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 .
Summary of Claim Status
Currently, Claims 1-11 are pending.
Claims 5-7 are objected (see comments below).
Claims 1-10 are rejected (see comments below).
Claim 11 is withdrawn (see comments below).
The applicant’s proper response must address all outstanding issues in this office action. For clarity, the outstanding issues have been identified 1-12.
Election of Species
This application contains claims directed to the following patentably distinct species:
Species Group A: The Species Group A consists of a genus of Toll Like Receptor 7 and/or Toll Like Receptor 9 (TLR7/9) antagonists. The Species Group A consists of the species: quinine drug; and oligodeoxynucleotide 2088 (ODN 2088).
Distinctness
The species are independent or distinct because these are structurally different molecules that have different structure and mechanism of action and further searching for one would not likely yield art pertinent to the other species. In addition, these species are not obvious variants of each other based on the current record.
Search Burden
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: The Species of Group A fall within separate CPC codes, A61K31/4706 and A61K31/711 respectively, and therefore present and undue search burden on this examiner.
Applicant’s Response
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable.
Regarding Species Group A, applicant must select a single species for Claim 8.
Regarding Species Group A, Claims 9 and 10 are drawn to a quinine drug; Claim 11 is drawn to ODN 2088.
Currently, Claims 1-7 are generic.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
Means for Traversal
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
Inventorship
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Election/Restrictions
During a telephone conversation with Justin King on 02/18/2026 a provisional election was made without traverse to prosecute the invention of a quinine drug, Claims 1-7, 9, and 10. Claim 8 will only be considered in regards to the elected species, quinine drug, and will not be considered in respect to the non-elected species, ODN 2088.
1. Affirmation of this election must be made by applicant in replying to this Office action.
Claim 11 is withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. TW 111138092, filed on 10/06/2022.
Information Disclosure Statement
Applicant has failed to file an Information Disclosure Statement (IDS).
Due to the applicant’s failure to file an information disclosure statement, the application fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed.
Furthermore, the application fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement.
Claim Objections
2. Claims 5-7 are objected to because of the following informalities: Claim 5 lacks the article “a” before cochlea. Claims 6 and 7 presumably recite the cochlea of Claim 5. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 8-10 are rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 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.
3. Regarding Claim 8: Claim 8 contains the trademark/trade name “oligodeoxynucleotide 2088 (ODN 2088).” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an oligodeoxynucleotide and, accordingly, the identification/description is indefinite.
4. Regarding Claim 9, 10: Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
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.
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 1-10 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, because the specification, while being enabling for “A method for… preventing”, does not reasonably provide enablement for “A method for treating…” 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.
Breadth of the Claims
Regarding Claim 1: Claim 1 recites “A method for treating and/or preventing hearing loss, comprising administering to a subject in need thereof … a Toll-like receptor 7 and/or 9 antagonist (TLR7/9 antagonist).” The portion of the claim, “A method for treating…,” particularly the term “treating,” is interpreted to mean the subject has a treatable condition and the condition is, wholly or in-part, reversible. This examiner’s assessment of the preamble holding patentable weight was guided by MPEP 2111.02 §II, ¶1 (Nantkwest , Inc. v. Lee, 686 Fed. App'x 864, 867 (Fed. Cir. 2017)).
Regarding Claim 3: Claim 3 recites a particular type of hearing loss, “…idiopathic sudden sensorineural hearing loss…" Idiopathic sudden sensorineural hearing loss (ISSHL) is hearing loss whose cause cannot be determined (Suckfüll 2009). Therefore, ISSHL is potentially non-noise induced hearing loss.
Nature of the invention
Regarding Claim 1: The claims are directed toward treating hearing loss, by administering TLR7/9 antagonist thereby reducing the inflammatory response to noise with subsequent death or damage to outer hair cells (OHC). The method takes advantage of the inflammatory signaling pathway activated by TLR7/9 receptors. TLR7/9 activation induces an inflammatory response that includes macrophage recruitment and increased expression of inflammatory cytokines and chemokines including interleukin-1β (II-1ß), tumor necrosis factor-a (Tnf-α), Interferon regulatory factor 7 (Irf-7), C-C motif chemokine ligand 2 (Ccl2), C-C motif chemokine ligand 4 (Ccl4), and C-C motif chemokine ligand 12 (Ccl12) (Figs. 3-6). This inflammatory recruitment and response leads death of OHCs (Fig. 3).
Regarding Claim 3: The claim is directed the specific type of hearing loss, ISSHL.
State of the Prior Art an Level of Ordinary Skill
Regarding Claims 1 and 3: The state of the prior art regarding hearing loss treated via TLR7/9 antagonists is illustrated by Nedergaard (Nedergaard. US 2025/0049957 A1. 2025. Effectively filed December 23, 2021). Nedergaard teaches TLR7/9 antagonists prevent hearing loss [0007], [0012]. Nedergaard further teaches the mechanism for hearing loss is “damage or loss of inner ear cells, e.g., cochlear hair cells (OHCs).” Furthermore, it is well known that “macrophages… are recruited to sites of cellular injury” in the inner ear leading to OHC loss (Warchol et al. 2021. Macrophages Respond Rapidly to Ototoxic Injury of Lateral Line Hair Cells but Are Not Required for Hair Cell Regeneration. Front. Cell. Neurosci. 14:613246.). Additionally, macrophage induction via TLR7/9 is well known according to Karper, “Activation of endosomal TLRs like TLR7 and TLR9 may lead to upregulation of interferon-α (IFN-α), interleukin-6 (IL-6), IL-12, or tumor necrosis factor-α (TNF-α) by innate immune cells (e.g., macrophages). (Karper et al. Blocking Toll-Like Receptors 7 And 9 Reduces Postinterventional Remodeling Via Reduced Macrophage Activation, Foam Cell Formation, And Migration. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):e72-80.)”
Multiple modes of hearing loss are well known in the art. Nedergaard teaches many, including: “genetic hearing loss, such as autosomal dominant hearing loss, autosomal recessive hearing loss, or X-linked hearing loss. The hearing loss can be acquired hearing loss, such as noise-induced hearing loss, age-related hearing loss, disease or infection-related hearing loss, head trauma-related hearing loss, or ototoxic drug-induced hearing loss.” Suckfüll describes two types of hearing loss: “noise-induced” and “sudden, idiopathic sensorineural hearing loss (SSNHL)[ISSHL] (Suckfüll et al. Dtsch Arztebl Int 2009; 106(41): 669–76).” Suckfüll further states “SSNHL [ISSHL] is an acute dysfunction of the inner ear whose cause cannot be determined with the currently available methods of clinical diagnosis.” If the cause, and by default the mechanism, is indeterminable, then the mechanism of repair must also be indeterminable. The instant application has not shown any evidence that current methods have advanced to determine the cause, treatment, nor mechanism of either of ISSHL.
Guidance of Specifications and Working Examples
The specification does not show the applicant has enabled the full scope of the invention such that the invention as claimed reverses the condition of hearing loss, wholly or in-part. This examiner would have considered content in the specifications which describes subjects with a prior condition of hearing loss regaining at least some function of hearing after treatment using the method of this instant invention.
5. Regarding Claim 1: The specifications only provide enablement for “prevention of hearing loss” (Examples 1-5).
6. Regarding Claim 3: The specifications only provide enablement for "noise induced hearing loss" (Examples 1-5).
The specification show the prevention of hearing loss via prevention of OHC loss(Fig 3). However, the specifications do not show any restoration of OHC.
The specifications lack evidence of enablement toward “treatment” of hearing loss. Additionally, the specifications lack evidence of enablement toward any other type of hearing loss beyond noise-induced hearing loss, for example conductive hearing loss, mixed hearing loss, and Auditory Neuropathy Spectrum disorder hearing loss. The causes and treatments of non-noise induced hearing loss differ substantially phenotypically and mechanistically from noise induced hearing loss and the unknown nature of ISSHL, in particular, does not allow for a general treatment as described in the invention.
Predictability and Quantity of Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. It would be necessary to test TLR7/9 attenuation in subject models with multiple modes of existing hearing loss. However, this experimentation would be highly unpredictable from model to model since the specification provides no guidance toward restoring hearing loss wholly or in part. Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4-7 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Nedergaard (US 20250049957 A1, effectively filed December 23, 2021), as evidenced by Warchol (Warchol et al. 2021. Macrophages Respond Rapidly to Ototoxic Injury of Lateral Line Hair Cells but Are Not Required for Hair Cell Regeneration. Front. Cell. Neurosci. 14:613246) and Karper (Karper et al. Blocking Toll-Like Receptors 7 And 9 Reduces Postinterventional Remodeling Via Reduced Macrophage Activation, Foam Cell Formation, And Migration. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):e72-80).
7. Regarding Claim 1: Nedergaard teaches A method for treating and/or preventing hearing loss ([0012], [0069]), comprising administering to a subject in need thereof ([0012]) a pharmaceutical composition ([0061]) comprising an effective amount ([0012]) of a… Toll-like receptor antagonist and/or Toll-like receptor 9 antagonist (TLR9 antagonist) ([0007]). Whereas Nedergaard does not teach a TLR7 antagonist, the specification in the instant application teaches TLR7 and TLR9 are interchangeable [0006], [0010], [0011]… [0037], [0038], [0039]. Furthermore, the instant application uses Invivogen’s ODN2088 as a TLR7/9 antagonist [0039]. However, the specification sheet provided by Invivogen does not indicate ODN2088 is a TLR7 antagonist (Invivogen. ODN2088 spec sheet. Version 18J26-MM_tds). Therefore, since the instant application treats TLR7 and TLR9 as interchangeable, Nedergaard therefore teaches a TLR7/9 antagonist.
8. Regarding Claim 2: Nedergaard further teaches …wherein the hearing loss is acute sensorineural hearing loss ([0072]).
9. Regarding Claim 4: Nedergaard further teaches … wherein the noise-induced hearing loss is noise-induced outer hair cell loss ([0065], [0084]).
10. Regarding Claim 5, 6, and 7: Nedergaard further teaches Claim 5 …wherein the TLR7/9 antagonist attenuates noise-induced increased gene expression of cytokines and chemokines in cochlea; Claim 6 …. wherein the TLR7/9 antagonist attenuates noise-induced increase of nuclear factor kappa-B (NF-KB) expression in cochlea; and Claim 7 … wherein the TLR7/9 antagonist decreases noise-induced macrophage infiltration into cochlea. The instant claims simply state scientific truisms. TLR7/9 activation induces an inflammatory response that includes macrophage recruitment and increased expression of inflammatory cytokines and chemokines including interleukin-1β (II-1ß), tumor necrosis factor-a (Tnf-α), Interferon regulatory factor 7 (Irf-7), C-C motif chemokine ligand 2 (Ccl2), C-C motif chemokine ligand 4 (Ccl4), and C-C motif chemokine ligand 12 (Ccl12) (Figs. 3-6). This inflammatory recruitment and response leads to death of OHCs (Fig. 3). This truism is supported by Warchol, and Karper. “Macrophages… are recruited to sites of cellular injury” in the inner ear leading to OHC loss (Warchol et al. 2021. Macrophages Respond Rapidly to Ototoxic Injury of Lateral Line Hair Cells but Are Not Required for Hair Cell Regeneration. Front. Cell. Neurosci. 14:613246.). Additionally, macrophage induction via TLR7/9 is well known according to Karper, “Activation of endosomal TLRs like TLR7 and TLR9 may lead to upregulation of interferon-α (IFN-α), interleukin-6 (IL-6), IL-12, or tumor necrosis factor-α (TNF-α) by innate immune cells (e.g., macrophages) (Karper et al. Blocking Toll-Like Receptors 7 And 9 Reduces Postinterventional Remodeling Via Reduced Macrophage Activation, Foam Cell Formation, And Migration. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):e72-80.).”
A TLR7/9 antagonist will inherently inhibit the downstream effects, including downstream gene expression of cytokines, chemokines, and nuclear factor kappa-B (NF-kB) and macrophage infiltration in the cochlea. Therefore, Nedergaard anticipates the invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
11. Regarding Claims 8 and 9: Claim 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Nedergaard as applied to claim 1 above, and further in view of Sun (Sun et al. TLR7/9 Antagonists as Therapeutics for Immune-Mediated Inflammatory Disorders, Inflammation & Allergy - Drug Targets; Volume 6, Issue 4, Year 2007.).
Claim 8 depends from Claim 1 and is therefore rejected for all of the reasons inherited from Claim 1 as taught by Nedergaard. Particularly, Nedergaard teaches a method for treating and/or preventing hearing loss, by administering a TLR9 antagonist.
Regarding claims 8 and 9, Nedergaard does not teach that the TLR9 antagonist that was administered to the subject was a quinine drug, or chloroquine or hydroxychloroquine.
However, Sun teaches “TLR7/9 antagonists, such as… chloroquine, hydroxychloroquine and quinacrine, have been used since the 1950s (abstract).” Furthermore, the specifications of the instant application recognizes quinine drugs include chloroquine and hydroxychloroquine [0014]. Therefore, according to Sun, quinine drugs, specifically chloroquine and hydroxychloroquine, have long been known in the art to be TLR7/9 antagonists. Therefore, Sun teaches … wherein the TLR7/9 antagonist is a quinine drug.
Therefore, regarding claims 8 and 9, it would have been obvious to one of ordinary skill in the art to have modified the method of Nedergaard by specifically administering chloroquine or hydroxychloroquine because it would have merely amounted to a simple substitution of one known TLR9 antagonist for another to yield predictable results. A person having ordinary skill in the art (PHOSITA) at the time of the filed instant invention using the method of Nedergaard’s embodiment envisioned by a TLR9 antagonist would necessarily look to a specific antagonist. Motivated by this necessity, a PHOSITA would have found and used the quinine drug taught by Sun because they were known to have this common function of TLR7/9 antagonist activity.
12. Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Nedergaard and Sun as applied to claim 9 above, and further in view of Youle (Youle. US 2002/0016335 A1. 2002).
Claim 10 depends from Claim 9 and is therefore rejected for all of the reasons inherited from Claim 9 as taught by Nedergaard and Sun. In particular, a method for treating and/or preventing hearing loss, by administering a chloroquine TLR7/9 antagonist.
Nedergaard and Sun do not teach the 40-60mg/kg chloroquine dose of the instant claim.
However, Nedergaard contemplates a dosing regimen of “an effective amount” and further teaches delivering a pharmaceutical agent “… at dosages… necessary… ([0101]).”
Additionally, Youle teaches administering a therapeutic chloroquine dose of 45mg/kg ([0102]). Youle is in the same field of endeavor, medical health research, as Nedergaard and Sun. Furthermore, the 45mg/kg dose of Youle anticipates the 40-60 mg/kg range of the instant application. Therefore, Youle teaches … wherein the effective amount of the chloroquine is 40-60 mg/kg of the subject.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the dosage of Youle with the method and teachings of Nedergaard and Sun because a PHOSITA using the combined methods of Nedergaard’s TLR7/9 antagonist lacking a specific effective dosing amount and Sun’s chloroquine would necessarily look to a specific chloroquine dose. Motivated by this necessity, a PHOSITA would have found and used the chloroquine dose taught by Youle. This amounts to simply “applying a known technique (Youle’s chloroquine dose of 45mg/kg) to a known method (Nedergard and Sun’s treating hearing loss with an effective amount of chloroquine) ready for improvement to yield predictable results.
Therefore, it would have been obvious for a PHOSITA at the time of filing to combine the dosage of Youle with the method and teachings of Nedergaard and Sun to arrive at the same instant invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AARON DUREL WARD whose telephone number is (571)272-8495. The examiner can normally be reached Mon to Thursday 8:00AM 7:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 15712705919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AARON DUREL WARD/ Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636