9, 11, 13, and 31-33 of copending Application No. 18/044,232 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
The claims of the ‘232 application are directed to a method of treating urothelial carcinoma, comprising administering to a patient 8 mg/day of erdafitinib, and increasing the dose to 9 mg/day if certain thresholds in serum phosphate levels are reached.
The claims are not directed toward additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 48-58, 60-64, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/561,347 in view of Tabernero et al. (Journal of Clinical Oncology; IDS filed 11/09/2021) in view of Chang et al. (Transplantation Proceedings; IDS filed 11/09/2021), Xiao-peng et al. (Chinese Medical Journal; IDS filed 11/09/2021), Nishina et al. (Invest New Drugs; 2017), Yacyshyn et al. (Scand. J. Immunol.; 1996), Zimmerman (The AAPS Journal; 2004), Leucuta et al. (Current Clinical Pharmacology; 2006), Knowles (World J Urol; 2007), and Sridhar (Journal of Oncology Practice; 2017).
Claim 1 of the ‘347 application is directed toward a method of treating cancer comprising administering erdafitinib, wherein the cancer exhibits particular FGFR fusions.
The claims are not directed toward treating urothelial carcinoma or additionally administering a P-gp substrate, wherein the erdafitinib is administered 6 hours before or after the P-gp substrate.
Tabernero et al., Chang et al., Xiao-peng et al., Nishina et al., Yacyshyn et al., Zimmerman, Leucuta et al., Knowles, and Sridhar teach as above.
For the same reasons as in the above 103 rejections, it would have been prima facie obvious for one of ordinary skill in the art to arrive at the invention of the instant claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 01/28/2026 have been fully considered but they are not persuasive.
35 U.S.C. 112(a)
Regarding the rejection of claims 1, 48-58, and 60-72 (now 60-66 and 68-72) under 35 U.S.C. 112(a) written description, Applicant argues that one of ordinary skill in the art would understand the scope of “P-gp substrate” in view of the art. Applicant additionally cites a list of P-gp substrates found on the FDA website and through Drugbank. This is not persuasive.
The scope of the instant invention is incredibly broad, wherein “erdafitinib base or the pharmaceutically acceptable salt thereof is co-administered with a P-glycoprotein (P-gp) substrate and administration of erdafitinib… is separate by at least 6 hours before or after… the P-gp substrate.” Applicant provides no guidance as to what P-gp substrates are contemplated or a definition of what applicant considers a P-gp substrate. Moreover, no examples wherein erdafitinib is administered with a P-gp substrate can be found. Instead, support for the invention relies on purely generic statements, such as on page 75, “If co-administration of erdafitinib with P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic index.” The scope of “P-gp substrate” encompasses species that may have existed in the art at the time of filing but their properties were not known, and additionally encompasses compounds yet to be discovered. Furthermore, the instant specification is completely devoid of any species of P-gp substrate that would demonstrate possession of the instant invention. Has any testing been done before the time of filing to demonstrate that Applicant was in possession of the full scope of the claims at the time of filing? Does the scope of the claims pertain to all P-gp substrates, or only P-gp substrates with a narrow therapeutic index? What constitutes as a narrow therapeutic index in the context of P-gp substrates? Does the term “substrate” read on any compound that binds to P-gp, including compounds that inhibit or induce P-gp? Erdafitinib itself is on the Drugbank list of P-gp substrates referred to by Applicant (see Remarks filed 06/06/2025), which means any prior art disclosure of erdafitinib administered at least 6 hours apart could implicitly read on the instant claims.
Not one P-gp substrate has been contemplated to be within the scope of the instant invention, yet Applicant seeks protection across the whole scope of the genus for a drug interaction that may occur across an indeterminate number of species. "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54. The rejection is maintained.
Regarding the rejection of claims 1, 48-58, 60-66, and 68-72 (now 1, 48-58, 60-66, and 68-70) under 35 U.S.C. 112(a) enablement, Applicant argues that curing or preventing the condition is a possible outcome but is not required and is not a valid interpretation of the claims. This is not persuasive. Per the definition at paragraph [0032] of the specification, the scope of “treat” and “treatment” includes cure and prevention. The scope of treating urothelial carcinoma therefore necessarily includes curing or preventing urothelial carcinoma. As explained by Examiner, cure and prevention are not enabled. Applicant further argues that curing and preventing are being improperly read into the claims. This is also not persuasive. The specification has been referred to by Examiner to construe the full scope of the claims. Examiner is not reading curing or preventing into the claims in order to further limit their scope. MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). Thus, the full scope of treating urothelial carcinoma is not enabled. Applicant has provided no arguments or evidence regarding curing or preventing the claimed condition. The rejection is maintained.
35 U.S.C. 103 and NSDP
Regarding the outstanding rejections under 35 U.S.C. 103, Applicant argues that Examiner has failed to point to a disclosure of co-administration of erdafitinib with a P-gp substrate, nor has Examiner established that one of ordinary skill in the art would have expected a drug interaction between the two. Applicant further argues that this deficiency is not cured by Zimmerman because cyclosporine and erdafitinib are distinct in their structure and function. See Remarks, p. 10-11. This is not persuasive.
Examiner has provided motivation to combine rapamycin and erdafitinib, as in the above rejection. MPEP 2144.06, “’It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” Since rapamycin and erdafitinib are both known in the art to treat urothelial carcinoma, one of ordinary skill in the art would be motivated to combine the two medicaments for the same purpose. Therefore, it would be prima facie obvious to combine erdafitinib with a P-gp substrate.
Regarding Zimmerman et al., Examiner notes that the citation of this reference is not to argue that erdafitinib and cyclosporine are similar in structure or function, but to exemplify administration schedules of rapamycin with other medicaments such that a drug interaction is avoided. One of ordinary skill in the art would be apprised of other administration schedules of rapamycin, such that Zimmerman et al. would provide a starting point from which the administration of rapamycin and erdafitinib could be optimized based on the pharmacokinetics of erdafitinib.
Applicant further argues that one of ordinary skill in the art would not expect an interaction between erdafitinib and a P-gp substrate, and provides a declaration under 37 CFR 1.132 made by Dr. Loeckie De Zwart (“De Zwart Declaration”). The declaration under 37 CFR 1.132 filed 01/28/2026 is insufficient to overcome the rejections under 35 U.S.C. 103 as set forth in the last Office action. The De Zwart Declaration shows, in Figure 1, that a risk of P-gp inhibition by erdafitinib exists in the first 5 hours after dosing, which indicates that staggering administration of erdafitinib and a P-gp substrate by at least 6 hours would avoid interactions (p. 3 of 7). The De Zwart Declaration additionally provides a simulated plasma concentration-time profile for a P-gp substrate dosed alone, simultaneously with erdafitinib, and 6 hours before erdafitinib, wherein administration of the P-gp substrate 6 hours before the erdafitinib reduces the increase in Cmax and AUC of the P-gp substrate caused by a drug interaction (p. 4-5 of 7).
Notably, the results discussed on page 3 of the De Zwart Declaration particularly point to a risk of interaction after administration of the erdafitinib. Based on the data shown, and the conclusions reached in paragraph 9, it is unclear whether (and/or when) an interaction would be observed if the P-gp inhibitor was administered before administration of the erdafitinib. Moreover, in the models shown on page 4, the conditions tested are limited to simultaneous administration and administration of the P-gp inhibitor 6 hours before administration of the erdafitinib. No other staggered administration schedules are tested, nor are any other P-gp substrates that may have different pharmacokinetics or mechanisms (such as inhibitors or inducers). These factors may affect whether an interaction is observed or, to the contrary, is even avoidable. In fact, the P-gp substrate tested in the De Zwart Declaration is not even identified. Yet Applicant alleges that these “surprising” results would be expected across the full scope of the claims. It is unclear whether the 6-hour staggering concluded by Applicant is in fact critical based on the results of the De Zwart Declaration.
Per MPEP 716.02(d), “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).” The scope of the claims is incredibly broad and reads on any P-gp inhibitor administered at any time at least 6 hours before or after administration of the erdafitinib. This could include a patient who was initially treated by a chemotherapeutic agent that is also a P-gp substrate, failed to respond to treatment, and was administered erdafitinib months later. The claims encompass all P-gp substrates, which could include inhibitors or inducers (no definition is provided by the instant disclosure) and varying durations of exposure. It cannot be concluded, from the limited data provided in the De Zwart Declaration, that the allegedly unexpected effects occur over the entire scope of the claims or that they would not occur outside of the scope of the claims.
For these reasons, the rejection is maintained.
Applicant relies on similar arguments regarding the outstanding non-statutory double patenting rejections. For the same reasons as above, the non-statutory double patenting rejections are maintained.
Applicant additionally requests that Examiner withdraw the non-statutory double patenting rejections over applications with a later patent term filing date than the instant application (the ‘139, ‘129, ‘232, and ‘347 application). Per the procedure outlined in MPEP 804(I)(B)(1)(b)(i), “If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date.” In the instant case, other rejections remain outstanding against the claims. Examiner will consider withdrawing the non-statutory double patenting rejections against applications with a later patent term filing date when no other rejections against the claims are outstanding.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/M.E.B./Examiner, Art Unit 1624 04/01/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624
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