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 . 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.
Election/Restrictions
Applicants elected group I (formulations) and a formulation comprising poloxamer 407, neurotrophin 3, and SEQ ID 1 without traverse in the reply filed on 24 Sept, 2024.
Claims Status
Claims 1, 52, and 80 are pending.
Maintained/Modified Rejections
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.
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, 52, and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Suzuki et al (Sci. Rep. (2016) 6-24907) in view of Goycoolea et al (Microscop. Res. Tech. (1997) 36 p201-211, cited by applicants) and Bocsik et al (J. Pharma. Sci. (2016) 105 p754-765).
Suzuki et al describe the effect of neurotrophin 3 on acoustically damaged cochlear synapses (title). The therapy was effective in restoring cochlear function in mice after several days (2nd page, 5th paragraph). The material was formulated as a gel using a poloxamer to form extended release gels (8th page, 3d paragraph), specifically, poloxamer 407 with PBS (8th page, 9th page). However, the administration involved surgery to make a hole in the otic window (8th page, 5th paragraph), and mentions using a needle to do so in humans (abstract).
The difference between this reference and the claimed formulation is that this reference does not describe a permeation enhancer.
Goycoolea et al discuss the otic membrane in the context of permeability (title). The outer epithelial layer is a single layer of cells comprising tight junctions (p201, 1st column, 3d paragraph, continues to 2nd column). This covers a core of connective tissue, where the fibers are loosely arranged (p201, 2nd column, 2nd paragraph), i.e. porous. The inner layer is epithelial cells, but there are gaps in between them (p202, 1st column, 2nd paragraph, continues to 2nd column). This reference suggests that the main barrier to compounds is the tight junctions of the outer epithelial layer.
Bocsik et al discuss reversibly opening epithelial tight junctions using modulator peptides (title). Six different peptides, acting at different targets (some of which are unknown) were used (p755, 1st column, 2nd paragraph). Among the sequences tested is PN-159 (table 1, p755, bottom of page), identical with SEQ ID 1 of the examined application. These sequences were screened against two biological tight junctions; the intestinal wall and the blood brain barrier (p755, 1st column, 3d paragraph). PN-159 was one of the most effective sequences in opening up these model systems (p757, 2nd column, 6th paragraph, continues to p758, 1st column, 3d paragraph). Experiments used 1 mM concentrations (p756, 1st column, 2nd paragraph), which is, in round numbers, 0.2% w/vol. This reference describes screening sequences, including the one used by applicants, to find which ones work best for opening tight junctions, such as the ones described by Goycoolea et al.
Therefore, it would be obvious to screen the peptides of Bocsik et al in the formulation of Suzuki et al, to allow the formulation to open the tight junctions discussed by Goycoolea et al and allow the drug access past the otic membrane without compromising its integrity. As these are known tight junction modulator peptides, shown effective to open two different tight junctions, an artisan in this field would attempt these peptides with a reasonable expectation that one would be effective. Note that this is an obvious to try rejection, with the recognized problem of access across the otic window, a finite number of peptides identified as possible modulators of this window, and a finding that there is a reasonable expectation of success pursuing these solutions (MPEP 2143(I)(E)).
Adding the permeation enhancer sequence of Bocsik et al to the formulation of Suzuki et al will add a peptide of SEQ ID 1 to neurotrophin 3. Thus, the combination of references renders obvious claim 1.
The polypeptide was tested at about 0.2% w/vol, rendering obvious claim 52.
The formulation of Bocsik et al comprises PBS, an aqueous solution, rendering obvious claim 80.
response to applicant’s arguments
Applicants argue that Suzuki et al provides no motivation to find an alternative route of administration, that the tight junctions of Bosick et al are different from the ones of Goycoolea et al, making the combination non-obvious, that there is no reasonable expectation of success, that the rejection is an improper obvious to try, and that it is unexpected that the invention gives extended exposure of the drug without any change in auditory brainstem response.
Applicant's arguments filed 24 July, 2026 have been fully considered but they are not persuasive.
Applicants argue that there is no rationale for changing the dosing method of Suzuki et al. However, it is generally accepted that scientists and artisans are always looking for improvements on what is already known (MPEP 2144.05(II)(A)). In essence, applicant’s argument is that an artisan in this field would assume a method where the tissues of the ear are exposed through surgery is as good as can be gotten, and will not investigate it further. This seems unreasonable.
Applicants argue that the tight junctions of Bocsik et al are different from the tight junctions of the invention, and there is no nexus between them. However, Bocsik et al discuss successfully screening peptides against two different tight junction models. That is sufficient to render obvious running the same test against another tight junction.
Applicants argue that there is no reasonable expectation of success. However, Bocsik et al show that the screen found peptides that open tight junctions in every system tested. That is a reasonable expectation of success for screening another tight junction.
Applicants argue that it is improper to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result. This is not the rejection; the only variable screened is the identity of the peptide, which is a group of six possible sequences.
Applicants argue that it is unexpected that the invention provides extended exposure through the otic window without affecting ABR. It is not clear why this is unexpected. Suzuki et al teaches that the poloxamer in the formulation provides for extended release, as noted in the rejection, and that ABR had no significant differences between the test and control groups (p2, 4th paragraph). Bocsik et al teaches screening sequences to open tight junctions; the fact that one of them opens the tight junctions in the otic window, which would allow access though that barrier, is not surprising. In other words, the results applicants are claiming are unexpected are what would be predicted based on the references used in the rejection.
Examiner’s Note
Application 19/685,885 has no claims submitted yet, but the title is suggestive of an obvious variant of the claimed invention. Once the claims are submitted, it will be checked if they render obvious the examined claims.
Applicants have claimed a formulation with “an amino acid sequence of . . .” This language is typically interpreted as allowing for fragments of the sequence. If applicants want to limit to sequences comprising SEQ ID 1, they can amend to “the amino acid sequence of . . . “
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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