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 Claims 4, 20, and 21 are withdrawn.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NOTE: The 1/30/2023 election of species requirement between IC261 and the claimed list of casein kinase inhibitors was withdrawn (see 06/28/2024 non-Final Office action p.2).
New Claims 20 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 3/29/2023.
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 4/9/2025 has 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
Claim 1, 3, and 5 were 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.
Claim 3 was 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.
Applicant’s amendment and corresponding reply pertaining to the new limitation have overcome the 112(b) and 112(d) rejections made of record in the previous Office Action – specifically the change to recite “wherein the skin disorder, disease, or condition is caused by UV overexposure or the skin disorder, disease, or condition is caused by a defect in a signaling pathway”. Therefore, the rejections are hereby withdrawn.
Claim Rejections - 35 USC § 103
Maintained, modified to address amendments
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") 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.
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 selected from the group including CK17, D4476 and 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 selected from the group consisting of CKI7, D4476, and 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.
Although Snir-Alkalay teaches treatment of a disease mediated by casein kinase 1 (CK1) with topically applied pharmaceutical compositions comprising casein kinase I (CKI) inhibitors that increase eumelanin, Snir-Alkalay does not explicitly teach
1) CKI7 as a CKI,
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 CKI7 was already recognized as a CKI inhibitor with therapeutic utility:
Regarding CKI7, Zhao teaches CK1α inhibitors for therapeutic use and specifically claims the use of CKI7 (N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide) as the inhibitor. (See Abstract, Claims 1 and 10.)
Regarding UV exposure and MC1R variants associated with sunburn, Paterson teaches that individuals with certain variants of MC1R produce lower amounts of protective eumelanin and have increased sensitivity to UV-radiation (UV-R) and, consequently, become sunburned easily. (See Paterson p. 20; paragraph bridging pages 2 and 3; see also p. 22.)
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 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) CKI7 is a known CK1α-inhibiting agent used for therapeutic treatment and 3) sunburn from UV-radiation (UVR) can easily occur 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, such as CKI7, 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 CKI7 since CKI7 inhibition was 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, Paterson teaches that melanin is protective against UVR through direct absorption mechanisms. (See abstract, see also p. 5.) The two primary melanins in humans include eumelanin (brown/black) and pheomelanin (red/yellow), and melanin gives skin its color. See p. 65. Skin color varies widely both within and between human ethnic populations, evolving over generations to be darker in indigenous equatorial populations to protect the skin from UV damage. See p. 64. Thus, the POSA seeking to increase the skins protection from UVR and sunburn damage would have found it obvious to increase eumelanin more so than pheomelanin, whether the CKI7 amount described was known or not to have this effect on the melanins. Paterson further teaches stem-cell factor (SCF or KitL) is secreted by keratinocytes after UVR exposure and is critical for melanogenesis (production of melanin) and melanocyte survival. Thus, the POSA seeking to increase the skin’s protection from UVR and sunburn damage would have found it obvious to increase SFC, i.e., KitL, levels to 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. Paterson also teaches that UVR causes sunburn especially in individuals with MC1R variants that predispose them to the damaging effects of UVR.
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). Paterson 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 pp. 20, 22 and para. bridging pp. 2 and 3.)
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. In addition to this, notably, Paterson teaches that melanin is protective against UVR through direct absorption mechanisms. (See abstract, see also p. 5.) The two primary melanins in humans include eumelanin (brown/black) and pheomelanin (red/yellow), and melanin gives skin its color. See p. 65. Skin color varies widely both within and between human ethnic populations, evolving over generations to be darker in indigenous equatorial populations to protect the skin from UV damage. See p. 64. Thus, the POSA seeking to increase the skins protection from UVR and sunburn damage would have found it obvious to increase eumelanin more so than pheomelanin, whether the CKI7 amount described was known or not to have this effect on the melanins. Paterson further teaches stem-cell factor (SCF or KitL) is secreted by keratinocytes after UVR exposure and is critical for melanogenesis (production of melanin) and melanocyte survival. Thus, the POSA seeking to increase the skin’s protection from UVR and sunburn damage would have found it obvious to increase SFC, i.e., KitL, levels to 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 Zhou teaches CKI7 is a CKIα inhibitor (see Abstract, Claims 1 and 10).
Response to arguments
Applicant’s arguments have been fully considered but are not deemed to be persuasive.
Applicant argues that the prior art does not teach that administering CKI7, D4476 or IC261 “thereby increases a eumelanin level and a KitL level,” and that Zhao teaches cell death rather than melanogenesis. This argument is not persuasive because 1) Snir-Alkalay teaches topical administration of CK1 inhibitors for UV-related skin disorders and reports increased eumelanin, 2) Zhao teaches CKI7 as a therapeutic CKlα inhibitor, and 3) Paterson teaches that UV-induced melanogenesis involves secretion of KitL which stabilizes melanocytes and produce melanin and that MC1R variants predispose individuals to reduced eumelanin and UV sensitivity. Thus, the combination renders increases in eumelanin and KitL levels predictable consequences of administering a CK1 inhibitor in this biological context.
KitL
Applicant argues Snir-Alkalay leads away from the claimed invention and that CKI7’s structure differs from Snir-Alkalay’s formula IA compounds. This is not persuasive because Snir-Alkalay is cited for CK1-mediated skin conditions and topical administration, not for CKI7 specifically. Zhao explicitly teaches CKI7 as a known CK1 inhibitor suitable for therapeutic use. The structural difference between Snir-Alkalay’s Formula IA compounds and CKI7 do not negate obviousness because Zhao already identifies CKI7 as a CKlα inhibitor. A POSA would reasonably substitute one known CK1 inhibitor for another in Snir-Alkalay’s method. See MPEP 2144.06.
Applicant argues Paterson simply discloses the information related to MC1R mutations but fails to provide any disclosure related to the claimed CKI7, D4476, and IC261 of the present application and, therefore, cannot remedy these missing limitations. However, Paterson is not relied upon to teach the inhibitors, but rather to teach the biological motivation: MC1R variants cause reduced eumelanin; melanin protects against UVR; and KitL is secreted and is critical in melanogenesis and melanocyte survival. These teachings provide the POSA with a reason to combine Snir-Alkalay and Zhao to increase KitL and eumelanin for UV protection.
Applicant alleges to have obtained unexpected results (i.e., increase eumelanin and KitL levels) with the claimed invention. However, Applicant has not provided any objective data to support the claim of an unexpected result. See MPEP 716. Furthermore, Snir-Alkalay already teaches CK1 inhibitors cause increase in eumelanin.
For the above reasons, the rejection is maintained.
Conclusion
No claims are allowed.
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.
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/CHRIS E SIMMONS/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622