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
Claims 1, 3-5, 7-12, 14, 15, 17, 18, 20 and 21 are pending, wherein Claims 20 and 21 are newly added. Claims 4, 20, and 21 are withdrawn. Independent Claims 1, 7 and 15 were amended include increasing a eumelanin level and a KitL Level in the subject. Therefore, Claims 1, 3, 5, 7-12, 14, 15, 17, and 18 are presented for examination.
Election/Restrictions
Applicant elected with traverse the treatment of epidermal cell as the skin cell in the reply filed on 3/29/2023. NOTE: The 1/30/2023 election of species requirement between IC261 and the claimed list of casein kinase inhibitors was withdrawn (see 06/28/2024 non-Final Office action p.2).
Therefore, Claims 1, 3, 5, 7-12, 14, 15, 17, and 18 are presented for examination.
Prosecution on the merits will be restricted to the claimed species if no generic claim is finally held to be allowable.
Information Disclosure Statement
The Information Disclosure Statement filed 4/27/2026 and 4/13/2026 have been considered by the Examiner. The submission is in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Response to Arguments that the amendment overcomes the rejection
Claims 1, 3, 5, 7-12, 14, 15, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Snir-Alkalay et al. (WO 2019/155468 - "Snir-Alkalay") in view of Zhao et al. (WO 2005/046726 A2) and Paterson, E. K. (2015), “Retinoids Modulate MITF: A Novel Mechanism in the Regulation of Melanogenesis”, [Doctoral dissertation, Univ. of California Irvine (2015)]. UC Irvine Electronic Theses and Dissertations.
Applicant’s amendment and corresponding reply pertaining to deletion or “CKI7” from the list of CK1 inhibitors is persuasive. Therefore, the rejections are hereby withdrawn.
Claim Rejections - 35 USC § 103
New rejection, necessitated by amendment
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.
Claims 1, 3, 5, 7-12, 14, 15, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Snir-Alkalay et al. (WO2019155468 - "Snir-Alkalay" – previously cited by Examiner) in view of Aud et al. (US 2009/0099237 A1) and Chang et al. (“CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation.” Proc Natl Acad Sci U.S.A. (2017 Sep 6);114(38):E8035–E8044. doi: 10.1073/pnas.1702763114).
Claimed invention
Claim 1 is drawn to a method for preventing, ameliorating, or treating a skin disorder, disease, or condition (sunburn caused by UV exposure or by a defect in a signaling pathway involving MC1R) in a subject in need thereof, comprising administering an effective amount of a casein kinase 1 inhibitor to the subject, thereby increasing a eumelanin level and a KitL level in the subject, wherein the casein kinase inhibitor is D4476 or IC261, wherein the skin disorder, disease, or condition is not skin cancer.
Claim 15 is drawn to a method for inhibiting activity of a casein kinase 1 in a skin cell, comprising contacting the skin cell with an effective amount of a casein kinase 1 inhibitor, thereby increasing a eumelanin level and a KitL level in the subject, in skin cell wherein the casein kinase 1 inhibitor is D4476 or IC261.
Prior art
Snir-Alkalay teaches a method of treating one or more symptoms of a disorder, disease or condition mediated by a casein kinase 1 (CK1), including CK1α (see 0393), in a subject comprising administering to the subject a pharmaceutical composition comprising a CK1-inhibiting compound, particularly a CK1α-inhibiting compound (see 0270). (See Snir-Alkalay: abstract, par. 0270, Claims 1, 90.) Snir-Alkalay discloses that the compounds increase eumelanin level in a skin cell when a pharmaceutical composition comprising a compound of Formula IA contacts the skin cell. Snir-Alkalay specifies an embodiment wherein the compounds are used for treating skin disorder, disease, or condition is caused by UV overexposure. The skin disorder, disease, or condition is solar erythema, solar allergy, solar urticaria, solar elastosis, photoaging, or a sunburn. In yet in a more specific embodiment, the skin disorder, disease, or condition is a sunburn including an acute sunburn. See 0366. The compositions containing the compounds of the invention are topically applied. See 0283-0284. Snir-Alkalay expressly provides topical administration to the skin, UV protection, skin pigmentation, and selective increase eumelanin over pheomelanin. See 0285; 0369; 0398; see also 0003; 0366.
Although Snir-Alkalay teaches treatment of skin disorders mediated by casein kinase 1 (CK1) with topically applied pharmaceutical compositions comprising casein kinase 1 (CK1) inhibitors that increase eumelanin, Snir-Alkalay does not explicitly teach
1) D4476 as a CK1 inhibitor,
2) that the skin disorder, disease, or condition is caused by UV exposure or a defect in a signaling pathway involving melanocortin 1 receptor (MC1R) such as sunburn, or
3) that KitL levels are increased.
However, certain MC1R variants were already known to be associated with increased sensitivity to sunburn and D4476 was already recognized as a CK1 inhibitor with therapeutic utility:
Regarding D4476, Aud teaches CK1 inhibitors for therapeutic use and specifically identifies D4476 and IC261 as examples of such inhibitors. See Aud; 0031. Aud further teaches D4476 is an example of a selective CK1α-CK1δ-CK1ε inhibitor (see Id.) with an IC50 of 1.10 μM against CK1α (see 0084, Table 1). Aud provides administration of D4476 for treating an inflammatory disease or disorders in a mammal including skin disorders (e.g., inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis; spondyloarthropathies; scleroderma.) See claim 3; see also par. 0014. Aud additionally teaches that the compounds may be administered in therapeutically effective amounts and may be formulated for topical administration, including “topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.” See 0069, 0070, 0074. Thus, D4476 was known in the art as a CK1α inhibitor and such inhibitors were known for their biological usefulness for treating skin diseases.
Regarding UV exposure and MC1R variants associated with sunburn, Chang discloses that individuals with certain variants of MC1R have difficulty producing amounts of protective eumelanin against exposure to UV-radiation (UV-R) and, further teaches that CK1α inhibition may be an effective strategy for sunburn protection in MC1R-deficient individuals. (See Chang, E8059 (section ‘Eumelanin Production Following CK1α Ablation Protects the Skin from Sunburn Damage.’; see E8040-2; see also Fig. 6.)
One of ordinary skill in the art (POSA) would have found it obvious to treat sunburn in a subject by administering an effective amount of CK1α inhibitor such as D4476, IC261 or CKI7 to the subject, wherein the sunburn is associated with an MC1R variant that predisposes the subject to sunburn, because 1) Snir-Alkalay teaches the use of CKI inhibiting compounds in amounts effective for treating conditions mediated by CK1, including skin disorder conditions caused by UV overexposure, including sunburn or acute sunburn, 2) D4476, IC3261 and CKI7 are known CK1-inhibiting agent used for therapeutic treatment and 3) sunburn from UV-radiation (UVR) can occur relatively easy in individuals with certain variants of MC1R that produce lower amounts of protective eumelanin. The POSA would have had a reasonable expectation of success that a CK1-inhibiting compound can be used to provide its CKI inhibiting function in the treatment of a condition mediated by CK1, such as acute sunburn, in an individual predisposed to UVR-induced sunburn. The POSA would have reasonably sought to take advantage of the known CKI-inhibiting function of the CK1-inhibiting compound (e.g., D4476, IC261, CKI7) since they were described as being useful for conditions associated with CKI activity such as UV overexposure and acute sunburn. The POSA would have especially sought to protect individuals with MC1R variants that predispose them to sunburn due to UVR exposure to minimize the predisposition to sunburn and resulting damage. Therefore, the claimed invention as a whole would have been prima facie obvious at the time of filing.
Regarding increasing KitL (and eumelanin) levels, these are drawn to intended outcomes that are intrinsic features of the compositions containing the claimed compounds for administration to an individual including: wherein the eumelanin and KitL levels are increased in the subject. As outlined above, the compounds are applied to the skin and increase eumelanin. Regarding the limitation wherein the effective amount of a CK1 inhibitor is administered thereby increasing the KitL level and eumelanin level, the specification does not define exactly the amount required to effectively achieve the claimed outcome. The definition provided only states that the effective amount sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated or an amount sufficient to elicit a biological or medical response of a biological molecule:
The term "therapeutically effective amount" or "effective amount" is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.”
See par. bridging pages 11 and 12 of the specification.
Given that the specification states that the effective amounts to practice the instant invention include amounts as low as 1.2 mg (applied at 0.3 mg per week) and 5 mg (see p. 33; see also Fig. 1B and Fig. 1D), and Snir-Alkalay teaches that the inhibitors can be used at amounts 20 mg/kg per day (see Snir-Alkalay at 0381), then the amount disclosed in the art is more than sufficient to provide amounts effective to elicit the claimed biological or medical response, e.g., increase levels of KitL and eumelanin. In addition to this, notably, Change teaches that loss/inhibition of CK1α in keratinocytes causes p53-dependent skin hyperpigmentation, increases the number of melanocytes and dramatically increases eumelanin. Chang further teaches that CK1α inhibition results in p53-dependent upregulation of KitL and that the resulting pigmentation requires the KitL/Kit pathway. Chang also demonstrate in human primary keratinocytes that depletion of CK1α increases KitL expression. See Chang, Abstract; Figs 2, 4, 5 and S5. Chang further reports that eumelanin increases while pheomelanin remains unchanged and demonstrates protection against acute UV-induced sunburn. See Chang, Fig. 2D and Fig. 6. Thus, the POSA seeking to increase the skins protection from UVR and sunburn damage would have found it obvious to increase eumelanin, whether the CK1 inhibitor amount described was known or not to have this effect on the melanins. Thus, the POSA seeking to increase the skin’s protection from UVR and sunburn damage would have found it obvious that CK1 inhibition would increase KitL levels and encourage increased melanogenesis and melanin for increased protection against UVR and sunburn.
Therefore, the claimed invention as a whole would have been obvious to a POSA at the time the invention was filed.
Claim 3 limits Claim 1, wherein the skin disorder, disease, or condition is caused by UV exposure and is, inter alia, sunburn, an acute sunburn, or any combination thereof. As outlined above, Snir-Alkalay teaches that the CKI inhibiting compounds are used for diseases or conditions such as a sunburn. See 0366. They are used to protect a subject from ultraviolet radiation (UVR). See Claim 87. Chang also teaches that UVR causes sunburn including in individuals with MC1R variants that predispose them to the damaging effects of UVR. Chang further teaches eumelanization resulting from CK1 inhibition protects against such damage. See E8041, Fig. 6 and accompanying text.
Claim 5 limits Claim 1, wherein the skin disorder, disease, or condition is caused by a defect in a signaling pathway involving melanocortin 1 receptor (MC1R). Chang teaches that UVR causes sunburn especially in individuals with MC1R variants that produces lower amounts of protective eumelanin and predispose them to the damaging effects of UVR. See E8040. Chang further teaches pigmentation induced independently of POMC/MC1R signaling provides a strategy for protection against UV damage and specifically concludes that CK1α inhibition may be an effective strategy for sunburn protection in MC1R-deficient individuals. See Chang, E8042, Discussion. Therefore, a POSA would have sought to provide CK1α inhibition treatment as described above in a subject having defectiveMC1R signaling, given that the CK1α/KitL/Kit pathway provides a route to protective eumelanin that bypasses defective POMC/MC1R signaling.
Independent Claim 7 is drawn to a method for increasing a eumelanin level and a KitL level in a subject in need thereof, comprising administering an effective amount of a casein kinase 1 inhibitor (e.g., CK17, D4476, and IC261) to the subject for the eumelanin level to be selectively increased over a pheomelanin level in skin of the subject, and the KitL level is increased in the subject. As outlined above, the compounds are applied to the skin and increase eumelanin. Regarding the limitation wherein the effective amount of a CK1 inhibitor is administered to the subject for the eumelanin level to be selectively increased over a pheomelanin level in skin, the specification does not define exactly the amount required to effectively achieve the claimed outcome. The definition provided only states that the effective amount sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated or an amount sufficient to elicit a biological or medical response of a biological molecule:
The term "therapeutically effective amount" or "effective amount" is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.”
See par. bridging pages 11 and 12 of the specification.
Given that the specification states that the effective amounts to practice the instant invention include amounts as low as 1.2 mg (applied at 0.3 mg per week) and 5 mg (see p. 33; see also Fig. 1B and Fig. 1D), and Snir-Alkalay teaches that the inhibitors can be used at amounts 20 mg/kg per day (see Snir-Alkalay at 0381), then the amount disclosed in the art is more than efficient to provide amounts effective to elicit the claimed biological or medical response, e.g., increase levels of KitL and eumelanin. And noted above for Claim 2, the POSA seeking to increase the skins protection from UVR and sunburn damage would have found it obvious to increase eumelanin, whether the CK1 inhibitor amount described was known or not to have this effect on the melanins. Thus, the POSA seeking to increase the skin’s protection from UVR and sunburn damage would have found it obvious that CK1 inhibition would increase KitL levels and encourage increased melanogenesis and melanin for increased protection against UVR and sunburn.
Therefore, the claimed invention as a whole would have been obvious to a POSA at the time the invention was filed.
Claims 8-12 are drawn to intended outcomes that are inherent features of the compositions containing the claimed compounds for administration to an individual including: wherein increasing the eumelanin level increases skin pigmentation in the subject, wherein the skin pigmentation protects the subject from ultraviolet radiation, wherein the eumelanin level is increased in epidermis of the subject, wherein increasing the eumelanin level involves an increase in a KitL level in epidermis of the subject, and wherein increasing the KitL level in the epidermis induces movement of melanocytes from dermis to the epidermis in the subject. As explained for Claim 7 above, the amount is sufficient to elicit the claimed biological or medical responses.
Claim 14 limits Claim 7, wherein the subject is a human. Humans are contemplated for treatment. See Snir-Alkalay, Claim 85.
Independent Claim 15 is drawn to a method for inhibiting activity of a casein kinase 1 in a skin cell, comprising contacting the skin cell with an effective amount of a casein kinase 1 inhibitor, thereby increasing eumelanin and KitL levels. Claim 17 limits Claim 15, wherein the skin cell is an epidermal cell. As outlined above, the compounds are applied to the skin and increase eumelanin. The epidermal skin cells are contacted with the compound to elicit the intended response. The See Snir-Alkalay, 0398. As outlined above, the prior art teaches amounts that meet the effective amounts described in the specification and suggests that eumelanin protects against UVR.
Therefore, the claimed invention as a whole would have been obvious to a POSA at the time the invention was filed.
Claim 18 limits Claim 15, wherein the casein kinase 1 inhibitor is a casein kinase la inhibitor. Snir-Alkalay discloses CKlα inhibition (see paragraph [0402]) and Aud teaches D4476 and IC261 are CKIα inhibitors (see Aud, Table 1).
Response to arguments
Applicant’s arguments have been fully considered but are not deemed to be persuasive. Applicant’s argument that the prior art does not teach D4476 or IC261 are not persuasive because Aud teaches both D4476 and IC261 are useful CK1 inhibitors for treating inflammatory diseases/disorders.
Applicant argues that the declaration was not substantively addressed. The declaration has been fully considered. The declaration provides comparative data showing that under particular conditions tested, topical administration of A51 caused an inflammatory response and related issues, whereas D4476 and IC261 did not. However, the evidence is not sufficient to overcome the present prima facie case of obviousness because the prior art already demonstrated that both D4476 and IC261 are used to inhibit inflammation. Thus, demonstrating that they do not cause inflammation and related problems does not distinguish them from the teachings in the prior art and does not indicate anything surprising when compared to a different compound.
For the above reasons, the rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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/CHRIS E SIMMONS/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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