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 .
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 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.
Priority
The instant application, filed 12/19/2023, is a 371 filing of PCT/EP2022/069292, filed 07/11/2022, and claims foreign priority to EP21305968.6, filed 07/12/2021
Status of Claims/Application
Applicant’s preliminary amendment of 12/19/2023 is acknowledged. Claims 3 and 6-7 are amended and claims 9-10 are new. Claims 1-10 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/19/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
In the amended specification filed 11/25/2024, Table 1 Parts 1 and 2 on pages 16-17 have poor resolution and the text within is difficult to read.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 5-6 are 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 which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 depends on claim 1 and recites the limitation “wherein the patient retains a scaly erythrodermic phenotype.” The definition of “retain” is to continue to have, to hold, or to keep in possession. As such, the claim limits the patient to one that maintains or continues to have the scaly erythrodermic phenotype over some duration of time. The time over which the patient is claimed to retain the scaly erythrodermic phenotype; however, is unclear, rendering the metes and bounds of the claim indefinite. For instance, the claim could be interpreted as requiring that the patient retain the SE phenotype before and after the method of treatment recited in claim 1. Alternatively, the claim could be interpreted as requiring that from diagnosis up until treatment the patient has retained the SE disease phenotype.
Appropriate correction/clarification is required.
Claim 5 recites the limitation that the antibody binds to the amino acid sequence that ranges from the amino acid residue at position 20 to the amino acid residue 335 in SEQ ID NO: 1. The claim recites a definite range of amino acids, specifically 20-335, and recites that the antibody binds to this sequence. It is unclear if the intention of the limitation is to require that the antibody bind somewhere within the sequence range recited or if the limitation requires that the antibody bind all amino acids in the sequence of SEQ ID NO: 1 AA 20-335. As the metes and bounds of the claim is unclear, the claim is indefinite.
Appropriate clarification/correction is required.
In the instant office action, the claim is interpreted as requiring that the antibody bind within the amino acid sequence represented by amino acid residues 20-335 in instant SEQ ID NO: 1.
Claim 6 is rejected by virtue of its dependency on rejected claim 5.
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.
Claim 6 is 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.
The instant claim is drawn to the method of claim 5 and ultimately to claim 1 and encompasses a method of treating Netherton syndrome in a patient by administering an IL-36 antibody that binds to the extracellular domain of IL1RL2. Claim 6 recites limits the antibody to binding a conformational epitope that comprises at least one of the recited amino acid sequences.
The instant disclosure defines “epitope” as referring to a specific arrangement of amino acids located on a protein or proteins to which an antibody binds. Epitopes often consist of a chemically active surface grouping of molecules such as amino acids or sugar side chains, and have specific three dimensional structural characteristics as well as specific charge characteristics. Epitopes can be linear or conformational, i.e., involving two or more sequences of amino acids in various regions of the antigen that may not necessarily be contiguous (page 6, line 31 – page 7, line 3).
Claim 6 limits the antibody by what it does (at least one of the specific amino acid sequences in conformational epitope that it binds) rather than what it is (the structure of the antibody that performs the claimed function).
MPEP 2173.05(g) states that “Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C. 112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197.”
The claim is drawn to a genus of antibodies that are limited by the function that they perform, specifically the epitope that they bind. The disclosure does not provide a representative number of species of the claimed genus nor does the disclosure identify a structure-function correlation that would allow for the predictable identification of which species within the genus would have the claimed functions.
The instant disclosure teaches that anti-IL36R antibodies are well known in the art and includes those described in WO2013074569 and WO2016168542 as well as that of Ganesan, R., et al and the antibody Spesolimab (page 7, line 29 – page 8, line 2). However, of these, only the antibody presented in Ganesan is clearly identified as binding to the claimed epitope. The examples of the instant disclosure demonstrate that IL-17 and IL-36 are elevated in NS and drive immune response in the skin and peripheral blood (page 13) and establish IL-36 as a target in the treatment of NS patients (page 15). The examples do not demonstrate the production of an IL-36 antibody that binds to the claimed conformational epitope. The disclosure also does not provide a predictable correlation between antibody structure and function that would allow an ordinarily skilled artisan to identify which antibodies, which what structure, would perform the claimed binding.
The prior art also does not provide a representative number of species of the claimed antibody having the claimed function nor does the art provide a predictable structure function correlation. Rather, the art suggests that, even up approximately a year after the effective filing date, the correlation between antibody structure and epitope binding was unpredictable.
Ganesan, R., et al (2017) Generation and functional characterization of anti-human and anti-mouse IL-36R antagonist monoclonal antibodies MABS 9(7), 1143-1154 identified high affinity anti-IL-36R antibodies by immunizing mice with recombinant human IL-36R. The selection of mice for fusion was driven by assessment of serum titers. In all, Ganesan performed 4 fusions and screened >50,000 fusion product supernatants that led to the identification of ~7100 clones specific for binding to huIL-36R. The 150 hits were subsequently sub-cloned and the purified mouse antibodies were subsequently screened. Eight functionally potent mAbs were identified. The antibodies were then binned by cross-competition using SPR and clone mMAB92 ranked as the top hit based on profiling criteria which included binding, function, and sequence quality, and was chosen for humanization (page 1144-1145, Immunization, screening, and epitope binning to identify functional lead mouse anti-human IL-36R monoclonal antibody).
To map the binding site of clone mMAB92 on human IL-36R, epitope mapping was performed. The protection map and further refinements of the analysis showed significant protection in regions identified as residues 9 to 14 (MKNEIL), 96 to 110 (EKHWCDTSIGGLPNL), 113 to 119 (YKQILHL), 149 to 154 (IKGERF) and 117 to 186 (QAILTHSGKQ) on IL-36R (page 1146, right column, paragraph 2). This antibody, mMAB92, represents a single species of the claimed genus and, as described, the antibody was created then the epitope was determined indicating that the antibody was not created based on the epitope alone.
Ganesan further teaches the development of MAB04, an anti-mouse IL-36R antibody by immunization in the rat. The epitope of the antibody is shown along with the epitope of mMAB892 in Fig 3 (page 1147, Fig. 3; left column, paragraph 2). While both antibodies showed overlapping binding preference to domain-2 on IL-36R, and one of the epitopes overlap, the epitopes that the antibodies bind are unique to each antibody, further demonstrating that epitope binding is a function of the specific antibody structure.
Hummer, A.M., et al (2022) Advances in computational structure-based antibody design Current Opinion in Structural Biology 74(102379); 1-7, published approximately a year after the effective filing date of the claimed invention, further demonstrates unpredictability in antibody structure-function correlation. Hummer teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function.
It is not evident by the disclosure, or the prior art, that applicant was in possession of a representative number of species of antibodies binding to the conformational epitope of the instant claim. Additionally, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable generation of antibodies that bind to the claimed epitope. Therefore, the instant claim was determined not to meet the written description requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for disease modifying treatment of patients who are ill or have been diagnosed as suffering from Netherton syndrome, does not reasonably provide enablement for prophylactic, preventative, or curative treatment of Netherton syndrome. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instantly claimed invention is drawn to a method of treating Netherton syndrome comprising administering a therapeutically effective amount of an IL-36 inhibitor.
The breadth of the claims
The claims are broad in that they encompass the application of the claimed method as a prophylactic, preventative, or curative treatment.
Specifically, the claims recite a method of treating Netherton syndrome and the instant specification defines “treatment” or “treat” as referring to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of a patient at risk of contracting the disease. The treatment may be administered in order to prevent or cure the disorder (page 4, lines 1-10).
The specification does not explicitly define “prophylactic” or “prevention”. In absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure demonstrate that IL-17 and IL-36 are elevated in NS and drive immune response in the skin and peripheral blood (page 13) and establish IL-36 as a target in the treatment of NS patients (page 15). The examples do not demonstrate, through working examples, the prevention of NS using the claimed method nor does the disclosure identify a method that could be used to predictably identify patients who would develop NS in order to identify that NS was prevented using the claimed methods. The disclosure also does not demonstrate the cure of NS.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that could be used to predictably identify that Netherton syndrome was prevented using the claimed method. Additionally, there are no art recognized methods that could be used to identify subjects who would predictably develop the syndrome in order to determine that it was prevented using the claimed method. The art also suggests that there is no cure for Netherton syndrome.
For example, Ngan, V (2005) Netherton syndrome DermNet, 2 pages, accessed from https://dermnetnz.org/topics/netherton-syndrome on 29 Apr 2026 teaches that Netherton syndrome is a rare inherited disorder that presents with characteristics including ichthyosiform erythroderma, trichorrhexis invaginate (‘bamboo hair’), and atopic diathesis. Individuals with Netherton syndrome may show some or all of these features with varying degrees of severity in their symptoms (page 1, what is Netherton syndrome). Ngan teaches that Netherton syndrome may be evident at birth or during the first weeks of life (page 1, What are the signs and symptoms of Netherton syndrome). Ngan further teaches that Netherton syndrome is inherited as an autosomal recessive trait. The condition is caused by mutations in the PINK5 gene that is found on chromosome 5. In some cases, there is no family history of the trait and Netherton syndrome is revealed when two unaffected parents who are both carriers of the mutated recessive gene have a child who receives both copies of the recessive gene (page 2, paragraph 1). Ngan teaches that Netherton syndrome is diagnosed by examination of abnormal hair under a microscope and that diagnosis can be confirmed by skin biopsy and DNA testing. Ngan also teaches that abnormal hair shafts do not usually develop until after 2 years of age but may occur earlier (page 2, how is the diagnosis made?). Ngan also teaches that there is no specific treatment of Netherton syndrome and the goal is to manage the symptoms and prevent skin infections and other complications. Symptoms of Netherton syndrome tend to improve with age. Periods of little or no disease symptoms are interspersed with intermittent exacerbations (page 2, What is the treatment for Netherton syndrome?). Teachings which indicate that there is no cure for Netherton’s syndrome, suggesting that cure of the syndrome is unpredictable.
Reese, M.S., et al (2025) Netherton Syndrome: A systematic review of the challenges of diagnosis and treatment Cureus 17(12); e98322, pages 1-21 demonstrates that even as late as 2025, the onset of Netherton syndrome was also not predictable and that cure was not still not possible. Reese teaches that, being a rare disease, much remains unknown about why NS manifests, what therapies work best for it, and how to best distinguish it from other severe dermatological disorders. Pathophysiology is poorly understood and its clinical phenotype is variable. May symptoms overlap with other severe dermatological disorders which complicates diagnosis. While there are no current standardized therapies, accurate identification can rule out inappropriate treatment options and help patients receive care that may be beneficial sooner. Molecular genetic testing for the SPINK5 mutation is known to be key in confirming NS, but resources are variable and the test cannot always be ordered. Presently, much of the treatment for NS is supportive, but emerging therapies have potential in individualized and successful care (page 4, paragraph 2).
Due to its rarity, NS remains shrouded in relative obscurity, and as such, early accurate diagnosis and consequently treatment remains a challenge. This systematic review used a 34-patient sample size to identify common NS presentations, successful diagnostic modalities, and successful therapies. The review proposes a pathway-dependent individualized therapy in union with genetic counseling as potentially the most reliable route to successful treatment.
The teachings of Reece demonstrate unpredictability in the onset and diagnosis of NS and demonstrate that there was no method to predictably identify patients who would have developed NS. The teachings of Reece also demonstrate that there is not a known cure for NS, suggesting that cure of the syndrome is unpredictable.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the disclosure and the prior art, there is no known or disclosed method through which an ordinarily skilled artisan would have been able to predictably determine that a subject would have developed Netherton syndrome in order to determine that the claimed method resulted in the prevention of the syndrome. Additionally, the instant disclosure does not demonstrate cure of Netherton syndrome with the claimed method and the prior art suggests that the cure for Netherton syndrome is not predictable. Therefore, in order to practice the invention as claimed, an ordinarily skilled artisan would have to participate in undue experimentation to determine a method that would allow for the identification of patients who would have predictably developed Netherton syndrome without the claimed agents and to determine how the claimed treatment could act to cure Netherton syndrome.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-5, and 8-9 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2024/0392019 A1 (Fine, J., et al) 28 Nov 2024; effective filing date 17 Jul 2020 as evidenced by US 9,023,995 B2 (Brown, S., et al) 5 May 2015 and GenBank Interleukin 1 receptor-like 2 [homo sapiens] NCBI Reference Sequence: NP_003845.1 01 NOV 2000.
US’019 teaches a method for treating Netherton syndrome (NS) in a subject comprising administering to the subject a therapeutically effective amount of an anti-interluekin-36 receptor (anti-IL-36R) antibody (page 32, claim 1).
US’019 further teaches structures for the anti-IL36R antibody including CDRs, heavy and light chain variable regions, and heavy and light chains (pages 32-33, claims 2-4).
The antibodies disclosed by US’019 bind to the extracellular domain of IL1RL2 and positions 20-332 of the amino acid sequence of instant SEQ ID NO: 1, thereby anticipating instant claims 4-5 and 9, as evidenced by US’995 and GenBank Accession #NP_003845.
Specifically, US’019 teaches that the anti-IL36R antibodies are in U.S. Pat. No. 9,023,995 (page 4, [0059]; page 6, [0076]). As evidenced by US’995, the antibodies were generated with human IL-36R ECD- extracellular domain: amino acids 20-332 of Genbank Accession #NP_003845 (col. 75-76, Example 1). Amino acids 20-335 of Genbank Accession #NP_003845 are identical to instant SEQ ID NO: 1 positions 20-335, demonstrating that the antibodies of US’019, which are those produced in US’995, binds within the amino acid sequence that ranges from position 20-335 in SEQ ID NO: 1.
US’019 also teaches that the antibody can be administered orally, parenterally, by inhalation, or topically (page 12, [0164]). As the administration routes taught by US’019 are sufficiently small, one of ordinary skill in the art would “at once envisage” administration as a topical formulation based on the disclosure of US’019. Therefore, claim 8 is also anticipated. See MPEP 2131.02 III.
Thus, US’019 anticipates instant claims 1, 3-5, and 8-9.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Malik, K., et al (2019) Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature J Allergy Clin Immunol 143(2); 604-618 and Supplemental materials (21 pages).
Malik teaches that ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest most needed pathogenesis based therapy. Malik performed 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 concludes that, similar to patients with AD and psoriasis, immune dysregulation and lipid alterations characterize the ichthyoses. 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 teaches that IL-36α, IL-36β, and IL-36γ subunits exert their proinflammatory effects through binding and teaches that IL-36 receptor (IL-36R), activates the intracellular signaling pathways. Malik analyzed IL-36R protein expression through immunohistochemistry. IL-36R is known to form feedback loops driving IL-17 cytokine production in patients with psoriasis. Although in normal and AD lesions, IL-36R showed minimal epidermal expression, widespread expression of IL-36R was noted in psoriatic epidermis and patients with all types of ichthyoses, including NS (Fig. 3, E-H; paragraph bridging pages 608-609). In Fig. 3A, Malik also demonstrates increased expression of IL-36α, IL-36β, and IL-36γ in subjects with NS compared to control subjects (N).
Malik teaches that the data establishes a predominant TH17/IL-23 and IL-36 signature underlying the common and individual ichthyosis phenotypes. The study shows increased mRNA and protein expression of IL-36 family members and IL-36R involvement in the TH17 axis in the ichthyoses, similar to psoriasis. The data also extended the prominent severity associated TH17 profile in ichthyosis to the blood compartment, supporting an accentuated systemic inflammation phenotype, particularly in patients with NS (page 314, left column, paragraph 1).
Malik concludes that the study provided offers new insights into the possible role of the IL-17 pathway in perpetuating the barrier defects of ichthyosis and advocates for testing of IL-17, IL-36, and IL-23 antagonism in patients with these diseases. Such studies will not only help dissect disease pathogenesis, but might also provide hope for better treatment for these devastating disorders (page 615, left column, paragraph 3).
Although Malik does not conclusively demonstrate the treatment of Netherton syndrome in a patient with an IL-36 inhibitor, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to treat Netherton syndrome by administering an IL-36 inhibitor based on the teachings of Malik. Specifically, Malik demonstrates that 36α, IL-36β, and IL-36γ as well as IL-36R all have higher expression in NS compared to controls and expressly teaches that the data presented supports the testing of IL-36 targeted therapeutics for patients with ichthyosis, including NS, similar to those used in patients with psoriasis. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Malik, K., et al (2019) Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature J Allergy Clin Immunol 143(2); 604-618 and Supplemental materials (21 pages) as applied to claim 1 above, and in further view of Abdalrheem, W.O., et al (2020) A case report on Netherton Syndrome Cureus 12(7); e9166; 1-4.
Malik teaches the method of claim 1 as discussed above.
Malik provides the following demographics of the ichthyosis patients with Netherton syndrome in Table E3 (supplementary information), which is duplicated below for NS subjects:
PNG
media_image1.png
293
890
media_image1.png
Greyscale
Malik indicates that IASI is the Ichthyosis area and severity index with IASI-E being IASI-erythema, and IASI-S being IASI-scaling (supplemental materials page 1, paragraph 2).
Malik, however, does not explicitly indicate that the NS patient retains a scaly erythrodermic phenotype.
Abdalrheem teaches that Netherton syndrome (NS) is a rare severe autosomal recessive disorder of ichthyosis characterized by extensive skin desquamation, hair shaft abnormality and atopic manifestations with high immunoglobulin E levels and hypereosinophilia. The precise incidence of NS is unknown, but is estimated to be present in 1:100,000 to 1:200,000 live births. The syndrome presents at or soon after birth with the following characteristics: generalized erythroderma, scaling, and/or continuous peeling of the skin that resembles sparse, brittle hair containing trichorrhexis invaginate. Generalized scaly erythroderma is apparent soon after birth and usually persists. Ichthyosis linearis circumflexa (ILC), which typically consists of serpiginous patches bordered by double-edge scales, develops during the first years of life in patients with NS. NS is attributed to mutations in the gene encoding SPINK5. Abdalrheem provides a case study of a child Saudi female with NS and a brief literature review (page 1, paragraph 2). Abdalrheem’s teaching of NS patients having scaly erythroderma that is apparent at birth and persists is interpreted as meeting the instant claim limitation of a patient who retains a scaly erythrodermic phenotype.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the method taught by Malik in the treatment of Netherton syndrome patients with a persistent erythroderma phenotype as taught by Abdalrheem. It would have been obvious to treat patients with a persistent scaly erythroderma phenotype, and one of ordinary skill in the art would have had a reasonable expectation of success, as Abdalrheem teaches that in NS, scaly erythroderma is apparent soon after birth and persists and Malik teaches the treatment of NS. Additionally, Malik demonstrates the presence of erythema and scaling in the NS patients used in the study, suggesting similarities to NS with a scaly erythroderma phenotype.
Claims 3-6 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Malik, K., et al (2019) Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature J Allergy Clin Immunol 143(2); 604-618 and Supplemental materials as applied to claim 1 above, and in further view of US 2020/0017592 A1 (Fairhurst, J., et al) 16 Jan 2020.
Malik teaches the method of claim 1 as discussed in detail above.
Malik, however, does not expressly disclose that the IL-36 inhibitor is an antibody against IL-36 cytokine or IL-36R as recited in instant claims 3-6 and 9, or that the inhibitor is administered in a topical formulation.
US’592 teaches antibodies and antigen binding fragments that specifically bind to human IL-36 receptor as well as methods for treating diseases mediated by IL-36R including skin inflammatory conditions including psoriasis (abstract; page 1, [0002]).
US’592 teaches that IL-36 cytokines include 3 agonists, IL-36α, IL-36β, and IL-36γ that bind a common receptor composed of IL-36R and IL-1RAcP to simulate an inflammatory response. IL-36R is a single pass membrane receptor for a subset of the IL-1 family of cytokines, 36α, IL-36β, and IL-36γ, and upon binding to these ligands, there is recruitment of its co-receptor IL-1RAcP, which induces a signaling cascade that involves NFκB and mitogen activation kinase pathways (page 1, [0004]). A mediator of some inflammatory conditions, like psoriasis, is IL-36. Psoriasis is a common, immune mediated, inflammatory skin disease. Standard therapeutic guidelines include topical steroids, topical vitamin D, systemic immunosuppressants and various biologics. IL-36 members are overexpressed in psoriasis and activation of IL-36R may contribute to the persistence and perpetuation of psoriatic inflammation (page 1, [0005]). It is noted that IL-36R is the same as IL1-RL2 (page 13, [0097]).
US’592 teaches anti-IL36R antibodies and antigen binding fragments thereof that exhibit superior properties. For example, in pharmacokinetic studies, the anti-IL36R antibodies exhibited about a 1.2 fold greater exposure and higher potency than anti-IL36R antibody APE6155 in reducing skin thickness, pathology scores in IMQ-induced skin inflammation and in reducing pro-inflammatory cytokines in the skin. Additionally, the human anti-IL-36R antibodies disclosed are not expected to be highly immunogenic in humans (page 1, [0007]).
US’592 also teaches that the antibodies specifically bind to IL1RL2 extracellular domain (page 44, [0175]). US’592 teaches antibodies with antigen-binding proteins bind to a native IL36R (IL1-RL2), e.g., as set forth under UniProt Accession No. Q9HB29, as set forth in SEQ ID NO: 227. US’592 further teaches that the antibodies bind residues including YKQILHL: amino acids 113-119 of SEQ ID NO: 227; or YKQILHLGKD: amino acids 113-122 of SEQ ID NO: 227 (page 13, [0097]). US’592 SEQ ID NO: 227 comprises amino acids 20-337 of instant SEQ ID NO: 1, as shown in the ABSS alignment below:
PNG
media_image2.png
549
614
media_image2.png
Greyscale
Additionally, the residues YKQILHL or YKQILHLGKD taught by US’592 meet the instant claim 6 limitation of the epitope comprising an amino acid sequence consisting of YKQILHL.
US’592 further teaches that the term “epitope” refers to an antigenic determinant, e.g., on IL1RL2 that interacts with a specific antigen binding site of an antigen-binding protein, e.g., a variable region of an antibody molecule, known as a paratope. US’592 further teaches that the epitopes may be linear or conformational, that is, composed of non-linear amino acids (page 10, [0071]).
US’592 also teaches pharmaceutical compositions and formulations of the antibodies and
teaches that the mode of administration of an antigen-binding protein or composition thereof can vary. US’592 teaches routes of administration including topical (page 10, [0069]; page 18, right column, Combinations and pharmaceutical compositions; page 19, [0161]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Malik by using the anti-IL36R (IL1-RL2) antibodies disclosed by US’592 as the IL-36 antagonist. It would have also been obvious to administer the antibodies in a topical formulation as disclosed by US’592. An ordinarily skilled artisan would have been motivated to use the antibodies disclosed by US’592 as US’592 teaches that the antibodies provide higher exposure compared with other anti-IL36R antibodies while also exhibiting higher potency in reducing skin thickness and pathology scores in IMQ-induced skin inflammation. US’592 also teaches that the antibodies reduce pro-inflammatory cytokines in the skin and are human and, therefore, not expected to be highly immunogenic in humans. An ordinarily skilled artisan would have had a reasonable expectation of success as the antibody taught by US’592 blocks the IL-36α, IL-36β, and IL-36γ / IL-36R and IL-1RAcP pathway, which would antagonize IL-36 as disclosed by Malik. Additionally, Malik teaches IL-36 targeted therapeutics for patients with ichthyosis, including NS, similar to those with psoriasis and US’592 teaches the anti-IL-36R antibodies for the treatment of psoriasis, demonstrating overlapping patient populations. It would have further been obvious to administer the antibody in a topical formulation as US’592 teaches that the antibodies disclosed can be administered topically. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 7 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Malik, K., et al (2019) Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature J Allergy Clin Immunol 143(2); 604-618 and Supplemental materials as applied to claim 1 above, and in further view of Chustz, R.T., et al (2011) Regulation and function of the IL-1 family cytokine IL-1F9 in human bronchial epithelial cells American Journal of Respiratory cell and molecular biology 45; 145-153 and Deng, Y., et al (2016) Transdermal delivery of siRNA through microneedle array Scientific Reports 6(21422); 1-8 as evidenced by Ding, L., et al (2018) IL-36 cytokines in autoimmunity and inflammatory disease Oncotarget 9(2); 2895-2901.
Malik teaches the method of claim 1 as discussed in detail above.
Malik, however, does not disclose that the IL-36 inhibitor is an inhibitor of an IL-36 cytokine or receptor expression as recited in claim 7 or an inhibitor of IL1RL2 or IL1RAP expression as recited in claim 10.
Chustz teaches that the IL-1 family of cytokines, which includes 11 members, is well known to participate in inflammation. Six members of the IL-1 family cytokines, named IL-1F5 to IL-1F10 were identified. IL-1F6, IL-1F8, and IL-1F9 are ligands for a heterodimeric receptor consisting of the IL-1R like 2 (IL-1RL2) and IL-1RAP and are expressed in skin and other epithelial tissues (page 145, right column, paragraph 2). It is noted that IL-1F6, IL-1F8, and IL-1F9 are IL-36α, IL-36β, and IL-36γ, respectively, as evidenced by Ding, page 2896, left column, paragraph 2.
Chustz teaches the transfection of cells with siRNA against IL-1RL2 or IL-1RAP (page 146, left column, paragraph 3). Chustz teaches that, to clarify the mechanism of cytokine and chemokine production by recombinant IL-1F9, the IL-1F9 receptor complex was knocked down. Cells were transfected with siRNA against control, IL-1RL2, and IL-1RAP, and then were stimulated with IL-1F9 or IL-1β for 3 hours. Control experiments demonstrated that the target molecules were significantly suppressed by the siRNA against each target molecule, but not by control siRNA (page 151, left column, paragraph 2).
Deng teaches that successful development of siRNA therapies has significant potential for treatment of skin conditions cause by aberrant gene expression. Although hypodermic needles can be used to effectively deliver siRNAs across the stratum corneum, the major challenge is that this approach is painful and the effects are restricted to the injection site. Deng teaches the use of microneedle arrays and teaches that these arrays may represent a better way to deliver siRNA across the stratum corneum. Deng demonstrates that the arrays can effectively deliver the siRNA to relevant regions of the skin noninvasively (abstract). Deng also teaches that, theoretically, topical siRNA delivery to the skin is relatively easy as it allows direct access to the skin (page 1, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Malik by using the siRNA against IL-1RL2 or IL-1RAP taught by Chustz as the IL-36 antagonist, for instance by administering the siRNA according to the methods disclosed by Deng. It would have been obvious to use the siRNA targeting IL-1RL2 or IL-1RAP as Chustz demonstrates that the siRNA significantly suppressed the expression of IL-1RL2 or IL-1RAP, which are both components of the heterodimeric receptor of IL-36α, IL-36β, and IL-36γ as recognized by Chustz. An ordinarily skilled artisan would have had a reasonable expectation of success as the siRNA targeting IL-1RL2 or IL-1RAP suppresses the expression of IL-36R or IL-1RAP, which would act to antagonize the IL-36 pathway as disclosed by Malik. Additionally, Deng demonstrates methods through which siRNA can be administered to treat skin disorders further providing a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights