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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/20/2026 has been entered.
Applicants' arguments, filed 02/20/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 presently being applied to the instant application.
Claim Rejections - 35 USC § 103--Previous
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.
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) 1-2, 4-13, 21-22 remain rejected under 35 U.S.C. 103 as being unpatentable over Rolland et al., (Journal of Otolaryngology-Head and Neck surgery, 2019, cited in IDS).
Rolland et al. teaches a method of preventing cisplatin-induced ototoxicity in patients by way of trans-tympanic injection of a sodium thiosulfate gel (Title).
Rolland et al. states, “Antioxidants such as sodium thiosulfate (STS) can neutralize the effects of cisplatin. The objective of the trial was to test the efficacy of trans-tympanic injections of a STS gel to prevent cisplatin-induced ototoxicity” (Abstract).
“On the eve of each cisplatin treatment, a pharmacist prepared the gel for the injection by mixing 0.55 ml hyaluronate gel (Healon 10 mg, Abbott Medical Optics Inc) and 0.55 ml of a 25% solution of sodium thiosulfate pentahydrate (Seacalphyx, Ceaford Pharmaceuticals Inc). The sodium thiosulfate solution (STS) concentration in the resulting gel was 0.5M” (p. 2, right column last para. through p. 3, left column 1st para.).
“Since no previous clinical study used a thiosulfate sodium gel, the concentration of our gel was in part determined with the results of Berglin et al. [18]. In this study, a 0.1 M sodium thiosulfate-hyaluronan gel was injected in the guinea pigs’ middle ears and was found in the Scala tympani’s perilymph 1 hour after injection. We decided to maximize the concentration of sodium thiosulfate in the hyaluronan gel and to inject a quantity of gel sufficient only to fil the round window area. This was chosen in order to prevent a conductive hearing loss with a full middle ear packing. The highest sodium thiosulfate concentration that could be achieved in order to obtain a stable and homogenous gel was 0.5 M” (p. 3, left column. 2nd paragraph).
“After a local anesthesia of the tympanic membrane, the otologist performed a formal otoscopy with a microscope to localize the round window niche, and then deposited 0.1 ml of the gel exactly on it” (Id. 3rd paragraph).
“Also, the trans-tympanic injections were done the day before the patients received their cisplatin treatment, allowing some time to the gel to get through the inner ear. The average elapsed time between the injection and the cisplatin treatment was 20.5H” (p. 7, right column, 2nd paragraph). It was noted that his time was chosen solely for convenience of the of the patient stating, “We chose this timing because it was easier for the patients, according to their treatment’s schedule” (Id.).
Earlier times for injection were possible insofar as the prior art teaches, “In the study of Riga et al. [21], the trans-tympanic N-acetylcysteine injections were performed during the hydration procedure preceeding intravenous effusion of cisplatin” (Id.), where the Examiner understands the hydration procedure takes place a few hours before cisplatin therapy (see Technological Background below).
Rolland et al. admits, “Our study could not demonstrate statistically significant efficacy of a trans-tympanic injection of a viscous sodium thiosulfate-hyaluronate gel prior to cisplatin therapy to prevent its induced ototoxicity in patients with advanced HNSCC” (p. 6, right column, 3rd para.)
Nevertheless, the prior art encouraged further study, stating, “This trial showed that a trans-tympanic injection of a sodium thiosulfate-hyaluronate gel is feasible and innocuous for the middle and inner ears and that further investigations of this innovative gel could be conducted safely” (p. 7, last para.).
The trial demonstrated outcomes such as, “For all frequencies between 3 and 10 kHz the hearing loss was less pronounced for the treated ear than for the control” (p. 5, left column, last para.) and “Although not significant these differences pointed to less severe hearing loss in the treated ears: 22,2% (p = 0.99)” (Id, right column, last para.).
Accordingly, it would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to administer a sodium thiosulfate-hyaluronate gel to the round window of the middle ear of a human subject prior to cisplatin treatment to prevent cisplatin-ototoxicity.
The prior art does not recommend a time frame or concentration range for administering the sodium thiosulfate gel to the patient. In the study, the average time between injection and the cisplatin treatment was 20.5 hours, but only as a convenience factor for the patient, as opposed to effect. The reference also taught administration during the hydration period, i.e. moments before cisplatin injections stating “Additional studies are required to further determine the optimal dosage and protocol of the sodium thiosulfate-hyaluronate gel” (p. 7, last para). Further, since the reference teaches administering 0.1 M sodium thiosulfate to a patient, it would have been obvious to administer amounts falling within the claimed range of 0.025M and 0.2M. Accordingly, it would have been obvious to optimize when, as well as, how much, of the gel is administered prior to cisplatin injection. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)).
The adjustment of particular conventional working conditions of thiosulfate gel treatment prior to cisplatin (e.g., determining result effective amounts and times for when the injections take place, especially within the broad ranges instantly claimed), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
Concerning claims 5-6, Rolland et al. teaches, “The planed treatment included cisplatin 100 mg/m2 at days 1, 22 and 43” (Abstract).
Concerning claims 9-10, the artisan would have expected the gel to have a viscosity conducive to administering to the inner ear. Again, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)).
Concerning claims 1 and 11, the normal tympanic (inner ear) temperature is in the range of 35.8ºC to 37.9ºC. It would behoove the artisan to administer the gel within this range for the sake of the patient’s comfort. Rolland et al. remarked that “dizziness and transient mild vertigo could be explained by the gel that could have been colder than the inner ear temperature” (p. 6, right column, last paragraph).
Technological Background
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure ChemoExperts (chemoexperts.com, 2017). ChemoExperts is pertinent for teaching, “Typically, I.V. hydration is given both before and after cisplatin and can add up to two hours to infuse” (1st page, 3rd bullet point under “Estimated total infusion time for this treatment”).
Response to Arguments
i) Applicant argues, “a person of skill would not have found it obvious that the recited STS concentrations in the gel could be effective for the prevention or reduction of hearing loss” insofar as the claimed amounts were actually tested and found to be efficacious (p. 6). Applicant further argues that the claimed amounts could not be gleaned from the prior art since Rolland teaches a larger dosage of 0.5 M sodium thiosulfate solely to “minimize injected volume, not reduction of concentration to achieve therapeutic efficacy”; and “Berglin does not establish that 0.1 M STS gel prevents or reduces hearing loss in humans, nor does it provide a reasonable expectation of success for doing so” (p. 7).
The Examiner disagrees.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (Id.).
After acknowledging the failure of the combination of N-acetylcysteine and dexamethasone, Rolland et al. stated, “Thus, we conducted a randomized controlled trial to test the efficacy of a sodium thiosulfate gel administered locally in the middle ear to prevent cisplatin-induced ototoxicity” (Id.). The conclusions of the trial “showed that a trans-tympanic injection of a sodium thiosulfate-hyaluronate gel is feasible and innocuous for the middle and inner ears and that further investigations of this innovative gel could be conducted safely” (see p. 7, Conclusions).
Accordingly, administration of sodium thiosulfate (STS) to the middle ear of a subject, in association with the administration of a platinum-based drug, for preventing or reducing hearing loss would have been obvious.
Again, the prior art encouraged further study, stating, “This trial showed that a trans-tympanic injection of a sodium thiosulfate-hyaluronate gel is feasible and innocuous for the middle and inner ears and that further investigations of this innovative gel could be conducted safely” [emphasis added] (p. 7, last para.).
Applicant’s time frame of between 8 hours before and 8 hours after platinum-based drug administration, is deemed simply a matter of judicious selection and routine optimization. The artisan would have reasonably been expected to modify a time frame for administering STS, to patients receiving cisplatin, which would have included a time before, after or during cisplatin administration.
Further, the amended concentration range does not go beyond the scope of the prior art, insofar as the prior art teaches injecting 0.1 M sodium thiosulfate in the middle ear of guinea pigs. Testing a concentration of 0.1M sodium thiosulfate in a human patient would have been obvious to try. “[W]hen there is a motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1390.
Conclusion
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Walter E. Webb
/WALTER E WEBB/Primary Examiner, Art Unit 1612