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 .
DETAILED ACTION
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 03/23/2026 wherein claims 28-31, 33-37, 44 are canceled and new claims 47-51 are added.
Election/Restrictions
Applicant elected with traverse in the reply filed 10/28/2025 : Group I, claims 27-45, drawn to a method for the treatment of an inner ear disorder in a subject in need thereof
Species election without traverse:
Inner ear disorder species: tinnitus;
active agent: 7,8-dihydroxyflavone (7,8-DHF);
solubilizing agent in the pharmaceutically acceptable vehicle: apricot oil [a vegetable oil], and
diffusing agent in the pharmaceutically acceptable vehicle: u-(-)-bisabolol [a terpene].
Claim 46 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim, as the Restriction Requirement made FINAL in last office action .
The elected active agent, 7,8-dihydroxyflavone (7,8-DHF) is a Trk B agonist, not a Trk C agonist. Thus, new claim 48 reciting Trk C agonist is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species. The other non-elected TRK agonist species as recited in new claim 49 and 50 are also withdrawn as being drawn to a nonelected species.
Status of Claims
Claims 27, 32, 38-43, 45, 46 and 47-51 are pending.
Claim 46 and 48 are withdrawn.
Claims 27, 32, 38-43, 45, 47 and 49-51 are currently under examination in this office action.
Priority
This application 18/034,960 filed on is a 371 of PCT/EP2021/083195 filed on 11/26/2021, and claims priority of foreign Application No. EP 20306455.5 filed on 11/26/2020.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of foreign Application No. EP 20306455.5 in English is filed on 05/02/2023.
Information Disclosure Statement
The information disclosure statement (IDS) dated 03/23/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Action Summary/ Response to Arguments
Applicant’s remarks filed 03/23/2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks .The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office action.
35 USC§ 112(a) Scope of Enablement
Applicant argues extensively about the delivery of active ingredient across tympanic membrane and activity of 7,8 dihydroxyflavone taught by prior art (Remarks, page 7-19).
RESPONSE: The examiner does not dispute instant Tropomyosin Receptor Kinase (TRK) agonist could be delivered to tympanic membrane. Please note the amended Tropomyosin Receptor Kinase (TRK) agonist genus comprises variety of species as recited in new claim 49. Although the elected 7,8 dihydroxyflavone (7,8 DHF) might be enabled for treating hearing loss based on the prior art, the efficacy of other recited Tropomyosin Receptor Kinase (TRK) agonist species for treating hearing loss and tinnitus are not supported by instant specification and prior art. Please also note the presence of active agent in the inner ear does NOT always mean the active agent is effective for treating hearing loss and tinnitus. Instant specification does not disclose how the treatment outcome of hearing loss/ tinnitus are measured after the “active agent” was administered and does not disclose the efficacy of the active agents for the treatment of hearing loss/tinnitus. As such, the 35 USC§ 112(a) Scope of Enablement is maintained and reiterated as necessitated by amendment.
35 USC§ 112(b)
New claims 49 and 50 are rejected under 35 U.S.C. 112(b) as being indefinite, as necessitated by amendment.
35 USC§ 102 rejection:
Claim 27 is amended to recite active agent is Tropomyosin Receptor Kinase (TRK) agonist in combination with specific solubilizing agent and diffusing agent. Thus, rejections anticipated by YOSHPE, SIMONS and LIU under 35 USC102 are withdrawn.
35 USC § 103 rejection:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of 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). The test for obviousness is not 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.
Applicant argues against MELTSER, KUJAWA and SARAGOVI , “The technical effect of this difference is that the present invention provides a non-invasive treatment of inner ear disorders, by providing a pharmaceutical active ingredient in the inner ear without any injection nor invasive means” (Remarks page 21).
RESPONSE: Applicant’s argument fully considered, but not persuasive. MELTSER, KUJAWA and SARAGOVI teach the active ingredient 7,8 dihydroxyflavone (7,8 DHF) is administered for treating hearing loss or tinnitus. Instant claim 27 recites a method for treatment of inner ear disorder comprising administration of a therapeutically effective dose of a pharmaceutical composition comprising an active ingredient into the ear canal or onto the tympanic membrane of the subject. The step of “administration” is not limited to particular route and does not exclude any particular delivery. As long as the active ingredient can be administered into the ear canal or onto the tympanic membrane, whether the composition is delivered through injection, diffusion/ permeation across the membrane, or any other topical route, the prior art is considered as read on the step of “administration”.
Saragovi collectively teaches a method of treating inner ear disorder (e.g. tinnitus, hearing loss) comprising administration of a therapeutically effective dose of pharmaceutical composition comprising an active agent ( TrkB or TrkC agonist, e.g. 7.8-dihydroxy flavone) and solubilizing agent via tympanic membrane. Regarding the administration limitation recited in claim 27 and 39, Saragovi teaches intratympanic injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. Saragovi teaches embodiment wherein TrkB or TrkC agonist formulations are administered directly onto the round window membrane via transtympanic injection and another embodiment, the TrkB or TrkC agonist auris-acceptable formulations are administered onto the round window membrane via a non-transtympanic approach to the inner ear (See [0416]).
Further, Simons also teaches method of treating inner ear disease comprising administering tympanic membrane permeating ear drops.
Applicant argues MELTSER, KUJAWA and SARAGOVI do not teach a-(-)-bisabolol and apricot oil and further argues against a-(-)-bisabolol and apricot oil taught by combined teachings of SIMONS, YOSHPE, LATINO and MINAIYAN (Remarks, page 23-24).
RESPONSE: Simons and Yoshpe teach method of treating otitis disease which reads on instant inner ear disorder (e.g. Meniere's disease) that was previously claimed.
Yoshpe teaches variety of solubilizing agent and explicitly teaches embodiments comprising a-(-)-bisabolol in the composition applied to the ear canal.
Simons teaches tympanic membrane permeating ear drops comprising variety of solubilizing agent ( e.g. vegetable oils, etc.), and penetration enhancer (terpene and derivatives, e.g. limonene, linalool, etc.) across tympanic membrane. Simons teaches applying the composition into a subject’s ear canal or on the surface of the tympanic membrane wherein the therapeutic agent penetrates the tympanic membrane for treating inner ear disease. Please note bisabolol is also considered as functional equivalent of limonene, linalool and other terpene taught by Simons as diffusing agent. As Applicant agrees (Remarks, page 17), bisabolol is a well-characterized skin and membrane penetration enhancer that increases the fluidity of lipid bilayers which is also taught by Yoshpe . A skilled artisan would reasonably expect bisabolol as the diffusing agent/ penetration enhancer to facilitate permeation across tympanic membrane as other terpenes taught by Simons. Instant claims do not recite any amount/concentration of bisabolol for different TRK agonist.
Regarding the apricot oil which is considered as functional equivalent of sesame oil, and other vegetable oil as solubilizing agent taught by Simons, selection of a particular oil as solubilizing agent would have been constituted as optimizing within the level of ordinary skilled in the art. For example, Birbara (EP3345594B1) teaches apricot oil as surfactant/ solubilizing agent in pharmaceutical composition comprising flavonoid compounds. Applicant does not provide any evidence that instantly claimed apricot oil exhibits any super or unexpected result as solubilizing agent compared with vegetable oils taught by Simons. Instant claims do not recite any amount/concentration of apricot oil for different TRK agonist.
Applicant also argues against a-(-)-bisabolol as homeopathic medicinal product by LATINO , and apricot oil as traditional use taught by MINAIYAN (Remarks, page 23-24).
RESPONSE: As Applicant agrees, bisabolol is a well-known skin and membrane penetration enhancer in the art. A skilled artisan would have known to explore bisabolol as the terpene enhancer equivalent of limonene, linalool and other terpene taught by Simons. Latino’s teaching a-(-)-bisabolol as homeopathic medicinal product offering additional benefit for ear disease might further motivate a POSA to select /optimize bisabolol as diffusing agent/ penetration enhancer for ear drop composition . Traditional use of apricot kernel for otitis/ tinnitus might not have been studied extensively as Applicant argued, apricot kernel oil is already known to exhibit antioxidant, anti-inflammatory and antimicrobial activity as taught by Minaiyan. As explained in previous office action, apricot kernel oil is considered as functional equivalent of sesame oil, and other vegetable oil as solubilizing agent taught by Simons, The additional benefit of apricot kernel oil taught by Minaiyan might further motivate a POSA to select/optimize apricot oil as the solubilizing agent.
As necessitated by amendments. the following rejections are either reiterated, newly applied and partially newly reapplied and they constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112
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.
Claims 27, 32, 38-43, 45, 47 and 49-50 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 treating hearing loss with 7,8-dihydroxyflavone DHF, in light of prior art, does not reasonably provide enablement for treating with any instantly claimed TRK agonist. 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. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
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 need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Instant claim 27 is amended to recite a method for the treatment of an inner ear disorder, hearing loss and tinnitus, in a subject in need thereof, wherein said pharmaceutical composition comprises TRK agonist.
The scope of instant claims are broad compared with instantly disclosed working examples that are only directed to pharmacokinetic study of pharmaceutical compositions comprising 11 “active agents” without efficacy data of treating hearing loss and tinnitus.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
Instant claims are directed to a method of treating hearing loss and tinnitus with TRK agonist genus having different structures, different properties and different activities. The efficacies of treating hearing loss and tinnitus vary greatly due to a lot factors including the structures/ physical properties of the agents, mechanism of action, delivery route, dosage regimen, etc. Activity by in-vitro experiment does not necessarily translate into efficacy in animals and/or humans.
With respect to treatment for the elected tinnitus, McFerran (2019) reviews treatment options for tinnitus and states “ there are few treatment options and those that are available are aimed at reducing the impact rather than specifically addressing the tinnitus percept. In particular, there is no drug recommended specifically for the management of tinnitus. Whilst some of the currently available interventions are effective at improving quality of life and reducing tinnitus-associated psychological distress, most show little if any effect on the primary symptom of subjective tinnitus loudness”(See page 2, Introduction).
Regarding the elected species dihydroxyflavone, a selective tropomyosin receptor kinase B (TrkB) agonist for treating tinnitus, McFerran (2019) states “ By experimentally activating tropomyosin receptor kinase type B (TrkB) using a selective agonist, 7,8-dihydroxyflavone (DHF), the mice could be protected against nocturnally induced hearing loss; DHF made no difference to the temporary hearing loss produced by diurnal noise exposure. The relevance of these findings to humans, to tinnitus and to human drug administration remains to be established” (See page 802, right column, 2nd para).
Cederroth (2018, Applicant’s IDS dated 08/24/2023 ) reviews emerging drugs for tinnitus (See whole article). Cederroth (2018) states “In spite of the high clinical demand, attempts to treat tinnitus by various means have failed… Currently no drug is approved for the treatment of tinnitus by the FDA or the EMA” (See page 251, Existing treatment) and “ In spite of huge advances in pathophysiologic knowledge and research methodology in the last decades, pharmaceutical research in tinnitus still represents a high-risk field. Important research directions include the identification of potential therapeutic targets and the development of objective outcome measurements to facilitate translational research” (See Expert Opinion, Conclusion). Regarding the elected species dihydroxyflavone, a selective tropomyosin receptor kinase B (TrkB) agonist for treating tinnitus, Cederroth (2018) teaches systemic treatment of dihydroxyflavone protected from noise trauma at nighttime but not at daytime, which might not correlate with treatment of humans in day time( See page 256, left column, last para).
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 (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient guidance/protocols for a skilled artisan to practice the claimed method of treating hearing loss and tinnitus with TRK agonist genus having different structures in full scope.
Instant specification disclosed formulation comprising different active agents (e.g. 7, 8-dihydroxyflavone, etc.), pharmacokinetics study of different active agents ( See Examples 1-3, Table 7). Instant specification disclosed composition of active agents comprising solubilizing agent could be delivered to inner ear/perilymph after administration onto the tympanic membrane of subject. Instant specification does not disclose how the treatment outcome of treating inner ear disorder, e.g. tinnitus and are measured after the “active agent” was administered and does not disclose the efficacy of the active agents for the treatment of hearing loss/tinnitus. Please note the presence of active agent in the inner ear does NOT always mean the active agent is effective for treating the alleged inner ear disorder. It’s also noted the subject of assay is HEALTHY subject(See bridging page 40 and 41, Selection of Animals). In absence of any efficacy data to support the alleged method of treating inner ear disorder in a subject suffering inner hearing loss/tinnitus with any active agent, an ordinary skilled in the art would not know if any instantly claimed TRK agonist could be enabled for treating any of the instantly claimed inner ear disorder, e.g. tinnitus in a subject in need thereof.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to develop protocols for the claimed method of treating. Working examples would be needed to determine the therapeutically effective dose for hearing loss and tinnitus with different active agent. The therapeutically effective amount may vary depending on many factors, such as the structure, property(chemical, physical, toxicological, etc.), mechanism of action, efficacy of the agent, subjects being treated, the disease condition and intended treatment income, etc. The specific dosage may vary depending on the compound selected, the dosing regimen to be followed, administration route, the toxicological profile, etc. Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention for claimed method of treating loss and tinnitus with vast variety of agents, in full scope.
Conclusion
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 with respect to the claimed method of treating hearing loss and tinnitus with TRK agonist genus , in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention without undue experimentation.
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.
Claim 49 and 50 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.
New claim 49 recites the active agent selected from the group consisting of 7,8 dihydroxyflavone (7,8 DHF), a 7,8 dihydroxyflavone bisphosphonate, a 7,8 dihydroxyflavone prodrug, deoxygedunin, gambogic acid, demethylasterriquinone B1 (DMAQ-B1), LM22B 10, LM22A-4, and TRK agonist antibodies. Claim 50 also recites 7,8 dihydroxyflavone prodrug. The term “prodrug” is vague and might direct to compounds that have different chemical structure, different physical/ chemical property and different biological activity not related to TRK . An ordinary skilled in the art would not be appraised the scope of ‘”7,8 dihydroxyflavone prodrug”.
35 USC §103 Claim Rejections
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.
Claims 27, 32, 38-43, 45, 47, and 49 -51 are rejected under 35 U.S.C. 103 as unpatentable over Meltser et al. (Current Biology, February 27, 2014, Vol. 24, No. 6, pages 658-663, Applicant’s IDS dated 08/24/2023, "TrkB-Mediated Protection Against Circadian Sensitivity to Noise Trauma in the Murine Cochlea"), in view of Simons et al. ( US 8,822,410 B2), Yoshpe et al. (US 8758836 B2, Applicant’s IDS dated 08/24/2023) and Minaiyan et al. ( Res Pharm Sci. 2014 Jul-Aug;9(4):225-31.Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats) (partially newly reapplied as necessitated by amendment).
Meltser teaches administration of selective BDNF receptor, tropomyosin related kinase type B (TrkB), protected the inner hair cell’s synaptic ribbons and subsequent full recovery of hearing thresholds. Meltser teaches TrkB activation protects from noise-induced hearing loss (NIHL) wherein TrkB antagonist (e.g. 7,8-dihydroxyflavone ) boosted the amplitude of circadian rhythms in the isolated cochlea (See Summary, whole article).
Meltser explicitly teaches evaluation of 7,8-dihydroxyflavone (DHF) wherein DHF modulates PER2 oscillations in the cochlea via TrkB and preserves cochlear synaptic integrity after noise overexposure(See page 660; Figure 2 and 3). Meltser also teaches local delivery of DHF in the ear has been shown to rescue auditory neuronal loss and function in a mouse model of auditory neuropathy
(cCx26 null mice) and suggested DHF may (1) protect immediately, presumably by decreasing glutamate release during noise overexposure and subsequent excitotoxicity, (2) act on the recovery processes after noise overexposure by facilitating synaptogenesis (See page 661).
Meltser is silent about the solubilizing agent and terpen diffusing agent.
Simons teaches a method of treating ear disease (e.g. ear infections, otosclerosis, vertigo, Meniere's disease, etc.) comprising administering composition comprising active agent and penetration enhancer across tympanic membrane (See abstract, Col. 2, lines 55-65; Col. 14, lines 49-65; Examples 1-4; claim 11).
Regarding the active agent, Simons teaches therapeutic agent can be any agent used to treat ear disease, or symptom of an ear disease, e.g. antibiotics (e.g. ciprofloxacin, etc.), anesthetics(e.g. lidocaine, bupivacaine, etc.), anti-inflammatory, anti-fibrotic, anti-sclerotics, anticoagulants, etc. (See Col. 12, line 21-25; Col. 13, lines 1-55; Examples 1-4). Simons teaches various concentration of the active agent, e.g. between about 0.01 to about 10 percent, between about 0.01 to about 1 percent of the composition of the composition, etc.(See Col. 12, line 25-40)(which also reads on instant claim 32).
Regarding the administration route/step, Simons teaches applying the composition into a
subject’s ear canal or on the surface of the tympanic membrane wherein the therapeutic agent penetrates the tympanic membrane for treating inner ear disease (See Col. 14, lines 47-65; Col. 15, lines 11-27, Examples 1).
Regarding the inner ear disorder limitation, Simons teaches methods can be used to treat ear diseases, e.g. ear infections, otosclerosis, vertigo, Meniere's disease, mastoiditis, labryrinthitis, etc. (See Col. lines 55-59).
Regarding the solubilizing agent, Simons teaches dosage form comprising active compounds and commonly excipients used in the art, e.g. water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol. 1,3-butylene glycol, dimethylformamide, oils (in particular, cotton seed, groundnut, corn, germ, olive, castor, and sesame oils, etc.), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof …solubilizing agents such an Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof (See Col. 14, lines 15-30). Simons also teaches alcohol as penetration enhancers methanol, ethanol, propanol, isopropanol, butanol, isobutyl alcohol, etc. (See Col. 10,lines 65-67).
Regarding the diffusing agent, Simons teaches pharmaceutical composition comprising penetration enhancer (e.g., a surfactant, terpene), wherein the penetration enhancer that alters the stratum corneum of the tympanic membrane to increase the flux of the therapeutic agent across the tympanic membrane and facilitates delivery of the therapeutic agent into the middle and/or inner ear (See abstract, Col. 7, lines 37-44 ). Simons teaches variety of terpene penetration enhancers e.g. limonene, cymene, pinene, camphor, menthol, comphone, phellandrine, Sabinene, terpinene, borneol, cineole, geraniol, linalol, pipertone, terpineol, eugenol, eugenolacetate, Safrole, benzyl benzoate, humulene, beta-caryophylene, eucakytol, etc or terpenoid (See Col.10, lines 50-64).
Regarding claim 38, Simons teaches tympanic membrane permeating ear drops(See title, Example 4).
Simons collectively teaches a method of treating ear disease comprising administering composition comprising active agent, solubilizing agent (alcohol, vegetable oils, etc.), and penetration enhancer (terpene and derivatives, e.g. limonene, linalool, etc.) across tympanic membrane. Simons teaches tympanic membrane permeating ear drops. Please note instant claimed bisabolol is considered as functional equivalent of limonene, linalool and other terpene taught by Simons as diffusing agent in absence of evidence to the contrary. Instant claimed apricot oil is considered as functional equivalent of sesame oil, and other vegetable oil as solubilizing agent taught by Simons.
Yoshpe teaches a method of treating diseases and conditions associated with inflammation of the inner ear of a mammal, comprising applying to the ear canal of said mammal, a pharmaceutical composition comprising anti-inflammatory, anti-irritant, active agent ( hydrocortisone, also anti-edema) and polyhydroxy solvent (See abstract ; Col 1. lines 10-15; claims 1-14).
Regarding alpha-bisabolol, Yoshpe teaches composition embodiments comprising at least one active agent, 3-butylene glycol (solubilizing agent) and alpha-bisabolol (terpene and derivatives as diffusing agent ) (See Col. 8, lines 5-30; Col. 9, lines 1-18; Example ). Yoshpe also teaches alpha bisabolol has natural wound healing activity and anti-inflammatory property (See Col 6. lines 29-36).
Regarding the solubilizing agent, Yoshp teaches oils, polyhydroxy liquid solvent further comprises a lipid and glycol lubricating hydrophilic base formulation including combinations of glycol, glycerin, sugar alcohols (See claims 7 and 14).
Regarding claim 32, Yoshpe teaches concentration of active agent (hydrocortisone) at 0.2375% to about 0.2625% by weight (See Col. 7, lines 40-42) and variety of embodiments comprising 0.25% of hydrocortisone and alpha-bisabolol (See Col 8, lines 9, 32).
Regarding claim 38, Yoshpe teaches the ear drop formulation (See Col. 5, lines 11, 58, 61) and the ear drop is applied to the ear canal of the human(See claim 13).
Yoshpe collectively teaches a method of treating diseases and conditions associated with inflammation of the inner ear of a mammal, comprising applying to the ear canal of said mammal, a pharmaceutical composition comprising anti-inflammatory, anti-irritant active agent, at least one solubilizing agent and at least one diffusing agent selected from terpene and derivatives, e.g. alpha-bisabolol.
Minaiyan teaches apricot kernel have shown antioxidant, anti-inflammatory and radical scavenging properties, antimicrobial activity and antitussive effects, etc., and apricot kernel oil has also been used as remedy for otitis and tinnitus in drop dosage form (See page 226, left column, para1).
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instantly claimed invention, to formulate TrkB antagonist (e.g. 7,8-dihydroxyflavone) taught by Meltser with solubilizing agent and terpene taught by Simons and Yoshpe, together with experimentation/optimization based on general knowledge of pharmaceutical composition for treating ear disease/disorder. Minaiyan teaches apricot kernel oil having antioxidant, anti-inflammatory property used for treating otis and tinnitus. A skilled artisan would reasonably expect the pharmaceutical composition comprising active agent (e.g. TrkB or TrkC agonist, 7,8-dihydroxyflavone (DHF), solubilizing agent (vegetable oils, etc.) and terpene (limonene, linalool, alpha-bisabolol) would provide a method for treating inner ear disorder (e.g. hearing loss) with enhanced penetration /delivery of active agent (e.g. TrkB or TrkC agonist).
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 27, 32, 38-43, 45, 47, and 49 -51 are rejected under 35 U.S.C. 103 as unpatentable over Kujawa et al. (WO 2017120465 A1, Applicant’s IDS dated 08/24/2023) in view of Simons et al. (US 8,822,410 B2), Yoshpe et al. (US 8758836 B2, Applicant’s IDS dated 08/24/2023) and Minaiyan et al. ( Res Pharm Sci. 2014 Jul-Aug;9(4):225-31.Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats)(partially newly reapplied as necessitated by amendment).
Kujawa teaches a method of treating or reducing the risk of developing hidden hearing loss by administering a small molecule Trk agonists (e.g., 7, 8-dihydroxyflavone (DHF), amitriptyline, imipramine, , 7,8,3'-Trihydroxyflavone (THF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) (See abstract, page 2, lines 30-34; page 3, lines 1-32; page 11, lines 29-33; Examples1-4; Figures 1-6; claims 1-14).
Regarding the solubilizing agent, Kujawa teaches pharmaceutically acceptable carrier, e.g. oils, polyethylene glycols, glycerine, propylene glycol , benzyl alcohol (See page 12, lines 15-22).
Kujawa is silent about the terpene as diffusing agent.
The collective teachings of Simons, Yoshpe and Minaiyan are elaborated in preceding 103 rejection are applied as before. Simons collectively teaches a method of treating ear disease comprising administering composition comprising active agent, solubilizing agent (alcohol, vegetable oils, etc.) and penetration enhancer (terpene and derivatives, e.g. limonene, linalool, etc.) across tympanic membrane. Simons teaches tympanic membrane permeating ear drops.
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instantly claimed invention to incorporate the terpene penetration enhancer and solubilizer taught by Simmons and Yoshpe into Kujawa’s composition comprising TrkB or TrkC agonist for treating inner ear disorder (e.g. tinnitus, hearing loss), together with experimentation/optimization based on general knowledge of pharmaceutical composition for treating ear disease/disorder, and arrive at the instant invention with reasonable expectation of success. A skilled artisan would be motivated to combine the teachings of Kujawa, Simons and Yoshpe, for treating ear disease/disorder because all teachings are directed to treating ear disease and Simons teaches penetration enhancer across tympanic membrane. Minaiyan teaches apricot kernel oil having antioxidant, anti-inflammatory property used for treating otis and tinnitus. The combined teaching of prior art, together with experimentation/optimization based on general knowledge of pharmaceutical composition for treating ear disease/disorder, would provide a method for treating inner ear disorder (e.g. hearing loss) with enhanced penetration /delivery of active agent (e.g. TrkB or TrkC agonist).
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of pharmaceutical composition for treating ear disease(e.g. inner ear disorder, etc.). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 27, 32, 38-43, 45, 47 and 49-51 are rejected under 35 U.S.C. 103 as unpatentable over Saragovi et al. (US 2017/0029511 A1), in view of Simons et al. (US 8,822,410 B2), Latino (The Hearing Journal 63(11):p 49-50, November 2010, DOI: 10.1097/01.HJ.0000390822.09995.ba, The ingredients and benefits of Quietus, a homeopathic treatment for tinnitus) and Minaiyan et al. ( Res Pharm Sci. 2014 Jul-Aug;9(4):225-31.Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats)(reapplied/reiterated as necessitated by amendment) .
Saragovi teaches a method for treating otic diseases or conditions comprising administering an otic composition comprising a therapeutically effective amount of TrkB or TrkC agonist to an individual in need thereof, through direct application of aforementioned compositions onto or via perfusion into the targeted auris structure(See abstract, [0005], [0059], Examples 1-11, claims 1, 7, 16-23).
Regarding the active agent recited in claims 27 and 47-51 , Saragovi teaches TrkB or TrkC agonist selected from a group consisting of 7.8-dihydroxy flavone, 7.8.3'-Trihydroxyflavone…N-acetylserotonin, and amitryptiline (See [0021],[0042], [0177]). Saragovi also teaches embodiments wherein the TrkB or TrkC agonist is a chemically modified analog of a neurotrophic agent, wherein the neurotrophic agent is brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophin-4, fibroblast growth factor(FGF)(See [0023], [0157]).
Regarding the inner ear disorder recited in claims 41-43, Saragovi teaches the otic disease is ototoxicity, chemotherapy induced hearing loss, excitotoxicity, sensorineural hearing loss, noise induced hearing loss, Meniere's Disease/Syndrome, labyrinthitis, Ramsay Hunt's Syndrome, age-related hearing loss (presbycusis), vestibular neuronitis, tinnitus, etc. (See [0059]-[0061], [0115]-[0149], Examples 3-9). Saragovi teaches embodiments wherein a TrkB or TrkC agonist reduces or inhibits auris sensory cell damage and/or death associated with tinnitus, and other treatment options for tinnitus, e.g. lidocaine, selective neurotransmitter reuptake inhibitors, benzodiazepines, etc. ( See [0122]).
Regarding the administration limitation recited in claim 27 and 39, Saragovi teaches intratympanic injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. Saragovi teaches embodiment wherein TrkB or TrkC agonist formulations are administered directly onto the round window membrane via transtympanic injection and another embodiment, the TrkB or TrkC agonist auris-acceptable formulations are administered onto the round window membrane via a non-transtympanic approach to the inner ear (See [0416]). Saragovi also teaches delivery system (e.g. syringe and needle apparatus) that is capable of piercing the tympanic membrane and directly accessing the round window membrane( See [0417]-[0419]). Saragovi explicitly teaches embodiments wherein the pharmacokinetic profile of active agent (e.g. BDNF and NT3) is evaluated/measured after intratympanic injection (See [0052], Example 3, FIG. 2A and FIG. 2B).
Regarding the solubilizing agent, Saragovi teaches commonly used solvents/carrier for administration to the ear, e.g. alcohols, propylene glycol, etc.(See [0064], [0358] ). Saragovi teaches solubilizer that assist or increase the solubility of the TrkB or TrkC agonists, e.g. ethanol, n-butanol, isopropyl alcohol, polyethylene glycol, glycofurol, transcutol, propylene glycol and the like(See [0097]) (which also reads on instant claim 35). Saragovi also teaches auris-acceptable surfactants, e.g. polyoxyethylene fatty acid glycerides, vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil;. (See [0387], [0389]). Saragovi teaches embodiments of lipid nano capsules comprising emulsifying capric and caprylic acid triglycerides(See [0369]). Please note the apricot oil recited in claim 34 is considered as functional equivalent of castor oil and other vegetable oil as solubilizing agent in absence of evidence to the contrary.
Regarding the diffusing agent, Saragovi teaches round window membrane penetration enhancers , e.g. surfactants, Tween 80, fatty acids and derivatives, etc. alcohols (ethanol, isopropanol, glycerol, propanediol and the like) also function as round window membrane penetration enhancers (See [0397]).
Regarding claim 32, Saragovi teaches various concentration of a TrkB or TrkC agonist between about 0.01%-about 20%, between about 0.01%-about 10%, between about 0.01%-about 7.5%, between about 0.01%- 6%, between about 0.01-5%, between about 0.1-about 10%, or between about 0.1-about 6% of the active agent by weight of the formulation (See [0289]-[0290]). Saragovi explicitly teaches embodiments of TrkB or TrkC agonist formulation comprising 1% of active agent (See Example 1, Table 4).
Regarding claims 40-43 and 45, Saragovi teaches clinical trial of TrkB or TrkC agonist for treating tinnitus, wherein the dosage is administered in 10uL by intratympanic injection (See Example 4). Saragovi also teaches clinical trial of TrkB or TrkC agonist for treating noise induced hearing loss, wherein 4% by weight of TrkB or TrkC agonist is administered in 10uL by intratympanic injection (See Example 5).
Saragovi collectively teaches a method of treating inner ear disorder (e.g. tinnitus, hearing loss) comprising administration of a therapeutically effective dose of pharmaceutical composition comprising an active agent ( TrkB or TrkC agonist, e.g. 7.8-dihydroxy flavone) and solubilizing agent (e.g. alcohol) via tympanic membrane.
Saragovi is silent about ear drop and terpene and derivative as diffusing agent. A skilled artisan would have known ear drop is the common dosage form for treating otic disease.
The collective teachings of Simons as elaborated in preceding 103 rejection are applied as before. Simons collectively teaches a method of treating ear disease comprising administering composition comprising active agent and penetration enhancer (terpene and derivatives, e.g. limonene, linalool, etc.) across tympanic membrane. Simons teaches tympanic membrane permeating ear drops. Please note the bisabolol is considered as functional equivalent of limonene, linalool and other terpene taught by Simons as diffusing agent in absence of evidence to the contrary. The apricot oil is considered as functional equivalent of sesame oil, and other vegetable oil as solubilizing agent taught by Simons.
Latino teaches natural herbs remedy and benefits of homeopathic treatment for tinnitus (See whole article). Latino teaches α-bisabolol and its oxide and azulenes, including chamazulene and acetylene derivatives are principal components of the essential oil extracted from chamomile flowers for treating tinnitus. Latino teaches terpenoids and bisabolol have been shown to have anti-inflammatory, anti-allergic, antispasmodic, antibacterial, antipyretic, ulcer-protective, and antifungal properties (page 49, right column).
Minaiyan teaches apricot kernel have shown antioxidant and radical scavenging properties, antimicrobial activity and antitussive effects, and apricot kernel oil has also been used as remedy for otitis and tinnitus in drop dosage form (See page 226, left column, para1).
It would have been prima facie obvious to one of ordinary skilled in the art before the effective filing date of instantly claimed invention to incorporate the terpene penetration enhancer taught by Simmons into Saragovi’s composition comprising TrkB or TrkC agonist for treating inner ear disorder (e.g. tinnitus, hearing loss), together with experimentation/optimization based on general knowledge of pharmaceutical composition for treating ear disease. Latino further teaches α-bisabolol terpene is a natural herbs remedy for homeopathic treatment for tinnitus. Minaiyan teaches apricot kernel oil used for treating otis and tinnitus. A skilled artisan would be motivated to combine the teachings of prior art, together with experimentation/optimization based on general knowledge of pharmaceutical composition for treating ear disease/disorder, and reasonably expect the pharmaceutical composition comprising TrkB or TrkC agonist, solubilizing agent (alcohol, vegetable oils/apricot oil, etc.) and terpene penetration enhancer (e.g. bisabolol) would provide a method for treating inner ear disorder (e.g. tinnitus, hearing loss) with enhanced penetration /delivery of active agent (e.g. TrkB or TrkC agonist).
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Birbara et al. EP3345594B1. Birbarat teaches apricot oil as surfactant/ solubilizing agent in pharmaceutical composition comprising flavonoid compounds.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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