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.
Claims Status
Claims 14-17, 20, and 21 are pending.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(b)
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 14-17, 20, and 21 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.
Claim 14 requires the only active ingredient to be Aβ1-6A2V(D), and that non-active ingredients are compatible with contact with intranasal mucosa. There are two issues with this. Applicants have not defined what an active ingredient is. There are medicinal formulations that use water as an active ingredient (McKession Eye Wash solution, https://www.bettymills.com/mckesson-eye-wash-solution-active-ingredient-983-percent-purified-water-inactive-ingredients-boric-acid-sodium-borate-sodium-chloride-1-oz-squeeze-bottle-144-cs-mck19828-mon1188884cs?srsltid=AfmBOoqcw8aPOh79ikQ6rrsplbyIaFFWf_-Ot9U9h_ji0yhPBO-ZSXq7, downloaded 18 Nov, 2025). Humble (Arizona dept. health services blog post of 19 June, 2012) states that all chemicals are toxic if the dose is high enough (first paragraph). This means that all chemicals will have a therapeutic effect (which may be undesirable). This makes it unclear what applicants consider an active ingredient, and what the limitation of the peptide being the sole active ingredient excludes.
Applicants have also not defined what compatible with contact with intranasal mucosa means. As noted before, all chemicals are toxic with a high enough dose. This could mean anything from “does not usually melt user’s nose if used judiciously” to “harmless in the usual doses to almost all of the population.” Without a definition of the phrase, it is not clear what this limitation excludes.
response to applicant’s arguments
Applicants describe examples of excipients that meet the claim limitations, state that they are well known in the art, so do not need to be disclosed.
Applicant's arguments filed 7 May, 2026 have been fully considered but they are not persuasive.
Applicants have listed a number of common excipients, and state that these components are well known in the art. However, the claim does not limit the excipients to those described by applicants. Nor does this argument answer the two issues raised in the rejection, which are 1) what is excluded by limiting the active ingredient to the peptide (“consisting of . . as an active ingredient”) and 2) what is excluded by “compatible with contact with the intranasal mucosa.”
Note that there have been pharmaceutical formulations that were acidic enough to dissolve clothing (FYI column, Lufkin Daily News, issue of 2 Jan, 2009). The fact that something is known in the art does not clearly make it safe for nasal mucosa.
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) 14-17, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Di Fede et al (Sci Rep. (2016) e:20949, cited by applicants) in view of Erdo et al (Brain Bull. Res. (2018) 143 p155-170) and Le Tourneau et al (J. Natl. Canc. Inst. (2009) 101 p708-720).
Di Fede et al discuss treating Alzheimer’s disease with A2V variants of amyloidβ (title). The therapeutic is Aβ1-6A2V(D); the (D) signifies d-amino acids to increase its stability in vivo; this hinders AβWT oligomer production and amyloid fibril formation (p5, 2nd paragraph). The peptide is non-toxic to cells even at high concentrations (20 µM) and protects cells against WT amyloid (p5, 8th paragraph). This material was conjugated to TAT to make translocation across the BBB possible (p9, 9th paragraph). The conjugated material reduced AβWT production and aggregation, and prevented amyloid deposition with once weekly treatment in a mouse model of Alzheimer’s disease (p7, 9th paragraph).
The difference between this reference and the instant claims is that this reference does not discuss intranasal administration, nor does it discuss dose and dose schedule for the drug.
Erdo et al discuss intranasal administration for brain targeting of drugs (title). This allows for direct access to the brain, bypassing the BBB, and results in beneficial PK/PD profile (p155, 2nd column, 1st paragraph). A handful of studies using this form of administration to direct peptides to the brain to treat animal models of Alzheimer’s disease are mentioned (table 3, p161, table 4, p162, top of page). Various administration forms, including direct application with a cannula, pipette or syringe, a spray, or an atomizer are mentioned (table 1, p158, bottom of page).
Le Tourneau et al discuss dose escalation methods (title). The main goal of a phase I clinical trial is to establish the dose and dose schedule for new drugs or combinations of drugs (abstract). The point of this is to have as many patients as possible in the therapeutic dose range, while preserving safety and maintaining rapid accrual (p708, 1st column, 2nd paragraph). If toxicity is not a limiting factor, the occurrence of drug related biological effects can be used as an endpoint (p708, 2nd column, 1st paragraph). A number of different protocols are mentioned for optimizing these parameters (fig 2, p711, top of page). This reference discusses optimizing the dose and dose schedule.
Therefore, it would be obvious to use the peptide of Di Fede et al (without the TAT) as a substitution of one known element (the TAT of Di Fede et al) with another (the intranasal administration of Erdo et al) yielding expected results (administration to the brain). As the method of Erdo et al is well known for this purpose, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to optimize the dose and dose schedule of the drug of Di Fede et al, to have as many patients as possible in the therapeutic dose range while preserving safety and maintaining rapid accrual, as discussed by Le Tourneau et al. As all drugs need to have their dose and dose schedule optimized before use in the general public, an artisan in this field will have experience in such optimizations, leading to a reasonable expectation of success.
As Erdo et al provides an alternative method to gain access across the BBB, the TAT is optional in this administration scheme. Di Fede et al discuss using Aβ1-6A2V(D) to treat Alzheimer’s disease if it can cross the BBB. Erdo et al teaches using intranasal administration to cross the BBB, rendering that route of administration obvious. Le Tourneau et al discuss optimizing the dose and dose schedule of the therapeutic. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also 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.”) (MPEP2144.05.II). Thus, the combination of references renders obvious claims 14, 17, and 20.
This is the same peptide used to treat the same disease as Di Fede et al, so it will necessarily have the same effects, rendering obvious claims 15, 16, and 21.
response to applicant’s arguments
Applicants argue that d-peptides are not interchangeable, cite several examples of different peptides of d-amino acids having different uptake, that Erdo is limited to a high level discussion of nasal routes, and did not teach the specific peptide used in the claims, that the cited references teach away from the modification in the rejection, that there is no reasonable expectation that the peptide, delivered intranasally, would resist proteases, effectively traverse mucosal barriers, reach sufficient brain concentrations, and modulate tau pathology, claim an unexpected result that the material worked as described in the rejection, and that dose and dose schedule is not routine optimization in the unpredictable art of CNS delivery. These arguments are supported by a declaration by Prof. Giuseppe Di Fede, applicant.
Applicant's arguments filed 7 May, 2026 have been fully considered but they are not persuasive.
Applicants have cited a number of papers describing various formulations comprising a d-amino acid cell penetrating peptide and a therapeutic sequence, and demonstrate that different d-amino acid cell penetrating peptides will yield different bioavailabilities to the therapeutic sequences. This is used to argue that different d-amino acid sequences are not interchangeable, and would not be expected to work. However, the system described by these papers is different than the system claimed by applicants. The claims do not require (although arguably do not exclude) a cell penetrating sequence in the formulation, and the rejection does not discuss such sequences except that the it is not necessary to have the TAT of Di Fede et al conjugated to the sequence. In other words, the references are discussing a different phenomenon (the ability of a cell penetrating sequence to improve bioavailabilty) than what applicants are arguing (the uptake of a peptide dosed intranasally). Note that all the references cited by applicants that provide a control without the cell penetrating peptide demonstrate some bioavailability, albeit less than that than with the cell penetrating peptide. However, even low bioavailability can be compensated by using higher dose, note Hammerle et al (Bone (2012) 50 p965-973). In that reference, oral dosing of a peptide therapeutic used a dose two orders of magnitude greater than the injected control to achieve therapeutic plasma levels (abstract). While this reference discusses oral administration, Erdo et al (cited in rejection) states that intranasal administration tends to have higher bioavailability than oral drugs (abstract), which would minimize the problem. Even if we take at face value the argument that different d-amino acid peptides would have different bioavailabilities, this would reasonably be discovered and compensated for in optimizing dosing.
Applicants argue that Erdo et al is a high level discussion of nasal dosing, and does not discuss the peptide used in applicant’s claims. While it is agreed that the reference does not anticipate applicant’s claims, there is no law, case law, or regulation that requires that all limitations of a claim be found in a single reference for a rejection under 35 USC 103.
Applicants argue that the cited references teach away from the claims. However, applicants are discussing cell penetrating peptides in intranasal delivery, which is not a feature of the references cited in the rejection (save for a generic reference to permeability enhancers that does not mention cell penetrating peptides, Erdo et al, p164, 2nd column, 6th paragraph). Presumably these are the references that applicants have cited. However, none of these references state that intranasal delivery will not work without cell penetrating peptide, and the claims do not exclude cell penetrating peptides, except those conjugated to the peptide.
Applicants argue that there is no expectation that the claimed method would be effective in going through the nasal mucosa, resisting proteases, and working effectively in the brain. This is incorrect. Erdo et al discuss numerous compounds, including polypeptides such as peptides (p163, 1st column, 3d paragraph to 2nd column, 4th paragraph) and proteins (p162, 2nd column, 2nd paragraph to 2nd column, 3d paragraph) that have been successfully dosed by this route for brain disorders. This provides a reasonable expectation that the peptide of the claims will also do so. Di Fede et al show that the sequence will be effective once it reaches the brain (as described in the rejection), and that it was designed to resist proteases (5th page, 2nd paragraph). Aside from applicant’s word, there is no evidence on record that a person of ordinary skill in the art would expect the combination of the active sequence of Di Fede et al, dosed intranasally, would be ineffective.
Applicants claim an unexpected result that the claimed method is effective in their animal models. The burden is on applicant to establish that results are unexpected (MPEP 716.02(b)(I)). Applicants have not provided any evidence that a person of skill in the art would be surprised that the invention works as described in the rejection.
Finally, applicants argue that dose and dose schedule determination is not mere optimization with CNS drugs. Again, there are references on record showing similar experiments as those described by Le Tourneau et al for CNS disorders, note Phuphanich et al and the Xenon pharmaceuticals press release of 17 Oct, 2017. Applicants have provided no evidence beyond their word that dose and dose schedule optimization discussed by Le Tourneau et al is ineffective for CNS disorders. That is not sufficient to overcome the evidence of record.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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