DETAILED ACTIONNotice 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/16/25 has been entered.
Application Status and Election
Claims 1, 3, 4, 9-11, 22-26, and 28-34 are pending. Claims 1, 22, and 28 have been amended.
Claims 2, 5-8, and 27 are canceled.
New claims 29-34 are added.
Examination on the merits commences on claims 1, 3, 4, 9-11, 22-26, and 28-34.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(a) – 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, 9, 22, and 28 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims are drawn to a method of treating a subject having a disorder associated with loss or absence of skin pigmentation, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of ROCK1 and SIK, wherein the disorder associated with loss or absence of skin pigmentation is vitiligo, and the inhibitors are administered topically to, or by injection into, an area of skin exhibiting the loss or absence of pigmentation. These claims are not limited to any definition of ROCK1 or SIK inhibitor provided in the disclosure. The specification has not adequately described the entire genus of these gene modulators for the following reasons.
Size and Breadth of Genus
The genus of “inhibitors” is extensive and diverse and includes chemical and biological molecules in variable combinations with variable size, structure, and folding patterns such as nucleic acids including shRNA, miRNA, siRNA, dsDNA, short hairpin RNA, or other agents such as proteins, small organic molecules, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, radiation phototherapy, kinase enzymes, chemical inhibitors, fusion proteins, and monoclonal antibodies, and chromatin modifiers like histone acetyl transferases and deacetylases, as well as epigenetic modifiers like DNA methyltransferases, among others.
Species disclosed in the Specification
The Specification teaches numerous small molecule inhibitors of ROCK1 (page 7) and SIK (page 9) as well as inhibitory nucleic acids such as RNAi, LNAs, siRNA, miRNA, ASO, shRNA (page 10) and in Examples 1 and 2 (page 32).
Although the specification discloses potential embodiments of ROCK1 and SIK inhibitors, the specification fails to sufficiently describe representative species, i.e. structure or secondary structures, for the skilled artisan to predict what other molecules for example can function in inhibition or how the structures relate to the function of inhibiting or promoting gene expression.
Species Disclosed in the Art
The genus of “inhibitor” is diverse in the art and includes biological molecules described in the specification as well as genome editing compositions that knock down or knock out the a gene, including CRISPR-Cas reagents, transcription activator-like effector nuclease (TALEN) reagents, or zinc finger nucleases (ZFN) reagents. Such inhibitors can be used by themselves or in combination for gene inhibition or inhibiting gene/protein activity.
Regarding ROCK1 inhibitors, Chapman teaches ROCK inhibition rapidly and conditionally induces indefinite proliferation of keratinocytes in a method that has far-reaching applications for basic research, as well as for regenerative and personalized medicine (abstract). Chapman teaches keratinocytes cultured with small molecule ROCK inhibitors such as Y-27632 show that the effect of ROCK inhibition on cellular proliferation is immediate and ROCK inhibited cells proliferate rapidly and without differentiation or stratification and efficiently enhance the survival lifespan of keratinocytes (abstract; Chapman, Sandra, et al. "The effect of Rho kinase inhibition on long-term keratinocyte proliferation is rapid and conditional." Stem cell research & therapy 5.2 (2014): 60.).
Regarding SIK inhibitors, Mujahid teaches a safe, viable method of topical pigment production through localized delivery to skin of topical SIK inhibitors applied for localized SIK inhibition (pg 2182 col 1 para 3). Mujahid teaches administering an inhibitor of salt induced kinase (SIK), optimized in composition for human skin penetration, to stimulate melanocytic pigment synthesis and induce skin darkening in a topical application for pigment and skin disorders (pg 2177 para 2) Mujahid teaches the second-generation SIK inhibitors, YKL 06-061 and YKL 06-062, induce darkening pigmentation as measured by reflective colorimetry analysis after topical treatment of human breast skin explants (Figure S3B and pg 2180 para 1; Mujahid, Nisma, et al. Cell reports 19.11 (2017): 2177-2184.).
Further regarding nucleic acids gene modulators, Wang teaches that the ability to predict nucleic acid hybridization (i.e., via “rational design”) is generally limited to the use of unmodified nucleic acids, and that many broadly employed chemical modifications to DNA and RNA have not been included in predictive models (pg. 2, para. 1 and pg. 14, para. 1; Wang et al., 2022, PLOS ONE, 17(5), e0268575). Wang teaches thermodynamic models of hybridization for nucleic acid molecules with phosphorothioate linkages, where each linkage modification decreases duplex stability (pg. 13, para. 4) Wang teaches that backbone and sugar ring modifications, in conjunctions with nucleotide sequence, would likely require a combinatorially large (and synthetically intractable) set of duplexes to fully characterize (pg. 13, para. 3). Therefore, it is unpredictable that nucleic acid hybridization without a rational design incorporating thermodynamics, phosphorothioate linkages or backbone/sugar ring modifications would successfully promote nucleic acid binding.
Regarding such non-nucleic acid based inhibitors, given the lack of structure-function relationship in proteins, the skilled artisan could not predictably design a protein that would bind to a particular RNA transcript for RNA mediated gene expression inhibition. This is evidenced by Hentz (Hentz et al., Nature Reviews Molecular Biology (2018), 19: 327-341). Hentz teaches RNA-binding proteins (RBP) can interact with RNA through defined RNA-binding domains to regulate RNA metabolism and function, establishing a functional crosstalk between proteins and RNA (Fig. 1 pg 328). However, Hentz teaches that binding of RBPs to RNA constantly changes, where the composition of RNA interactomes is context-dependent, responds to stimuli, and has regulation of binding activity by multiple agents (pg 331 co 2 para 2). Hentz teaches long non-coding RNAs lncRNAs are currently assumed to participate in the recruitment of transcription factors or chromatin-modifying complexes ---or inhibit protein complexes, however, these functions break with convention by indicating that RNAs may regulate RBP function rather than be regulated by RBPs (Fig. 1b pg 328). Given this dynamic regulation of functional crosstalk between proteins and RNA with context dependent response to stimuli, it is not predictable that a person of ordinary skill in the art could design a protein to bind a particular RNA transcript for the purpose of gene expression inhibition without knowledge of that structure function relationship.
As the prior art establishes, there is substantial variation within the genus of ROCK1 and SIK inhibitor. Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus. Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus and lack of predictability of undefined nucleic acids, proteins, and small molecules as sufficiently inhibiting gene expression, the ROCK1 and SIK inhibitors in the specification disclosure are not sufficient to show that the Applicant was in possession of all such ROCK1 and SIK inhibitors at the time the invention was filed. However, given evidence in the art and specification regarding oligonucleotides RNAi and small molecule ROCK1 and SIK inhibitors, Examiner interprets these as sufficiently predictable within Applicant’s written description.
Claim Rejections - 35 USC § 103 - New
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.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Claim(s) 1, 3, and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Peuker (Peuker, H., EP-1759700-A1, 2007) in view of Liu (Liu, L., CN 108795842 A, published 11/13/2018) and Chapman (Chapman, Sandra, et al. "The effect of Rho kinase inhibition on long-term keratinocyte proliferation is rapid and conditional." Stem cell research & therapy 5.2 (2014): 60.) and Shaw (Shaw, Peter X., et al. "Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury." Experimental eye research 158 (2017): 33-42.).
Regarding claim 1, Peuker teaches topical application of small molecule inhibitors to treat hypopigmentation disorders [0001] such as vitiligo [0003]. Peuker teaches mechanisms for disease destruction of melanocytes are caused from a of composite of several normal processes influencing melanocyte function, proliferation and/or survival [0002]. Peuker teaches application of combinations of small molecule inhibitors and adjuvant active agents in the pro-pigmentation skin therapeutic method [0106].
Peuker does not teach the small molecule inhibitor as a Rock1 inhibitor.
Liu teaches preparation of melanocytes using the growth activating Rock1 small molecule inhibitor Y27632 then administering those melanocytes to the skin of subjects with the skin de-pigmentation disorder vitiligo (claim 9 and 10 and (pg 4 para 5). Liu teaches the melanocytes prepared by the invention are transplanted onto the skin of the subject (pg 4 para 5).
Chapman teaches ROCK inhibition rapidly and conditionally induces indefinite proliferation of keratinocytes in a method that has far-reaching applications for basic research, as well as for regenerative and personalized medicine (abstract). Chapman teaches keratinocytes cultured with small molecule ROCK inhibitors such as Y-27632 show that the effect of ROCK inhibition on cellular proliferation is immediate and ROCK inhibited cells proliferate rapidly and without differentiation or stratification and efficiently enhance the survival lifespan of keratinocytes (abstract).
Shaw teaches Rock1 inhibitors such as AR-13324 (Netarsudil, Rhopressa) as an effective topical agent (2.2) which promotes cellular growth (pg 34 para 3).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Peuker’s method of topical combination small molecule inhibitor treatment of vitiligo, which causes skin pigmented cell death, to also include a ROCK1 inhibitor so as to enhance pigmented cell survival and proliferation. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Liu’s ROCK1 inhibitor could be effectively applied topically because Shaw teaches Rock1 inhibitors as effective topical agents. It would have been predictable that Rock1 inhibitors added to Peuker’s vitiligo treatment would be effective at treating subjects with vitiligo because Peuker teaches vitiligo as a disease caused by melanocyte/keratinocyte destruction and Chapman and Shaw teach Rock1 inhibitors promote cell survival. The skilled artisan would be motivated to employ Liu’s Y27632 ROCK1 inhibitor in Peuker’s topical application in order to expand survival of pigmentation cells on the skin of subjects suffering from the hypopigmentation disorder vitiligo.
Regarding claims 3 and 4, Liu teaches preparation of melanocytes using the growth activating Rock1 small molecule inhibitor Y27632 then administering those melanocytes to the skin of subjects with the skin de-pigmentation disorder vitiligo (claim 9 and 10 and (pg 4 para 5).
Claim(s) 9-11, 22-26, and 28-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Peuker (Peuker, H., EP-1759700-A1, 2007) in view of Liu (Liu, L., CN 108795842 A, published 11/13/2018) and Chapman (Chapman, Sandra, et al. "The effect of Rho kinase inhibition on long-term keratinocyte proliferation is rapid and conditional." Stem cell research & therapy 5.2 (2014): 60.) and Shaw (Shaw, Peter X., et al. "Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury." Experimental eye research 158 (2017): 33-42.) as applied above to claim 1, in further view of Mujahid of record (Mujahid, Nisma, et al. Cell reports 19.11 (2017): 2177-2184.), claims 31 and 32 as evidenced by Lin (Lin, Cheng-Wen, et al. "Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma." Journal of Ocular Pharmacology and Therapeutics 34.1-2 (2018): 40-51.).
The teachings of Peuker, Liu, Chapman, and Shaw as applied above for claim 1 are incorporated here.
Regarding claims 9-11, Peuker does not teach the combination therapy of ROCK1 small molecule inhibitors applied topically to treat vitiligo which also includes a small molecule SIK inhibitor.
Mujahid teaches a safe, viable method of topical pigment production through localized delivery to skin of topical SIK inhibitors applied for localized SIK inhibition (pg 2182 col 1 para 3). Mujahid teaches administering an inhibitor of salt induced kinase (SIK), optimized in composition for human skin penetration, to stimulate melanocytic pigment synthesis and induce skin darkening in a topical application for pigment and skin disorders (pg 2177 para 2) Mujahid teaches the second-generation SIK inhibitors, YKL 06-061 and YKL 06-062, induce darkening pigmentation as measured by reflective colorimetry analysis after topical treatment of human breast skin explants (Figure S3B and pg 2180 para 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified Peuker’s modified method of topical combination small molecule inhibitor treatment of vitiligo, which causes skin pigmented cell death, to include along with a ROCK1 inhibitor such as Y-27632 (as deemed obvious in the rejection above) to also include Mujahid’s YKL 06-061 SIK inhibitor so as to enhance pigmentation and pigmented cell survival and proliferation. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Mujahid’s YKL 06-061 SIK inhibitor could be effectively applied topically because Mujahid teaches effective topical application of SIK inhibitors. It would have been predictable that Mujahid’s YKL 06-061 SIK inhibitor added to Peuker’s modified vitiligo treatment including Rock1 inhibitors would be effective at treating subjects with vitiligo because Peuker teaches vitiligo as a disease caused by pigmented keratinocyte destruction, Mujahid teaches the YKL-06-061 SIK inhibitor increases skin pigmentation and Chapman and Shaw teach Rock1 inhibitors promote cell survival which would promote the survival and proliferation of those cells with enhanced pigmentation. The skilled artisan would be motivated to employ SIK inhibitors in Peuker’s modified topical application in order to expand pigmentation in cells and enhance survival of pigmented cells on the skin of subjects suffering from the hypopigmentation disorder vitiligo.
Regarding claims 22, 29, 30, 33, and 34, Mujahid (pg 2177 para 2, Figure S3B and pg 2180 para 1) and Liu (pg 4 para 5) teach SIK inhibitors YKL 06-061 and YKL 06-062, and the ROCK small molecule inhibitor Y27632, respectively, for topical application.
Regarding claims 23 and 24, Liu teaches growth activating Rock1 small molecule inhibitor Y27632 then administering those melanocytes to the skin of subjects with the skin de-pigmentation disorder vitiligo (claim 9 and 10 and (pg 4 para 5).
Regarding claims 25 and 26, Mujahid teaches the second-generation small molecule SIK inhibitors, YKL 06-061 and YKL 06-062, induce darkening pigmentation as measured by reflective colorimetry analysis after topical treatment of human breast skin explants (Figure S3B and pg 2180 para 1).
Regarding claim 28, Peuker teaches the medicament according to the present invention is prepared in a form suitable for topical use, preferably in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream, a cream of a mixed phase or amphiphilic emulsion system (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder, or a solution or suspension [0059].
Regarding claims 31 and 32, Shaw teaches Rock1 inhibitors such as AR-13324 as an effective topical agent (2.2) which promotes cellular growth (pg 34 para 3), as evidenced by Lin who teaches netarsudil is also known as AR-13324 (pg 41 para 4).
Response to Arguments
Applicants arguments in the Remarks filed 7/16/25 are directed to withdrawn §102 and §103 rejections, therefore the arguments are moot. Applicant’s amendments necessitate a new §103 rejection.
Conclusion
No claims are allowable.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/ Primary Examiner, Art Unit 1637