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 .1
Status of the Claims
Claims 1-5,8,14-15,71 and 93-96 are under examination and are directed to elected species reserpine (without traverse) as per the response dated 5/27/2025.
Response to Arguments
Applicant's arguments filed Dec 3 2025 have been fully considered but they are not persuasive, with regard to the written description and scope of enablement rejections of amended claim 1 and claims 2-5,8,14-15,71 and 93-96. See detailed response to Attorney arguments below.
Applicant’s arguments, Dec 3 2025, with respect to the rejection of claims 1-5, 8, 14-15, 71 and 93-96, provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/289,823 have been fully considered and are persuasive. Amended claim 1 is directed generally to reserpine, tetrabenazine and their analogs, which are known as Vesicular Monoamine Transporter 2 (VMAT2) blockers. Reference Application 18289823 is specifically directed to serotonin receptor antagonists, an entirely different class of compounds. Further, neither reserpine nor tetrabenazine are claimed by Application 18289823. The rejection of claims 1-5, 8, 14-15, 71 and 93-96 has been withdrawn.
New Claim Rejections - 35 USC § 112 - Written Description
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 1-5, 8, 14-15, 71 and 93-96 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method for improving or accelerating wound healing, regenerating alveolar bone, regenerating connective tissue at a wound site, or decreasing wound area size, or minimizing scarring, in a subject comprising administering to a wound of the subject in need thereof an agent that suppresses expression of a clock gene, wherein the clock gene is neuronal PAS domain protein 2 (Npas2), for compounds including reserpine and tetrabenazine.
Initially, it is noted that Applicant has provided evidence that tetrabenazine has a healing effect when applied to an in vitro osteogenic assay of human periodontal mesenchymal stem cells, and wound healing using a mouse chronic wound mode, thus providing written support for tetrabenazine for methods of treating wound healing and decreasing wound size. See paragraphs 5-6, Rule 132 Declaration of Inventor Dr. Ichiro Nishimura, DDS.
Claim 1 recites use of the following agents,
Reserpine, rescinnamine, benzoyl reserpine, 3- methoxybenzoyl reserpine, 4-methoxybenzoyl reserpine, 3,4-dimethoxybenzoyl reserpine, 3,5-dimethoxybenzoyl reserpine, methylenedioxy reserpine, cinnamoyl reserpine, deserpidine, methyl reserpate, syrosingopine, evodiarnine, tetrabenazine, deutetrabenazine, or a stereoisomer of dihydrotetrabenazine
that suppresses a clock gene, specifically neuronal PAS domain protein 2 (Npas2), where it only provides sufficient written description for reserpine as an Npas2 suppressing agent. Examples 4-5, 8 16 and 20, as detailed below, provide written description support for the claimed invention with regard to reserpine (aka Dwn1 or Dwn-1 as identified in the specification).
Example 4 demonstrates in vivo skin wound healing with reserpine. Example 5 evidences periodontal tissue regeneration in a mouse model. Example 6 notes that reserpine’s selection for in vitro biological assays based on its best combined z score (HTS) from Example 2. Example 8 discloses reserpine’s efficacy in a known model for alveolar bone regeneration mouse ligature induced periodontitis mode. Example 16 is noted to only demonstrate that reserpine (aka Dwn1) was topically applied to palatal gingiva. Example 20 notes the use of reserpine in a murine model of surgical scar healing/prevention.
In summary Examples 4, 5, 8, 16 and 20 provide adequate written description to support the Npas2 suppressor agent, reserpine, for the claimed method of treating or accelerating wound healing, etc., as presently claimed.
The specification’s other working examples, Examples 1-3, 7, 9-15, and 17-192 merely are directed to demonstrating the role of Npas2 gene knockout (for example in mouse models); high throughput screening (HTS) of Npas2 suppressor compounds and/or prophetic working examples directed to reserpine and other compounds. None of these examples provide written description for the full scope of improving or accelerating wound healing, regenerating alveolar bone/connective tissue at a wound site or decreasing wound area size as claimed with the Npas2 suppressing agents as claimed.
While Example 2, Tables 1-2 disclose about 30 plus compounds, including lead and elected compound reserpine (aka Dwn1), and their high throughput screening for their Npas2 suppression activity, these tables are insufficient to demonstrate that the inventors has possession of the claimed invention. The mere HTS screening of compounds for activity cannot provide full written description support for the claimed use of any Npas2 suppressing agent to improve or accelerate wound healing, regenerating alveolar bone, regenerating connective tissue at a wound site or decreasing wound area size. While there is a demonstration that the inventors had possession of the invention for reserpine and the claimed methods of treatment, and tetrabenazine for wound healing/decreasing wound area size only, it cannot be said there is adequate written description support for any of the particular Npas2 inhibitors of claim 1.
Note while claim 1 recites various analogs of reserpine and tetrabenazine, there is no evidence on the record to support written description to treat the claimed conditions of claim 1.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states the claims are limited to reserpine and tetrabenazine and their analogs and therefore meet the written description requirement.
As noted in the rejection adequate written description support is on record for reserpine and tetrabenazine, with respect to wound healing. However, there is no evidence of record to support written description for the full scope of analogs that are still claimed.
New Claim Rejections - 35 USC § 112 - Scope of Enablement
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 1-5, 8, 14-15,71 and 93-96 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 reserpine for the claimed method for improving/accelerating wound healing, regenerating alveolar bone/connective tissue at a wound site, or decreasing wound area size with reserpine (also identified in the specification as Dwn1), it, does not reasonably provide enablement for any of the compounds of claim 1,3 that suppresses a clock gene, specifically neuronal PAS domain protein 2 (Npas2), and tetrabenazine for the improving/accelerating of wound healing and decreasing wound area size only. See paragraphs 5-6, Rule 132 Declaration of Inventor Dr. Ichiro Nishimura, DDS that provides enabling support for tetrabenazine for wound healing and decreasing wound size area.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Because claim 1 is directed Npas2 inhibiting/suppressing agents/compounds beyond the scope of reserpine and tetrabenazine, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate with the full scope of these claims.
Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set eight forth factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The predictability or unpredictability of the art:
The instant claimed invention is highly unpredictable since a person having ordinary skill in the art (PHOSITA) recognizes even in updated post filing work, reserpine is the lead Npas2 inhibitor/suppressing agent directed to the claimed method of wound healing.
Shibuya et al.4 (2022 article sharing co-authorship with inventors Hokugo, Sasaki, Okawa and Wang) noted the updated state of the art as per 2022, that downregulation of Npas2 gene with a HTS compound, reserpine, resulted in significant decreases in type I collagen and α-smooth muscle actin expression in [reserpine aka] Dwn-1 treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 [reserpine] treatment. See abstract.
Shibuya et al. teaches despite the HTS screen to identify a number of compounds to downregulate Npas2 activity, only one preferred hit compound was selected as “[t]he hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model.” See abstract.
The Editor’s evaluation of the Shibuya et al. article notes “study attempts to use high-throughput drug screening to identify a compound, Dwn1 [reserpine], that downregulates Npas2 activity. . . . [which is] a significant advance towards improving the outcomes of surgical wound healing with translational implications.” See abstract, page 1.
Thus, even updated state of the art, updated to 2022, demonstrates the unpredictability of any HTS identified Npas2 suppressing agent, other than the elected/lead/enabled compound, reserpine, aka Dwn-1. See also paragraph 5-6 of the Ishimura Declaration to provide support for tetrabenazine for improving/accelerating wound healing and decreasing wound area size.
Therefore, the unpredictability of the art, the of use of compounds other than reserpine is a Wands factor in support of the non-enablement of the full scope of claim 1 as claimed.
The breadth of the claims
The instant claims are broad since these claims for the method of treatment per se, where only evidence is on record to support enablement of reserpine and tetrabenazine. The breadth of non-reserpine and non-tetrabenazine compounds for the breadth of the claims is Wands against the enablement of the full scope of the invention.
The amount of direction or guidance presented, and the presence or absence of working examples
It has been established that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839 166 USPQ 18, 24 (CCPA 1970).
It is pointed out that the specification only provides for guidance for the use of reserpine to treat wounds, regenerate alveolar bone/connective tissue, decrease wound size, etc. as claimed. See working Examples 4, 5, 8, 16 and 20.
Other working Examples 1-3, 7, 9-15, and 17-19, are merely directed to demonstrating the role of Npas2 gene knockout (for example in mouse models); high throughput screening (HTS) of Npas2 suppressor compounds and/or prophetic working examples directed to reserpine and other compounds. None of these examples provide written description for the full scope of improving or accelerating wound healing, regenerating alveolar bone/connective tissue at a wound site or decreasing wound area size as claimed with ANY Npas2 suppressing agent.
See also paragraphs 5-6, Rule 132 Declaration of Inventor Dr. Ichiro Nishimura, DDS that provides enabling support for tetrabenazine for wound healing and decreasing wound size area.
Therefore, in view of the Wands factors as discussed above, particularly the lack of guidance in the art beyond reserpine and tetrabenazine, the breadth of the claims beyond reserpine and the guidance of the specification beyond reserpine, Applicant fails to provide information sufficient to practice the invention as claimed.
RESPONSE TO ATTORNEY ARGUMENTS
The Attorney response states the claims are now limited to reserpine, tetrabenazine and their various analogs.
As noted in the enablement rejection, support is on record for reserpine and tetrabenazine, with respect to wound healing. However, there is no evidence of record to support the enablement for the full scope of analogs that are still claimed.
Conclusion and Correspondence
In summary, no claims are allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application is a 371 of PCT/US2020/049529 09/04/2020
PCT/US2020/049529 has PRO 62/895,821 09/04/2019
This application has published as US 20230013402.
2 Examples 1-3 note Npas2 deficient fibroblasts for accelerated wound healing, HTS screen of compounds an in vitro phenotype study, etc. Example 7 notes rapid bone regeneration in Npas2 knockout mice. Examples 9-10 discloses screening of NPas2 downregulating compounds via HTS. Examples 11-13 are mere prophetic examples to establish the efficacy of NPas2 suppressing compounds for osteogenic differentiation in vitro; alveoloar bone regeneration in mouse models; a future Phase II study. Examples 14-15 merely notes the role Npas2 in knockout mouse. Examples 17-19 merely discloses a chrono biological HTS and other prophetic examples.
3 Reserpine, rescinnamine, benzoyl reserpine, 3- methoxybenzoyl reserpine, 4-methoxybenzoyl reserpine, 3,4-dimethoxybenzoyl reserpine, 3,5-dimethoxybenzoyl reserpine, methylenedioxy reserpine, cinnamoyl reserpine, deserpidine, methyl reserpate, syrosingopine, evodiarnine, tetrabenazine, deutetrabenazine, or a stereoisomer of dihydrotetrabenazine
4 Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing eLife 2022;11:e71074. DOI: https://doi.org/10.7554/eLife.71074