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 Application, Amendments and/or Claims
Claims 1-8 are pending and under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 24 November 2025; 15 December 2024; 01 November 2024 (4); and 09 August 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
On the IDS of 09 August 2024, the Bai et al. citation has been crossed off because a copy has not been provided.
It is noted that the following citations have been crossed off of the IDS of 01 November 2024 because they were cited in duplicate:
Revillet et al. 2014; Satoh et al.; Towne et al. 2004; Towne et al. 2011; Vajdos et al.; and Zouboulis 2015
Specification
1. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: “ANTI-IL-36R ANTIBODIES FOR THE TREATMENT OF NETHERTON SYNDROME”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
2. Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (U.S. Patent 9,023,995; or US 2013/0236471; or WO 2013/074569) (as evidenced by Wucherpfenning et al. (US 2022/0356258) and IUPHAR/BPS Guide to Pharmacology, (“spesolimab”, www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=12169, accessed 26 January 2024)) and Malik et al. (J Allergy Clin Immunol 143: 605-618, 2019, published online 24 May 2018). All references are cited on the IDS of 01 November 2024.
It is noted that the ‘995 patent, US201302326471, and WO 2013/074569 have the same disclosure. Thus, for brevity, relevant portions of the ‘995 patent will be cited below.
Brown et al. disclose that expression of IL-36Ra and IL-36α is significantly upregulated in IL-1β/TNFα-stimulated human keratinocytes, and IL-36Ra and IL-36γ mRNA are highly increased in lesional psoriatic skin (column 1, lines 63-67 through column 2, lines 1-2). Brown et al. teach antibodies that bind IL-36R and block IL-36 ligand-mediated signaling (column 2, lines 31-35). Brown et al. disclose administering the anti-IL36 antibodies to treat such diseases as psoriasis, palmoplantar pustulosis; generalized pustular psoriasis; deficiency in the IL-36 receptor antagonist autoimmune disease (DITRA); deficiency in the IL-1 receptor antagonist autoimmune disease (DIRA); or cryopyrin associated periodic syndromes (CAPS) (column 51, lines 1-17).
Brown et al. disclose that the anti-IL36R antibodies comprise the identical light chain and heavy chain variable region CDR sequences as those recited in instant claim 2 (see columns 25-30; 35-40). Brown et al. also teach anti-IL36R antibodies that comprise the identical light chain variable region and heavy chain variable region amino acid sequences as those recited in instant claim 3 (see columns 31-36). Brown et al. disclose anti-IL36R antibodies that comprise the identical light and heavy chain amino acid sequences as those recited in instant claim 4 (see columns 39-46). It is noted that the anti-IL36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127 (Antibody B6) of Brown et al. (column 46, lines 47-51; columns 49-50, Table A) is known as spesolimab, as evidenced by Wucherpfenning et al. (page 5, [0037] and IUPHAR/BPS Guide to Pharmacology, under “Comment”). For example, the amino acid sequences of SEQ ID NOs: 118 and 127 of Brown et al. are 100% identical to the amino acid sequences of SEQ ID NOs: 2 and 1, respectively, as disclosed in Wucherpfenning et al. Therefore, the anti-IL36R antibody disclosed in Brown et al. is “spesolimab”, absent evidence to the contrary, and meets the limitations of instant claim 5.
Furthermore, Brown et al. teach that depending upon the type and severity of disease, about 1 μg/kg to 20 mg/kg (e.g. 0.1-15 mg/kg) of antibody is an initial candidate dosage for administration to the patient (column 72, lines 4-14; see also column 74, lines 50-67 through column 75, lines 1-11). If, for example, the patient is a human and the average adult human weighs 60-80 kg, according to the dosage amounts of Brown et al., a 60 kg human would receive 0.06 mg to 1,200 mg of antibody per dose. An 80 kg human would receive 0.08 mg to 1,600 mg of antibody per dose. Thus, the administered antibody dosage range of Brown et al. overlaps with the dosage range of instant claim 6.
Brown et al. also teach that the pharmaceutical compositions comprising the IL-36R antibody may comprise an additional therapeutic agent (column 75, lines 12-17). Brown et al. state that the therapeutic agent may be administered before, after, or concurrent with the IL-36R antibody, meeting the limitations of instant claim 7 (column 75, lines 22-32).
Brown et al. do not teach administering the anti-IL36 antibodies to treat ichthyoses, such as Netherton syndrome.
Malik et al. teach that ichthyoses are a heterogeneous group of rare genetic, debilitating cutaneous disorders (such as Netherton syndrome) that share defective keratinization, a compromised epidermal barrier, and increased transepidermal water loss (page 604, column 2, 1st paragraph; page 605, column 1, 2nd paragraph). Malik et al. teach a detailed genomic and cellular profiling of the most common forms of ichthyosis (page 605, column 2, 1st full paragraph). Malik et al. perform gene, protein, and serum studies on skin and blood samples from 29 patients, including 4 with Netherton syndrome (NS), as well as age matched healthy control subjects, patients with psoriasis, and patients with atopic dermatitis (abstract, background and methods). Malik et al. state that, similar to patients with AD and psoriasis, immune dysregulation and lipid alterations characterize the ichthyoses (abstract). Malik teaches that the data presented support the testing of IL-17/IL-36 targeting therapeutics for patients with ichthyosis similar to those used in patients with psoriasis (abstract, conclusion).
Malik et al. disclose that patients with psoriatic epidermis and all types of ichthyoses, including Netherton syndrome, show widespread expression of IL-36R as compared to normal and AD controls (page 608, column 2, last paragraph through page 609, column 1; Figure 3B-H; see Figure 3H for Netherton syndrome, “NS”). Malik et al. also indicate that patients show significant increases in IL-36α, IL-36β, and IL-36γ mRNA (page 608, column 2; Figure 3A). Malik et al. teach that “[o]ur study shows increased mRNA and protein expression of IL-36 family members and IL-36R and highly significant correlations with ichthyosis severity and TWEL [transepidermal water loss], further suggesting IL-36/IL-36R involvement in the TH17 axis in ichthyosis, similar to psoriasis” (page 614, column 1). The data of Malik et al. also extend the prominent severity associated TH17 profile in ichthyosis to the blood compartment, supporting an accentuated systemic inflammation phenotype, particularly in patients with NS (page 614, column 1, last sentence of the 1st paragraph).
Malik et al. disclose that their study offers new insights into the possible role of the IL-17
pathway in perpetuating the barrier defects of ichthyosis and advocate for testing of IL-17, IL-36, and IL-23 antagonism in patients with these diseases (page 615, column 1, 2nd and 3rd full paragraphs).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of treating an inflammatory/autoimmune disease (including psoriasis, palmoplantar pustulosis; generalized pustular psoriasis; DITRA; DIRA; or CAPS) comprising administering an anti-IL-36R antibody as taught by Brown et al. by administering the anti-IL-36R antibody to patients with the ichthyosis, Netherton syndrome, as taught by Malik et al. The person of ordinary skill in the art would have been motivated to make that modification because (i) ichthyoses are a group of rare skin disorders that lack effective treatment strategies; (ii) similar to patients with psoriasis, Netherton syndrome patients demonstrate significant increases in IL-36α, IL-36β, and IL-36γ mRNA and show widespread expression of IL-36R (see Brown et al., columns 1-2; see Malik et al., abstract; page 604, bottom of column 2; page 608, column 2; Figure 3A; page 609, column 1; Figure 3; page 614, column 1); and (iii) Malik et al. clearly suggest the testing of IL-36 antagonism in patients with diseases, such as Netherton syndrome (page 614, column 1, last sentence of the 1st paragraph). The person of ordinary skill in the art reasonably would have expected success because the anti-IL-36R antibody administered in the methods of Brown et al. binds and blocks IL-36 signaling (Examples 6 and 7) and reduces epidermal thickness in a model of psoriasis (Example 15). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
3. Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (U.S. Patent 9,023,995; or US 2013/0236471; or WO 2013/074569) (as evidenced by Wucherpfenning et al. (US 2022/0356258) and IUPHAR/BPS Guide to Pharmacology, (“spesolimab”, www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=12169, accessed 26 January 2024)) and Malik et al. (J Allergy Clin Immunol 143: 605-618, 2019, published online 24 May 2018) as applied to claims 1-7 above, and further in view of Oji et al. (Am J Clin Dermatol 10(6): 361-364, 2009).
The teachings of Brown et al. and Malik et al. are set forth above.
Brown et al. and Malik et al. do not teach that the additional therapeutic agent administered with the IL-36R antibody is an anti-bacterial agent or corticosteroid.
Oji et al. teach that therapeutic management for ichthyoses is multi-disciplinary (page 351, 2nd paragraph). Oji et al. disclose that in Netherton syndrome, improvement of the skin barrier by the frequent application of creams containing antibacterials can help protect against frequent superinfections (page 361, column 1, 1st full paragraph). Oji et al. also indicate that many Netherton syndrome patients need anti-inflammatories or topical corticosteroids (page 361, bottom of column 1 through column 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of treating an ichthyosis, such as Netherton syndrome, comprising administering an anti-IL-36R antibody as taught by Brown et al. and Malik et al by administering an additional therapeutic with the anti-IL36R antibody, such as an anti-bacterial agent or corticosteroid, as taught by Oji et al. The person of ordinary skill in the art would have been motivated to make that modification because Oji et al. state that therapeutic management for ichthyoses is multi-disciplinary (page 351, 2nd paragraph). The person of ordinary skill also would have been motivated to make that modification to enhance the therapeutic efficacy of the administered anti-IL36R antibodies. One skilled in the art would have expected success because “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) and MPEP § 2144.06. Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
4. Claims 1 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over
Bowers et al. (WO 2016/168542; or US 20180094065; or U.S. Patent 10,526,410) and Malik et al. (J Allergy Clin Immunol 143: 604-618, 2019). All references are cited on the IDS of 01 November 2024.
It is noted that WO 2016/168542; US 20100094065; and U.S. Patent 10,526,410 have the same disclosure. Thus, for brevity, relevant portions of WO 2016/168542 will be cited below.
Bowers et al. disclose that expression of IL-36Ra and IL-36α is significantly upregulated in IL-1β/TNFα-stimulated human keratinocytes, and IL-36Ra and IL-36γ mRNA are overexpressed in psoriasis skin lesions (page 1, [0003]). Bowers et al. teach an isolated antibody that binds and inhibits IL-36R (page 10, [0061]; page 20, [0094]). Bowers et al. disclose a method of treating a disorder in a mammal that is responsive to IL-36R inhibition and neutralization by administering an IL-36R antibody (page 20, [0095-0096]; pages 29-30, [000124-00125]). Bowers et al. indicate that such diseases treated include psoriasis, pustular psoriasis, generalized pustular psoriasis (GPP), and palmo-plantar pustulosis (PPP) (pages 30-31, [00127-00128]).
Bowers et al. state that a typical dose can be, for example, in the range of 1 pg/kg to 20 mg/kg (page 32, [00134]). If, for example, the patient is a human and the average adult human weighs 60-80 kg, according to the dosage amounts of Bowers et al., a 60 kg human would receive 6 x 10-8 mg to 1,200 mg of antibody. An 80 kg human would receive 8 x 10-8 mg to 1,600 mg of antibody. Thus, the administered antibody dosage range of Bowers et al. overlaps with the dosage range of instant claim 7.
Bowers et al. also teach that the IL-36R antibody may be administered alone or in combination with other drugs (page 35, [00140]). Bowers et al. indicate that the other drugs include, for example, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) (page 35, [00140]).
Bowers et al. do not teach administering the anti-IL36R antibodies to treat ichthyoses, such as Netherton syndrome.
Malik et al. teach that ichthyoses are a heterogeneous group of rare genetic, debilitating cutaneous disorders (such as Netherton syndrome) that share defective keratinization, a compromised epidermal barrier, and increased transepidermal water loss (page 604, column 2, 1st paragraph; page 605, column 1, 2nd paragraph). Malik et al. teach a detailed genomic and cellular profiling of the most common forms of ichthyosis (page 605, column 2, 1st full paragraph). Malik et al. perform gene, protein, and serum studies on skin and blood samples from 29 patients, including 4 with Netherton syndrome (NS), as well as age matched healthy control subjects, patients with psoriasis, and patients with atopic dermatitis (abstract, background and methods). Malik et al. state that, similar to patients with AD and psoriasis, immune dysregulation and lipid alterations characterize the ichthyoses (abstract). Malik teaches that the data presented support the testing of IL-17/IL-36 targeting therapeutics for patients with ichthyosis similar to those used in patients with psoriasis (abstract, conclusion).
Malik et al. disclose that patients with psoriatic epidermis and all types of ichthyoses, including Netherton syndrome, show widespread expression of IL-36R as compared to normal and AD controls (page 608, column 2, last paragraph through page 609, column 1; Figure 3B-H; see Figure 3H for Netherton syndrome, “NS”). Malik et al. also indicate that patients show significant increases in IL-36α, IL-36β, and IL-36γ mRNA (page 608, column 2; Figure 3A). Malik et al. teach that “[o]ur study shows increased mRNA and protein expression of IL-36 family members and IL-36R and highly significant correlations with ichthyosis severity and TWEL [transepidermal water loss], further suggesting IL-36/IL-36R involvement in the TH17 axis in ichthyosis, similar to psoriasis” (page 614, column 1). The data of Malik et al. also extend the prominent severity associated TH17 profile in ichthyosis to the blood compartment, supporting an accentuated systemic inflammation phenotype, particularly in patients with NS (page 614, column 1, last sentence of the 1st paragraph).
Malik et al. disclose that their study offers new insights into the possible role of the IL-17
pathway in perpetuating the barrier defects of ichthyosis and advocate for testing of IL-17, IL-36, and IL-23 antagonism in patients with these diseases (page 615, column 1, 2nd and 3rd full paragraphs).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of treating a disorder that is responsive to IL-36R inhibition and neutralization comprising administering an IL-36R antibody as taught by Bowers et al. by administering the anti-IL-36R antibody to patients with the ichthyosis, Netherton syndrome, as taught by Malik et al. The person of ordinary skill in the art would have been motivated to make that modification because (i) ichthyoses are a group of rare skin disorders that lack effective treatment strategies; (ii) similar to patients with psoriasis, Netherton syndrome patients demonstrate significant increases in IL-36α, IL-36β, and IL-36γ mRNA and show widespread expression of IL-36R (see Bowers et al., page 1; see Malik et al., abstract; page 604, bottom of column 2; page 608, column 2; Figure 3A; page 609, column 1; Figure 3B; page 614, column 1); and (iii) Malik et al. clearly suggest the testing of IL-36 antagonism in patients with diseases, such as Netherton syndrome (page 614, column 1, last sentence of the 1st paragraph). The person of ordinary skill in the art reasonably would have expected success because the anti-IL-36R antibody administered in the methods of Bowers et al. binds and blocks IL-36 signaling (Examples 1-7) and has good pharmacokinetic characteristics and subcutaneous bioavailability when administered in vivo (Example 10). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Conclusion
No claims are allowable.
The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Bai et al. J Eur Acad Dermatol Venereol (JEADV) 39: e261-e262, 2025 (teach treatment of Netherton syndrome by administration of anti-IL-36R, spesolimub)
Chiticariu et al. J Invest Dermatol 140: 1129-1130, June 2020 (review of Netherton syndrome)
Gouin et al. J Invest Dermatol 140: 1184-1194, June 2020 (cited on the IDS of 11/01/2024; generate a transgenic murine model overexpressing human KLK14 (TghKLK14) that displays Netherton syndrome clinical features (abstract; page 1184); teach that IL-36α, IL-36β, IL-36γ are upregulated in skin extracts (page 1189, column 1, 2nd and 3rd paragraphs; Figure 5)
References that disclose IL-36R antibodies (other than spesolimab) (all cited on the IDS of 11/01/2024)
Bowers et al. WO 2016/168542
Blumberg et al. J Immunol 185: 4354-4362, 2010
Ganesan et al. Mabs 9: 143-154, 2017
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BEB
Art Unit 1647
26 September 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
