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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed June 29th, 2026, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 2, 5 – 6, 8, 11, and 18 – 19 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/039988 A1 to Burgess et.al. (herein after Burgess’988; cited in the Office Action dated April 7th, 2025) in view of Liu et. al. ((2011), Comparison of gene expression profiles reveals aberrant expression of FOXO1, Aurora A/B and EZH2 in lesional psoriatic skins, Mol Bio Rep., 38, 4219 – 4224; cited in the Office Action dated April 7th, 2025) and Bradley et. al. ((2014), EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation, Cell Press Chemistry & Biology, 1463 – 1475; cited in the Office Action dated November 3rd, 2025).
Regarding claims 1 – 2, 5 – 6, 8, 11, and 18 – 19, Burgess’988 teach that the disclosure relates to substituted azaindoles which inhibit EZH2 (page 1 line 4). Specifically, Burgess’988 teach substituted azaindoles of formula (I) (page 3 lines 1 – 2) that are useful for the treatment of disorders mediated by inhibiting EZH2 (page 5 lines 23 – 25). More specifically, Burgess’988 teach disorders mediated by inhibiting EZH2 includes psoriasis (claims 1) (page 22 line 22). Additionally, Burgess’988 teach that the compounds of the disclosure can be combined with or co-administered with other therapeutic agents (page 22 lines 25 – 26).
Moreover, Burgess’988 teach that pharmaceutical compositions comprising the EZH2 inhibitors of the disclosure may be adapted for administration by any appropriate route which includes topically by buccal, sublingual or transdermal (claims 1 and 2) (page 33 lines 19 – 24). Furthermore, Burgess’988 teach that that such compositions may be prepared by any method known in the art of pharmacy (claim 11), for example by bringing into association a compound of formula (I) with the carrier(s) or excipient(s) (claim 8) (page 33 lines 22 – 24). Additionally, Burgess’988 teach that the pharmtuically compositions comprising the EZH2 inhibitor can be adapted for vaginal administration as a cream, gel, or paste (page 35 lines 7 – 8 ). Now while Burgess’988 teach the formulation of creams, gels, and pastes for vaginal administration; given that Burgess’988 does teach that that such compositions may be prepared by any method known in the art of pharmacy and the relatively high skill of one of ordinary skill in the pharmaceutical arts it would have been obvious to such artisan to formulate a topical cream, gel or, paste to be applied directly to the skin (claim 8) using the appropriate topical carrier or excipient (claim 11).
Furthermore, Burgess’988 teach an assay protocol for evaluating the disclosed compounds ability to inhibit the methyltransferase activity of EZH2 (claim 14) within the PRC2 complex (page 215 lines 13 – 21). While the assay taught by Burgess’988 focused on the screening of the disclosed compounds in methods of treating cancer, as mentioned above, the prior art of Burgess’988 specifically taught an embodiment for the use of the compounds of the disclosure in treating psoriasis through the inhibition of EZH2. Thus it would have been obvious that the assay taught by Burgess’988 can be used to screen compounds that are useful against psoriasis since both disease share a common mechanistic pathway that involves the inhibition of EZH2 activity.
While Burgess’988 taught the use of EZH2 inhibitors for psoriasis, the prior art reference failed to exemplify the topical use of the disclosed EZH2 inhibitor to treat psoriasis (claim 1). In addition, Burgess’988 fails to teach a method wherein theEZH2 inhibitor is CPI-169 (claims 1, 5, and 18 - 19) or a method wherein the EZH2 inhibitor is administered with an additional agent active against psoriasis-associated symptoms (claim 6).
Nevertheless, Liu et. al. teach the identification of de-regulated expression of FOXO1, AURKA/B and EZH2 in lesional psoriatic skins (page 4219 column 2 paragraph 2). Furthermore, Liu et. al. teach that the expression of FOXO1, AURKA/B and EZH2 in lesional psoriatic skins were reversed upon Etanercept treatments (page 4219 column 2 paragraph 2). Additionally, Liu et. al. teach that aberrant expression of FOXO1, AURKA/B and EZH2 may contribute to the progress of psoriasis (page 4420 column 1 paragraph 1). Furthermore, Liu et. al. teach that it would be worthwhile to test whether the EZH2 inhibitor (DZNep) can enhance the therapeutic effects of Etanercept (claim 6) in psoriasis management (page 4223 column 1 paragraph 2). Thus, Liu et. al. suggest a reasonable expectation of success for the inhibition of EZH2 in combination with etanercept for the treatment of psoriasis.
While Liu et. al. fails to teach the EHZ2 inhibitor as recited in newly amended claim 1, Liu et. al. does teach the administration of an EZH2 inhibitor, specifically, EZH2 (DZNep).
Nevertheless, Bradley et. al. teach that CPI-169 (claims 1, 5, and 18 – 19) was identified as a more potent EZH2 inhibitor with improved microsomal stability (page 1468 column 2 paragraph 3). Furthermore, Bradly et. al. teach that that CPI-169 significantly increased EZH2 thermal stability and–compared to CPI-360–maintained stabilization for a longer time period after compound removal (page 1468 column 2 paragraph 3).
Therefore, since the prior art of both Burgess’988, Liu et. al. taught that EZH2 inhibitors were possible treatment strategies for treating psoriasis and since the prior art of Bradley et. al. taught that CPI-169 was a more potent EZH2 inhibitor it would have been obvious to one of ordinary skill in the art to substitute either the substituted azaindoles of Burgess’988 or EZH2 (DZNep) of Liu et. al. with the more potent EZH2 inhibitor CPI-169.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Burgess’988 to treat psoriasis using EZH2 inhibitor topically applied in view of Liu et.al. and Bradley et. al. specifically to use CPI-169 as a substitute for DZNep with Etanercept as the additionally agent active against psoriasis-associated symptoms. One would have been motivated to use CPI-169 instead of DZNEP as an EZH2 inhibitor because the prior art of Lui et. al. and Bradley et. al. teach both DZNEP and CPI-169 as inhibitors of EZH2. One of ordinary skill in the art would have had a reasonable expectation of success since aberrant expression of EZH2 may contribute to the progress of psoriasis.
Claims 3 – 4, 9, and 12 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/039988 A1 to Burgess et.al. (herein after Burgess’988; cited in the office action dated April 7th, 2025), Liu et. al. ((2011), Comparison of gene expression profiles reveals aberrant expression of FOXO1, Aurora A/B and EZH2 in lesional psoriatic skins, Mol Bio Rep., 38, 4219 – 4224; cited in the office action dated April 7th, 2025), and Bradley et. al. ((2014), EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation, Cell Press Chemistry & Biology, 1463 – 1475; cited in the Office Action dated November 3rd, 2025) as they applied to claims 1 – 2, 5 – 6, 8, 11, and 18 – 19 in view of Gisondi et.al. ((2017), Treatment Approaches to Moderate to Severe Psoriasis, Int. J. Mol. Sci., 18, 1 – 8; cited in the office action dated April 7th, 2025) and Colombo et.al. ((2012), Calcipotriol and betamethasone dipropionate in the treatment of mild-to-moderate psoriasis: a cost effectiveness analysis of the ointment versus gel formulation, ClinicoEconomics and Outcomes Research, 4, 261 – 268; cited in the office action dated April 7th, 2025).
The teaching of Burgess’988, Liu et. al., and Bradley et. al. as they relate to claims 1, 8, and 11, from which claims 3 – 4, 9, and 12 – 13 depend, are given previously in this office action and are fully incorporated here.
However, Burgess’988, Liu et. al., and Bradley et. al. are silent about a method or pharmaceutical composition comprising an EZH2 inhibitor wherein the skin-permeable formulation (claim 3, 9, and 12) is selected from the group consisting of: creme, gel, lotion (claims 4, and 13).
Nevertheless, Gisondi et. al. teach that there are many factors influencing psoriasis severity which include the extent of the disease, the location of lesions, the degree of inflammation, the responsiveness to treatment, and the impact on quality of life (page 1 paragraph 1). Furthermore, Gisondi et. al. teach that treatments of pessaries can be classified as topical, systemic, or phototherapeutic (page 2 paragraph 2). Additionally, Gisondi et. al. teach that topical therapy alone is indicated in mild psoriasis (page 2 paragraph 2) and Gisondi et. al. teach that for patients with moderate to severe psoriasis topical therapy could be indicated in association with systemic treatments (page 2 paragraph 2 and page 3 paragraph 1).
However, Gisondi et. al. is silent about a method or pharmaceutical composition wherein the skin-permeable formulation is selected from the group consisting of: creme, gel, lotion (claims 3 – 4, 9, and 12 – 13).
Nevertheless, Colombo et.al. teach that topical therapy has an important role in the treatment of psoriasis (page 262 column 1 paragraph 3). Colombo et. al. teach a pharmacoeconomic simulation aimed at assessing the costs of two topical formulations gel and ointment showing different levels of adherence with treatment of mild-to-moderate psoriasis, applying it to the Italian population, and correlating costs with varying degrees of disease severity (page 262 column 1 paragraph 3 and column 2 paragraph 1). More specifically, Colombo et. al. teach the use of two formulations of calcipotriol and betamethasone dipropionate, that is, Dovobet® gel and ointment, in the treatment of mild-to-moderate psoriasis (page 262 column 2 paragraph 2).
Furthermore, Colombo et. al. teach that the use of Dovobet gel reduces the number of patients potentially needing treatment with more costly therapies by 5%, in spite of an increase in resource consumption for topical therapies (page 264 column 2 paragraph 1). Moreover, Colombo et. al. teach that the Dovobet gel strategy showed better overall adherence and, at the proposed selling price (€33.17), appears to be a more favorable choice than the ointment formulation from the clinical and economic points of view for the treatment of mild-to-moderate psoriasis (page 264 column 2 paragraph 3). While Dovobet is not an EZH2 inhibitor; Colombo et. al. suggest that the gel formulation as being a favorable choice over an ointment based formulation.
Therefore it would have been obvious before the effective filing date of the instant application to modify the method Burgess’988, Liu et. al., and Bradley et. al. to treat psoriasis using a topical application of an EZH2 inhibitor in view of Gisondi et. al. and Colombo et. al., that is in a gel skin-permeable formulation. One of ordinary skill in the art would have been motivated to make this modification for better compliance by the patient to the prescribed treatment regimen. One of ordinary skill in the would have a reasonable expectation of success because the gel formulation, for a conventional psoriasis therapy, showed better overall adherence and cost point for the patients.
Claims 16 – 17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/039988 A1 to Burgess et.al. (herein after Burgess’988; cited in the office action dated April 7th, 2025), Liu et. al. ((2011), Comparison of gene expression profiles reveals aberrant expression of FOXO1, Aurora A/B and EZH2 in lesional psoriatic skins, Mol Bio Rep., 38, 4219 – 4224; cited in the office action dated April 7th, 2025), and Bradley et. al. ((2014), EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation, Cell Press Chemistry & Biology, 1463 – 1475; cited in the Office Action dated November 3rd, 2025) as they applied to claims 1 – 2, 5 – 6, 8, and 11, in further view of Makita et. al. ((2018), Targeting EZH2 with tazemetostat, The Lancelet Oncology, 19, 586 – 587).
The teaching of Burgess’988, Liu et. al., and Bradley et. al. as they relate to claims 1, 8, and 11, from which claims 16 – 17, and 20 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Burgess’988, Liu et. al., and Bradley et. al. are silent about a method or pharmaceutical composition comprising an EZH2 inhibitor where the EZH2 inhibitor selected is EPZ-6438 (tazemetostat) (claims 16 – 17, and 20).
Nevertheless, Makita et.al. teach that Enhancer of zeste homolog 2 (EZH2) is a subunit of the chromatin remodelling polycomb repressive complex 2 (page 586 column 1 paragraph 1). Moreover, Makita et. al. teach tazemetostat (claims 16 – 17, and 20), that is EPZ-6438, as a first-in-class oral selective EZH2 inhibitor (page 586 column 1 paragraph 2). Thus, the prior art of Makita et. al. suggest the feasibility of using tazemetostat, that is EPZ-6438, in diseases or conditions that are mediated through EZH2 inhibition. Given the relatively high skill level of one of ordinary skill in the medicinal arts being that of an MD or PhD it would have been within the purview of such artisan to take the prior art teachings of Burgess’988, Liu et.al., and Bradley et. al., in further view of Makita et.al., to substitute the EZH2 inhibitor DZNEP for tazemetostat, that is EPZ-6438.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Burgess’988 to treat psoriasis using EZH2 inhibitor topically applied in view of Liu et.al. and Bradley et. al., to use CPI-169 as a substitute for DZNep, in further view of Makita et.al., that is to substitute the EZH2 inhibitor EZ-6438. One would have been motivated to use EZ-6438 instead of DZNEP as an EZH2 inhibitor because of the combination of the prior art of Lui et. al., Bradley et., and Makita al. that teach DZNEP, CPI-169, and EZ-6438 are inhibitors of EZH2. One of ordinary skill in the art would have had a reasonable expectation of success since aberrant expression of EZH2 may contribute to the progress of psoriasis.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2013/039988 A1 to Burgess et.al. (herein after Burgess’988; cited in the office action dated April 7th, 2025), Liu et. al. ((2011), Comparison of gene expression profiles reveals aberrant expression of FOXO1, Aurora A/B and EZH2 in lesional psoriatic skins, Mol Bio Rep., 38, 4219 – 4224, cited in the office action dated April 7th, 2025), and Bradley et. al. ((2014), EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation, Cell Press Chemistry & Biology, 1463 – 1475; cited in the Office Action dated November 3rd, 2025) as they applied to claims 1 – 2, 5 – 6, 8, 11, and 18 – 19, in view of Sun et. al. ((March 19, 2019), Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes, Cell Death and Disease, 10, 1 – 16; cited in the office action dated April 7th, 2025).
The teachings of Burgess’988, Liu et. al., and Bradley et. al. as they relate to claims 1, and 6, from which claim 7 depend, are given previously in this office action and are fully incorporated here.
However, Burgess’988, Liu et. al., Bradley et. al. are silent about whether the additional agent is an CDK4/6 inhibitor (claim 7).
Nevertheless, Sun et. al. teach although the molecular mechanisms involved in the pathogenesis of psoriasis are complex, growing evidence suggests that the activator of transcriptions 1 and 3 (STAT1 and STAT3), and nuclear factor-κB (NF-κB) is pivotal in the transcriptome network involved in the mechanism of psoriasis (page 2 column 1 paragraph 2). Furthermore, Sun et. al. teach that in particular, expression of constitutively active STAT3 (STAT3C) in keratinocytes leads to the spontaneous development of psoriasis in transgenic mice (page 2 column 1 paragraph 2). Moreover, Sun et. al. teach that CDK4/Cyclin D kinase was reported to be important in CDC6 transcription (page 4 column 2 paragraph 4). Thus, Sun et. al. suggest the targeting of CDK4 has a pathway for modulating CDC6 activity. Additionally, Sun et. al. teach that CDC6, induced by STAT3 activation in keratinocytes, is upregulated in psoriatic epidermal skin and contributes to proliferation of keratinocytes (page 2 column 1 paragraph 5). Moreover, Sun et. al. teach that Berberine (BBR), a plant alkaloid, inhibits CDK4/6-RB-CDC6 signaling, leading to cell cycle arrest and apoptosis in keratinocytes (page 2 column 2 paragraph 1). Furthermore, Sun et. al. teach that palbociclib significantly reduced both protein and mRNA levels of CDC6 in HaCaT cells (page 6 column 1 paragraph 1 and page 7 Figure 2h, i).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Burgess’988, Liu et. al., and Bradley et. al. to treat psoriasis using an EZH2 inhibitor in view of Sun et. al. that is to include a CDK4/6 inhibitor. One of ordinary skill in the art would have been motivated to make this modification because CDK4/6 is important in CDC6 transcription and thus STAT3 activation. One of ordinary skill in the art would have a reasonable expectation for success because Palbociclib, a CDK4/6 inhibitor, significantly reduced both protein and mRNA levels of CDC6 in HaCaT cells.
Response to Arguments
Applicant's claim amendments and arguments filed June 29th, 2026, with respect to the 35 U.S.C. 103 rejection of claims 1 – 9, 11 – 13, and 16 – 20 have been fully considered and but they are not persuasive.
Applicant argues that the combination of the cited prior art does not teach or suggest every element of the present claim 1, and that the examiner relies on hindsight reasoning for the 103 rejection (see applicants remarks pages 12 – 17).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As stated in the above prior art rejection, above Burgess’988 teaches inhibiting EZH2-mediated diseases by administering EZH2 inhibitors. Liu et. al. teaches that EZH2 activation causes psoriasis. Bradley et. al. teaches that CPI-169 is an EZH2 inhibitor. And Makita et. al. teach that EPZ-6438 (tazemetostat) is an EZH2 inhibitor. Thus, the rejection as delineated above does not depend on improper hindsight; but specifically, on what is taught by the prior art of record. Moreover, as delineated above, the rejection explains what the person of ordinary skill in the art would have understood to be the mechanism underlying psoriasis and then demonstrates that the skilled artisan would have used either CPI-169 or EPZ-6438 (tazemetostat) to inhibit that EZH2 pathway.
Applicant contends that the claimed method is an improvement over psoriasis treatments that administer "toxic IKK inhibitors." (see Applicant’s remarks page 17 paragraph). Moreover, applicant argues contends that the findings in the specification are statistically and practically significant, but none of the proffered data appears to support that statement. (see Applicant’s remarks page 17 paragraph 4, and page 18 paragraphs 1 – 2).
The examiner contends that as the applicant has acknowledged, Burgess’899 is the closest prior art. Thus, the fact that the claimed method presents improvements relative to a wholly unrelated therapy is of no clear relevance to the obviousness of the invention. Moreover, the examiner contends that for a showing of unexpected results there must be a comparison between the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).(MPEP 716.02( e)). Moreover, the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)(MPEP 716.02(b)). Thus, an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. Moreover, Figure 10g depicting the ear thickness demonstrates that at 0.05 mg abemaciclib and 0.02 mg CPI-169 had an effect only compared to the ethanol control vehicle (see specification page 19).
Conclusion
Claims 1 – 9, 11 – 13, and 16 – 20 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 DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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