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 .
Status of Claims
Claims 5-8 and 11-18 are pending.
Priority
Instant application 18/547,918, filed 08/25/2023 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 11/16/2023, 03/24/2025, and 12/09/2025 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 03/09/2026 has been entered. Applicant has amended claims 5-8 and 11-18. Claims 1-4 and 9-10 are cancelled.
The specification was previously objected to because the abstract exceeded 150 words and the disclosure contained an embedded hyperlink. In view of the amendments to the abstract and specification, applicant has overcome the aforementioned issues. Therefore, the previous objections to the specification are withdrawn.
Claims 4, 5, and 7 were previously objected to for typographical errors. Claim 4 has been canceled, rendering its objection moot. In view of the amendments to claims 5 and 7, applicant has overcome their objections. Therefore, the previous objection over claims 4, 5, and 7 is withdrawn.
Claims 6, 8, 9 and 11-14 were previously rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends. Claim 9 has been cancelled, rendering its rejection moot. In view of the amendments to claim 6, 8, and 11-14, applicant has overcome the original rejection. Therefore, the previous rejection over claims 6, 8, 9 and 11-14 is withdrawn. However, for claims 6 and 8, the amendment introduces a new issue. See the new rejection under 35 U.S.C. 112(d) further below.
Claims 4-9 and 11-14 were previously rejected under 35 U.S.C. 101 as being directed to a judicial exception (natural product) without significantly more. Claims 4 and 9 have been cancelled, rendering their rejections moot. In view of the amendments to claim 5-8 and 11-14, applicant has overcome the rejection. Therefore, the previous rejection over claims 4-9 and 11-14 is withdrawn.
Claims 4-9 and 11-14 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by KOSHINO (Bioscience, Biotechnology, and Biochemistry, vol. 56, no. 7, Jan. 1992, p. 1096–99). Claims 4 and 9 have been cancelled, rendering their rejections moot. In view of the amendments to claim 5-8 and 11-14, applicant has overcome the rejection. Therefore, the previous rejection over claims 4-9 and 11-14 is withdrawn.
Claims 4-9 and 11-14 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by MASUTANI (US 20170105965 A1; cited in IDS). Claims 4 and 9 have been cancelled, rendering their rejections moot. In view of the amendments to claim 5-8 and 11-14, applicant has overcome the rejection. Therefore, the previous rejection over claims 4-9 and 11-14 is withdrawn.
Claims 4-18 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by YOSHIHIRO (JP 2018095633 A). Claims 4, 9, and 10 have been cancelled, rendering their rejections moot. In view of the amendments to claim 5-8 and 11-18, applicant has overcome the rejection. Therefore, the previous rejection over claims 4-18 is withdrawn.
Claim Interpretation
Under broadest reasonable interpretation, the recitation “for preventing and/or improving wrinkles induced by the foreign body reaction” in claim 6 is being interpreted as a statement of intended use that does not further limit the method of independent claim 5, which claim 6 depends from. Similarly, the recitation “for preventing and/or treating atopic dermatitis induced by the foreign body reaction” in claim 8 is being interpreted as a statement of intended use that does not further limit the method of independent claim 7, which claim 8 depends from. The body of dependent claims 6 and 8 introduces no additional method steps, no change to the active ingredient, and no narrowing of dosage, formulation, or patient population beyond what is already recited in the independent claim. The method of claims 5 and 7 (administering 5-hydroxy-4-phenyl-2(5H)-furanone to the skin of a subject in need thereof) is complete without reference to whether wrinkles or atopic dermatitis are actually prevented or improved. And because prevention of wrinkles or atopic dermatitis are recited in the claims, they do not limit the patient population to subjects actually having wrinkles or atopic dermatitis.
See MPEP 2111.02, which states: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”.
Please note the duplicate claims warning and rejection under 112(d) further below which are necessitated by the aforementioned interpretation of claims 6 and 8.
Duplicate Claims Warning
Applicant is advised that should claims 5 and 7 be found allowable, claims 6 and 8 will be objected to under 37 CFR 1.75 as being substantial duplicates thereof. Should claims 11 and 13 be found allowable, claims 12 and 14 will be objected to as being substantial duplicates thereof. Should claims 15 and 17 be found allowable, claims 16 and 18 will be objected to as being substantial duplicates thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In view of the examiner’s above claim interpretation, claims 6 and 8 are being interpreted as substantial duplicates of claims 5 and 7, respectively. Claims 11-14 depend from claims 5-8 and all recite the same limitation (“wherein the agent is a composition comprising at least one additive…”). Therefore claims 12 and 14 are being interpreted as substantial duplicates of claims 11 and 13, respectively. Claims 15-18 depend from claims 11-14 and all recite the same limitation (“wherein the composition is the cosmetic product in the form of…”). Therefore claims 16 and 18 are being interpreted as substantial duplicates of claims 15 and 17, respectively.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In view of the examiner’s above claim interpretation, claim 6 fails to further limit claim 5 from which it depends; and claim 8 fails to further limit claim 7 from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 5-8 and 11-18 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
The claims recite the phrase “foreign body reaction”. In the dermatological arts, “foreign body reaction” is generally understood to refer to a granulomatous inflammatory tissue response to an implanted or embedded material. See, for example, HARLIM (Dermatologic Surgery, vol. 44, no. 9, Sept. 2018, pp. 1174–82), which states (Harlim, Abstract): “A foreign body reaction (FBR) is a typical tissue response to a biomaterial that has been injected or implanted in human body tissue”.
However, the specification uses the phrase “foreign body reaction” to describe a xenobiotic response in the skin (i.e. a response to a foreign chemical) mediated by the aryl hydrocarbon receptor (AhR) and xenobiotic responsive element (XRE) signaling pathway (see e.g. [0021] in the as-filed Specification).
The discrepancy between the art-recognized meaning of “foreign body reaction” and applicant’s apparent meaning renders the scope of the claims indefinite. The discrepancy appears to be a translation artifact, as the application derives from a Japanese-language priority filing.
In the interest of compact prosecution, the examiner suggests replacing “foreign body reaction” with terminology consistent with the specification’s disclosed mechanism, for example:
For claim 5: A method for inhibiting production of matrix metalloprotease 9 induced by a xenobiotic response in the skin, comprising administering 5-hydroxy-4-phenyl-2(5H)-furanone to the skin of a subject in need thereof.
For claim 7: A method for inhibiting production of artemin induced by a xenobiotic response in the skin, comprising administering 5-hydroxy-4-phenyl-2(5H)-furanone to the skin of a subject in need thereof.
Claim Rejections - 35 USC § 112(a)
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 5-8 and 11-18 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a scope of enablement rejection.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are considered to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims:
Independent claims 5 and 7 are broad. They encompass administering 5-hydroxy-4-phenyl-2(5H)-furanone (“Fraglide-1”) to the skin of any subject, in any formulation, at any concentration, by any route of topical administration, to inhibit matrix metalloprotease 9 (“MMP9”) production or artemin production induced by a xenobiotic response in the skin. The claims are not limited to any particular skin condition, patient population, dosage range, or formulation type. The specification ([0153] – [0161]) provides formulation examples containing Fraglide-1 at approximately 0.02% to 0.20% by mass, and in vitro efficacy data at specific micromolar concentrations, but the claims are not commensurate in scope with these disclosures.
Nature of the invention:
The claimed invention is a method of administering a topical active ingredient to living skin to achieve a specific molecular outcome. For claim 5, the required outcome is inhibition of MMP9 production mediated by aryl hydrocarbon receptor (“AhR”) and xenobiotic responsive element (“XRE”) signaling. For claim 7, the required outcome is inhibition of artemin production mediated by AhR and XRE signaling. The claimed method requires that Fraglide-1 penetrate the stratum corneum, reach viable keratinocytes at an effective concentration, and modulate gene transcription in vivo. Each of these steps introduces variables not addressed by the specification.
State of the prior art and predictability in the art:
The prior art recognized significant challenges in translating in vitro keratinocyte cell culture results to in vivo topical therapeutic outcomes. For example, see NEIL (Scientific Reports, vol. 10, no. 1, Dec. 2020, p. 21192). Neil discloses (page 1, 2nd para.) that the European Centre for the Validation of Alternative Methods (ECVAM) Skin Irritation Task Force suggested that monolayer keratinocyte cultures, while useful, lack the inherent barrier function and properties of skin and in particular its outermost stratum corneum, making them unsuitable for routine testing of chemicals for skin irritation.
See also BOUWER (Pharmaceutics, vol. 17, no. 12, Dec. 2025, p. 1586). Bouwer is a comprehensive review of dermal drug delivery models and confirms that “challenges remain in correlating in vitro, ex vivo, and in vivo outcomes and in replicating the skin’s dynamic physiology” (Bouwer, abstract). Notably, Bouwer reports that the stratum corneum’s highly organized lipid-protein matrix restricts molecular transport unless compounds possess favorable physicochemical properties (page 1, “Introduction”), and that even sophisticated reconstructed human epidermis models containing cell types similar to those found in vivo still lack essential structures such as blood vessels, hair follicles, glands, and organized lipid networks, resulting in permeability profiles that do not replicate intact human skin (page 10, 1st para.). Even synthetic membranes specifically engineered to simulate human epidermis (Strat-M®) showed absolute flux values differing by more than an order of magnitude from excised human skin (page 11, 1st para.). Additionally, Bouwer explains that under in vivo conditions, capillary circulation rapidly clears absorbed molecules from the viable tissue, whereas in diffusion cells (or cell culture systems) this clearance mechanism is absent (page 6, 3rd para.).
Prior to the filing date, Fraglide-1 was known as a PPARγ agonist with anti-obesity properties. See, for example, TSUJINO (Tsujino, Yoshio. “Journal of Oleo Science, vol. 66, no. 6, 2017, pp. 615–22). No prior art disclosed its skin permeation characteristics or its behavior in dermal formulations.
Pharmacological activity in general is a very unpredictable area. Note also that in cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In view of Neil and Bouwer above, the art of topical dermatological therapeutics is recognized as having low predictability in translating in vitro cell culture results to in vivo outcomes. The stratum corneum presents a formidable barrier to dermal absorption, and the bioavailability of the active ingredient depends on numerous factors not addressed in the specification. The specification provides no skin permeation data for Fraglide-1, no measurement of its bioavailability in viable epidermis following topical application, and no evidence to correlate in vitro concentrations with effective concentrations in living skin. The unpredictability in the art weights against enablement.
Level of ordinary skill in the art:
The artisans using applicant’s method would hold an advanced degree in dermatology, pharmacology, cosmetic science, or a related field, and possess several years of professional experience, with some familiarity for topical formulation development. Such a person would understand that demonstrating gene expression changes in a keratinocyte monolayer does not establish that a topically applied composition will achieve the same effect in intact skin.
The amount of direction provided and working examples:
The specification provides detailed direction for performing in vitro assays using HaCaT keratinocytes in culture (Experiments 1-1 through 6). It also provides formulation examples for various cosmetic products ([0154] – [0161]).
However, the specification provides no direction regarding (i) how to identify a “subject in need” of MMP9 inhibition or artemin inhibition; (ii) what concentration of Fraglide-1 in a topical formulation would deliver an effective amount to viable keratinocytes in vivo; (iii) how to confirm that MMP9 or artemin inhibition has been achieved in living skin following topical administration; or (iv) any dosing regimen, application frequency, or treatment duration. The gap between in vitro working examples and the claimed in vivo method is left entirely to the practitioner to bridge.
See also MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to conduct skin permeation studies to determine whether Fraglide-1 penetrates the stratum corneum in a given formulation, determine the concentration of Fraglide-1 that reaches viable keratinocytes in vivo, establish whether that concentration is sufficient to inhibit MMP9 or artemin production in the context of intact skin tissue, develop a method for identifying subject who are producing elevated XRE/AhR-mediated MMP9 or artemin, and confirm MMP9 or artemin inhibition in vivo following treatment. This constitutes undue experimentation.
The claims require administering Fraglide-1 to “a subject in need thereof”, which is a subject in need of inhibiting MMP9 or artemin production induced by a xenobiotic response in the skin. The specification provides no guidance on how a practitioner would identify such a subject. Although MMP9 and artemin are inducible enzymes whose expressions may be elevated by XRE-mediated signaling, elevated XRE-mediated MMP9 or artemin transcription is not a clinically recognized diagnosis. The specification discloses no biomarker, clinical indicator, or diagnostic threshold by which a practitioner could identify a subject experiencing such elevated expression, nor does the prior art provide an established method for doing so in a clinical or cosmetic setting.
The inability to identify the subject population for the claimed method represents an additional independent deficiency in enablement, as one cannot practice a method of treatment without being able to determine who should receive the treatment.
Therefore, weighing the above factors, claims 5-8 and 11-18 are rejected as failing to comply with the enablement requirement.
Consistent with MPEP 2164.04 and in the interest of compact prosecution, the following subject matter is considered enabled by the examiner:
For claim 5: A method for inhibiting production of matrix metalloprotease 9 in a human keratinocyte, comprising contacting the keratinocyte in vitro with 5-hydroxy-4-phenyl-2(5H)-furanone, or a salt thereof, in an amount effective to reduce expression of MMP9 induced by activation of an aryl hydrocarbon receptor.
For claim 7: A method for inhibiting production of artemin in a human keratinocyte, comprising contacting the keratinocyte in vitro with 5-hydroxy-4-phenyl-2(5H)-furanone, or a salt thereof, in an amount effective to reduce expression of artemin induced by activation of an aryl hydrocarbon receptor.
Conclusion
Claims 5-8 and 11-18 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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