The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-3 and 6-21 are presented for examination.
Applicant’s Amendment filed June 4, 2025 has been received and entered into the present application.
Claims 1-3 and 6-21 are pending. Claims 4-5 are cancelled. Claims 1 and 13-17 are amended. Claim 21 is newly added.
Applicant’s arguments, filed June 4, 2025, have been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Status of Objections/Rejections in the December 4, 2024 Non-Final Action
In reply to the objection to claim 14 as set forth at p.4-5 of the previous Office Action dated December 4, 2024, Applicant now amends claim 14 to recite an additional comma. Accordingly, the objection is now hereby withdrawn.
In reply to the objection to claim 15 as set forth at p.5 of the previous Office Action dated December 4, 2024, Applicant now amends claim 15 to recite an additional comma. Accordingly, the objection is now hereby withdrawn.
The provisional rejection of claims 1-3, 6-9 and 18-19 on the ground of nonstatutory double patenting as being unpatentable over claims 29-34 of U.S. Patent Application No. 17/626,262 in view of Chabbert et al. (WO 2010/133663 A1; 2010), as set forth at p.17-22 of the previous Office Action dated December 4, 2024 is withdrawn as the ‘262 application is now abandoned.
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.
(1) Claims 1-3 and 6-19, as well as newly added claim 21, are rejected under 35 U.S.C. 103 as being unpatentable over Tsukuda et al. (“A Randomized Crossover Comparison of Azasetron and Granisetron in the Prophylaxis of Emesis Induced by Chemotherapy Inducing Cisplatin”, Gan To Kagaku Ryoho, 1995 November; 22(13):1959-1967, Abstract Only, cited by Applicant on the 03/13/23 IDS) in view of Tahara et al. (U.S. Patent No. 4,892,872 A; 1990, cited by Applicant on the 03/13/23 IDS),
citing to (i) CAS Registry No. 123040-16-4 (“Azasetron Hydrochloride”, cited by Applicant on the 03/13/23 IDS), (ii) Ashton et al. (U.S. Patent Application Publication No. 2003/0229333 A1; 2003, cited by Applicant on the 03/13/23 IDS), and (iii) Kuhn et al. (“Sudden Sensorineural Hearing Loss: A Review of Diagnosis, Treatment, and Prognosis”, Trends Amplif, 2011 Sep; 15(3):91-105, cited by Applicant on the 03/13/23 IDS) as factual evidence,
each already of record, for the reasons of record set forth at p.5-14 of the previous Office Action dated December 4, 2024, of which said reasons are herein incorporated by reference.
Applicant’s cancellation of claims 4-5 necessitates the withdrawal of such claims from the statement of the rejection above.
Newly amended claim 1 now limits the subject to “a human subject” and further recites that the “(+)-azasetron is administered at a total daily dose ranging from 40 mg to 200 mg of free-base equivalent”.
The previously set forth grounds for rejection clearly address the treatment of a human subject, and further address the prima facie obviousness of administering (+)-azasetron within a range of about 6.5 mg to about 6500 mg per day for a human subject of average 65 kg in weight using a 0.1-100 mg/kg/day dosing range, which overlaps Applicant’s newly claimed range of “40 mg to 200 mg of free-base equivalent” in claim 1. Accordingly, Applicant’s claim 1 as amended remains properly included in the present rejection.
Newly amended claim 1 also now recites the resultant effect of “wherein the administration of (+)-azasetron prevents or reduces the loss of cochlear hair cells”.
As explained in the grounds for rejection and further explained above, Tsukuda et al. in view of Tahara et al. suggest executing the same active step as that instantly claimed in the same patient population (i.e., a subject in need of prevention of a cochlear disease, disorder or condition, wherein the cochlear disease, disorder or condition is sensorineural hearing loss induced by ototoxic cisplatin chemotherapy, wherein the subject is also diagnosed with cancer, and further wherein the subject is treated with the azasetron therapy before, during and/or after cisplatin chemotherapy) and, thus, must yield this same resultant effect to “prevent[s] or reduce[s] the loss of cochlear hair cells” observed in the patient following this same active step of administration recited in claim 1 and also suggested by the cited prior art teachings. This is because identical products must exert identical effects when utilized in an identical manner in an identical patient population.
Applicant’s remaining amendments to claim 13-17 are editorial in nature, seeking only to clarify that the subject is “human”, which was already addressed in the grounds for rejection. As a result, Applicant’s amended claims 13-17 remain properly included in the present rejection.
Newly added claim 21 recites “wherein the composition is administered for at least one day before and for at least one day after platinum-based chemotherapy”.
The cited prior art teachings document the prophylactic antiemetic effects of azasetron to mitigate chemotherapy-induced vomiting, particularly vomiting induced by cisplatin therapy. Here, Tsukuda et al. teaches that the head and neck cancer patient was treated concomitantly with cisplatin chemotherapy and azasetron therapy – with azasetron providing antiemetic efficacy. The azasetron therapy described by Tsukuda et al. is, thus, administered “during” cisplatin, but also “before” any subsequent cisplatin dosing, as well as “after” any previous cisplatin dosing, thereby providing for administration “before” and “after” platinum-based chemotherapy.
Given Tahara’s teaching that azasetron is administered daily for this prophylactic antiemetic purpose, the ordinarily skilled artisan would have found it prima facie obvious to administer the (+)-azasetron therapy daily with cisplatin chemotherapy, which necessarily provides for administration “for at least one day before” any cisplatin dosing and “at least one day after” any previous cisplatin dosing, as recited in newly added claim 21.
Response to Applicant’s Arguments
In reply, Applicant traverses the rejection, stating that “neither Tsukuda or nor Tahara teaches that administering (+)-azasetron at a total daily dose ranging from 40 mg to 200 mg of free base equivalent prevents or reduces the loss of cochlear hair cells” (Remarks, p.9).
The arguments have been fully and carefully considered, but are not found persuasive.
Applicant’s analysis of Tsukuda et al. or Tahara et al. individually to support his assertion that the individual references do not explicitly teach the claimed method is unavailing. Here, Tsukuda et al. was not applied alone, but rather in combination with the additional teachings to Tahara et al. There is, thus, no requirement that Tsukuda et al. (or the secondary reference to Tahara et al., for that matter) individually teaches the identical method instantly claimed (as would be required if Tsukuda et al. or Tahara et al. was applied as anticipatory prior art under AIA 35 U.S.C. §102). Applicant is reminded that there is no requirement that a single reference teach the entirety of the claimed invention to find obviousness. Rather, the test for obviousness is what the combined teachings of the prior art would have suggested to the skilled artisan. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually – as Applicant has done – where the rejections are based on a combination of the references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant goes on to argue that “Tsukuda teaches that a dose of 10 mg/day of azasetron (which corresponds to a lower dose of (+)-azasetron) was highly effective in the prophylaxis of acute and delayed emesis induced by chemotherapy” and that the skilled artisan “would have had no apparent reason to consider increasing the total daily dose of azasetron” because this “would go against standard pharmacological practice to administer a dose that is higher than that required to obtain the desired therapeutic/prophylactic effect” (Remarks, p.10).
The arguments have been fully and carefully considered, but are not found persuasive.
Applicant’s position fails to fully consider the reasons provided in support of the rejection. Though Applicant is correct that Tsukuda et al. teaches an intravenous dose of 10 mg/day azasetron to mitigate cisplatin-induced vomiting, Tahara et al. provides clear teachings that azasetron may be alternatively administered via a variety of routes and dosage forms for this same antiemetic purpose, and that a generally accepted therapeutically effective dose for this use ranges from about 0.1-100 mg/kg orally for human adults in single or multiple dosages (see, e.g., col.9, l.9-22). It cannot be asserted – as Applicant has done – that the prior art only recognized a 10 mg/day intravenous dose for mitigating cisplatin-induced vomiting, when Tahara et al. provides clear teachings demonstrating that ordinarily skilled artisan, well before the effective filing date of the claimed invention, recognized that azasetron may be administered for this therapeutic purpose using alternative routes (e.g., orally) using a suitable oral dosing range of about 0.1-100 mg/kg per day for a human adult, given as either single or multiple dosages. Such teachings explicitly document that the prior art was in no way limited solely to the 10 mg/day intravenous dose described by Tsukuda et al. Applicant’s restriction of his consideration only to the dosage and route described by Tsukuda et al. is unavailing, as it fails to consider the full scope and content of the prior art teachings and what they would have naturally suggested when combined to the ordinarily skilled artisan before the effective filing date of the claimed invention.
Applicant further argues that “one of ordinary skill in the art may thus have been motivated to modify the teaching of Tsukuda [with the teachings of Tahara] in order to administer a dose ranging from 6.5 mg/day to 10 mg/day” (Remarks, p.10-11).
The arguments have been fully and carefully considered, but are not found persuasive.
Applicant gives no explanation for his position that the combined teachings of Tsukuda et al. in view of Tahara et al. can only support dosing from 6.5 mg/day to 10 mg/day. In fact, this position cannot be accepted because Applicant attempts to connect the intravenous dose described by Tsukuda et al. (i.e., 10 mg/day) with the lower endpoint of the 0.1-100 mg/kg/day oral dosing range described by Tahara et al. (which correlates to a 6.5 mg/day to 6500 mg/day range for a human of average 65 kg in weight) to generate a new, unsupported dosing range as allegedly limiting the prior art teachings. This is flawed, as it pays no attention to the specific route of administration for the azasetron (or its optical isomers) and the dosing range described in the prior art to be applicable to that specific route of administration.
Applicant’s remarks, therefore, fail to rebut the teachings of Tahara et al. by explaining why the ordinarily skilled artisan – when considering oral dosing of azasetron or its optical isomers to a cancer patient receiving cisplatin chemotherapy for prophylaxis of cisplatin-induced vomiting – would not have considered the broader scope of Tahara’s teachings of oral dosing of 0.1-100 mg/kg/day for this therapeutic application, either as single or multiple doses (which, for a 65 kg human of average weight, constitutes an oral dosing range of 6.5 mg/day to 6500 mg/day).
Applicant contends that the skilled artisan “would not have had a reasonable expectation that administering (+)-azasetron at a total daily dose ranging from 40 mg to 200 mg of free base equivalent could prevent or reduce the loss of cochlear hair cells” (Remarks, p.11). Applicant opines that “both Tsukuda and Tahara teach that azasetron is a 5-HT3 receptor antagonist” and that Tahara documents that this function as a 5-HT3 receptor antagonist is useful in preventing cisplatin-induced vomiting (Remarks, p.11). Applicant asserts that “the IC50 of azasetron as a 5-HT3 receptor antagonist has long been reported to be 0.33 nM”, citing to an internet website in support of his assertion (Remarks, p.11). Applicant asserts that the function of azasetron to “prevent[ing] or reduce[ing] the loss of cochlear hair cells stems from its inhibition of the protein phosphatase calcineurin”, citing to U.S. Patent Application Publication No. 2018/0207167 (cited on the 03/13/23 IDS) in support thereof (Remarks, p.11). Applicant contends that “the IC50 of azasetron as a calcineurin inhibitor is about 100 nM” such that “there could be no reasonable expectation that a dose of azasetron sufficient for it to exert its function as a 5-HT3 receptor antagonist would also be sufficient for azasetron to exert its function as a calcineurin inhibitor” - and, therefore, function to “prevent or reduce the loss of cochlear hair cells in the cancer subject receiving cisplatin” (Remarks, p.12-13).
The arguments have been fully and carefully considered, but are not found persuasive.
As an initial matter, Applicant relies upon an internet website to document the alleged IC50 of azasetron as a 5-HT3 receptor antagonist as 0.33 nM, but fails to provide a copy of such document for consideration by the Office. As the Examiner may not take official notice of facts (see MPEP §2144.03 (“[A]ssertions of technical facts in the areas of esoteric technology or specific knowledge of the prior art must always be supported by citation to some reference work recognized as standard in the pertinent art”)), so Applicant must be held to the same standard. Also, see MPEP §2145, which states that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)).
Even if such evidence had been provided in the record, it would fail to support Applicant’s assertion of nonobviousness. Here, the teachings to Tahara et al. suggest employing azasetron (or any one of its optical isomers, including (+)-azasetron) within a range of oral dosage amounts that clearly circumscribe the claimed dosing range of “from 40 mg to 200 mg” (claim 1). Thus, whatever therapeutic effect Applicant attributes to this dosing range to yield the function to “prevent[s] or reduce[s] the loss of cochlear hair cells” must necessarily also yield from this same range of amounts disclosed by the prior art, as identical products must yield identical properties, particularly when used in an identical manner. MPEP §2112.
Moreover, even if Applicant’s arguments regarding the difference in IC50 values were adequately supported by factual evidence, the fact remains that identifying a difference in IC50 values for two different inhibitory functions does not, without more, demonstrate that the dosage amounts suggested by Tahara et al. for prevention of cisplatin-induced vomiting would not also function to “prevent[s] or reduce[s] the loss of cochlear hair cells” as instantly claimed. Applicant fails to provide any evidentiary showing to support his assumption that the dosage range described by Tahara et al. was in any way insufficient to yield the specific functions instantly claimed.
For these reasons supra, rejection of claims 1-3, 6-19 and 21 is proper.
(2) Claim 20 remains rejected under 35 U.S.C. 103 as being unpatentable over Tsukuda et al. (“A Randomized Crossover Comparison of Azasetron and Granisetron in the Prophylaxis of Emesis Induced by Chemotherapy Inducing Cisplatin”, Gan To Kagaku Ryoho, 1995 November; 22(13):1959-1967, Abstract Only, cited by Applicant on the 03/13/23 IDS) in view of Tahara et al. (U.S. Patent No. 4,892,872 A; 1990, cited by Applicant on the 03/13/23 IDS),
citing to (i) CAS Registry No. 123040-16-4 (“Azasetron Hydrochloride”, cited by Applicant on the 03/13/23 IDS), (ii) Ashton et al. (U.S. Patent Application Publication No. 2003/0229333 A1; 2003, cited by Applicant on the 03/13/23 IDS), and (iii) Kuhn et al. (“Sudden Sensorineural Hearing Loss: A Review of Diagnosis, Treatment, and Prognosis”, Trends Amplif, 2011 Sep; 15(3):91-105, cited by Applicant on the 03/13/23 IDS) as factual evidence,
as applied above to claims 1-3, 6-19 and 21,
further in view of Borges et al. (U.S. Patent Application Publication No. 2015/0038594 A1; Published February 5, 2015, cited by Applicant on the 03/13/23 IDS),
each already of record, for the reasons of record set forth at p.14-16 of the previous Office Action dated December 4, 2024, of which said reasons are herein incorporated by reference.
Response to Applicant’s Arguments
In reply, Applicant traverses the rejection, stating that Tsukuda and Tahara are deficient for the reasons set forth above and that “Borges relates to orodispersible films”, but is “entirely silent regarding cochlear disease, disorders or conditions” and concludes that “Borges does not remedy the deficiencies of Tsukuda and Tahara” (Remarks, p.14-15).
The arguments have been fully and carefully considered, but are not found persuasive.
Applicant’s arguments are predicated upon a finding that the combination of Tsukuda et al. in view of Tahara et al. is deficient, which it is not for the reasons above. Moreover, Applicant is reminded that this secondary reference to Borges et al. was relied upon for its specific teachings related to the prima facie obviousness of employing an orodispersible film for administration of azasetron to a subject. Piecemeal analysis of the references cannot establish nonobviousness because it fails to consider the totality of the teachings and what they would have reasonably suggested to the ordinarily skilled artisan when combined. Also, there is no requirement under 35 U.S.C. §103 that any one or more of the individual references cited in the rejection must teach the entirety of the claimed invention. Rather, the test for obviousness is what the combined teachings of the cited references would have suggested to the ordinarily skilled artisan. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
For these reasons supra, rejection of claim 20 is proper.
Conclusion
Rejection of claims 1-3 and 6-21 is proper.
No claims of the present application are allowed.
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Leslie A. Royds Draper whose telephone number is (571)272-6096. The examiner can normally be reached Tuesday to Thursday (08:30 AM to 05:00 PM).
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/Leslie A. Royds Draper/Primary Examiner, Art Unit 1629
October 9, 2025