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. Election/Restrictions Applicant’s election without traverse of the particular SNP that is rs1475658, and the agent that is an IL-33 binding antagonist, in the reply filed on 09/12/2025 is acknowledged. Applicants’ reply of 09/12/2025 (page 8) indicates that claim 46 requires each of the recited sequences (i.e.: SEQ ID NOs: 37-42), as such the election requirement directed to claim 46 (see page 4 of the Requirement of 06/03/2025) is unnecessary. In light of Applicants’ reply, the requirement as directed to claim 46 is withdrawn. Claims 11-12, 14-17, 19-21, 23-26, 28-29 and 48-49 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/12/2025. It is noted that in the reply of 09/12/2025 Applicants assert that claims 1, 4, 5, 8, 10, 11, 43, 45 and 46 are the elected invention. However, claim 11 is withdrawn as being directed to a non-elected combination, where claim 11 requires the non-elected SNPs of Cluster 3. Additionally it is noted that claim 3, 4 and 47 are considered part of the elected invention as they encompass the elected SNP that is rs1475658. Priority Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S .C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc. , 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure of the prior-filed application, US Provisional Application No. 62/988,983, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The instant claims encompass alleles that are claimed as “a n equivalent allele at a polymorphism in linkage disequilibrium therewith ” (i.e.: in LD with a SNP from Table 1, as recited in the claims of the elected invention), as well as some particular SNPs asserted to satisfy such a limitation (e.g.: as recited in claim 6). But the disclosure of the particular SNPs in the provisional application does not provide a written description of common or identifying features of the genus of SNPs that may be “ equivalent ” and “in linkage disequilibrium ” with the particular recited claims disclosed in the provisional application. Nor does the provision application disclose or contemplated the particular SNPs that are recited as SEQ ID NOs: 82-86 of claim 1. As such the effective filing date of the claimed methods is the filing date of the parent PCT application PCT/EP2021/056212, which is 03/11/2021. Claim Rejections - 35 USC § 112 - Indefiniteness 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 appl icant regards as his invention. Claims 1, 3-6, 8, 10, 43 and 45-47 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. Claims 1, 3-6, 8, 10, 43 and 45-47 are unclear over recitation of the phrase “ a Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith ”, as recited in each of claims 1 and 3. The recitation of the limitation related to a Table in the specification makes the required and encompassed limitations of the claims unclear. MPEP 2173.05(s) provides guidance regarding the reference to figures or tables in claims: Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola , 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) In the instant case the claims can be amended to recite rs1475658, as consonant with Applicants elections. Claims 3 and 4 are unclear over recitation of the intended purpose of the claims, as stated in the preamble of claim 3, as “ determining whether a patient is at increased risk of asthma ” in combination with the limitations “ the patient is at increased risk of an IL-33-mediated disorder if the genotype ”, because risk of “an IL-33-mediated disorder” is not constant with the requirement for asthma. Claim Rejections – Improper Markush Group Claims 1, 3-6, 8, 43, 45, 46 and 47 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch , 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi , 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117. The Markush grouping of alternative elements (i.e.: the different particular SNPs in Table 1 of the specification, and in Table A of the specification, and combinations thereof ) in the limitation s recited in claims 1 and 3, as well as recited as particular markers in claims 6 and 8 , are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use. Here it is noted that the election provides for the particular SNP that is rs1475658 . The different SNPs are each unique markers in distinct genomic loci , with different sequences of nucleotides required for their detection and analysis. Additionally, the asserted biomarkers have different association properties (e.g.: different alleles, with different functionalities related to gene expression or function ) as well as different strengths of association with the different phenotype s ( such as risk of asthma, or gene expression levels; see for example Table s 7 and 9 of the specification, and Fig 9 of the Drawings), indicating that each individual biomarker, and the different combinations thereof, may be used to diagnose asthma risk with different strengths of association. The rejection of claims for reciting an improper Markush group is further relevant to the different antagonist recited in claim 43 as an IL-33 binding antagonist, an ST-2 binding antagonist or an IL-1RAcP binding antagonist . In each case the different element requires a unique structure (e.g.: a different antibody with a unique three-dimensional structure provide by a unique polypeptide sequence) in order to bind to epitopes of the different particular target. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 3 , 4 and 47 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas (e.g.: mental processes, mathematical calculations) and a natural phenomenon without significantly more. The claim(s) recite(s) methods of determining an increased risk of asthma (as recited in claim 3) with a step of i dentifying a genotype from a sample obtained from the patient , where the patient is at increased risk of an IL-33-mediated disorder if a recited genotype is present. The claims are thus directed to the assessment of collected data, which is and abstract idea that is a mental process (e.g.: MPEP 2106.04(a)(2)(III)(A)); it is the observation and evaluation of information to reach a judgment or conclusion. Where the evaluation of data to reach a conclusion is based in the asserted correlation between gene content and likelihood of asthma or an IL-33-mediated disorder , such an association is accepted part of how a biological organism functions (i.e.: genotype:phenotype relationships), and as such this element of the claims is a natural phenomenon (e.g.: MPEP 2106.04(b)(I)). This judicial exception is not integrated into a practical application because there are no practical steps related to the determination of risk of asthma in a subject. There are no additional steps of the claims that are directed to a pplying or using the judicial exception (s) noted above (e.g.: MPEP 2106.04(d)(I)). The claims end with an asserted association between a genotype and a risk of pathology , which is an abstract idea (as noted above). Here it is noted while claim 4 recites “f urther comprising administering to the patient an I L-33 axis binding antagonist ”, there is no indication that this administration is performed as any sort of specific treatment for asthma (e.g.: as an effective amount to ameliorate asthma symptoms). Additionally, it is noted that the administration does not set forth any particular agent , only a broad functionality of being “ an I L-33 axis binding antagonist ”. The IL-33 axis refers to the signaling pathway between the cytokine Interleukin-33 (IL-33) and its receptor, ST2 (also known as IL1RL1), with downstream signaling components, and thus the claim broadly encompasses a variety of reagent with different functionalities (related to different protein targets). The administering step not considered significantly more since it includes agents that were not established treatments at the time the invention was made. Because of this, the claims are considered to require limitations that attempt to cover any solution for treating asthma targeting the I L-33 axis , with no restriction on how the result is accomplished and particular reagent using the recited mechanism for accomplishing the result, and therefore does not provide significantly more because this type of recitation is equivalent to the words “apply it.” See MPEP 2106.05(f)(1). The administering step of claim 4 cannot be considered a practical application of the judicial exceptions as the administering is not a treating step that is supported by the disclosure of the application as originally filed, and so it is not actually an application of the law of nature, but rather a suggestion to find such a treatment, in a prior art context were no therapeutic agents in the broad scope of the instant claims were known. The addition of a highly general treating step that , the breadth of which is not supported by the disclosure of the application, is not sufficient to demonstrate that the invention as a whole is significantly more . The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims only broadly recite steps of determining a genotype in a sample. However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example, the step of genotype detection is recited at a high level of generality, and the instant specification indicates that such method are routine in the art (e.g.: specification at pages 43-51 ). Additionally in this regard it is noted that detecting the genotype of rs1475658 was demonstrated by the prior art of Ran et al (2020) (cited on the IDS of 07/17/2023). And the database entry in dbSNP for rs 1475658 indicates a plurality of prior art submission demonstrating the detection of alleles at the polymorphic positions ; e.g.: see the Submitted SNP( ss) Details for: ss115680741 (related to rs 1475658) from Jan 15, 2009. Claim Rejections - 35 USC § 112 – Written Description Claims 1, 3, 4, 5, 43, 45, 46 and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The instant rejection of claims for lack of an adequate written description of the claimed subject matter in the application as originally filed is relevant to several aspects of the claimed methods. A first aspect is the generic breadth of the claims as they may encompass any “e quivalent allele at a polymorphism in linkage disequilibrium ” with a Cluster 2 polymorphism as defined in Table 1 . The claims thus encompass the detection of any nucleotide content, and include the detection of any ‘ allele’ that is an y single or multi-nucleotide insertion, deletion or substitution, as well as larger chromosomal rearrangements. The claims thus encompass an enormous genus of a variety of structures. But the claims also recite particular functionality of being an “equivalent” of a genotype from Cluster 2 in Table 1, and “in linkage disequilibrium” with the alleles of Cluster2 . However, neither the teachings of the specification nor the related art provides the skilled artisan with the ability to select, from the large encompassed genus, those particular elements which have the required functionality. The specification provides (page 9), that a definition of what is intended by the limitation requiring an “equivalent allele”: "Equivalent allele" or "surrogate allele," as used herein, refers to an allele that is expected to behave similarly to a risk allele and is selected based on allele frequencies and/or high r 2 value (greater than or equal to ( > ) 0.6) and/or high D' value ( > 0.6) with the risk alleles and/or selected SNP as defined herein. The specification provides a table of particular SNPs (i.e.: Table A o p.14; note that the elected SNP rs1475658 is recited in Table A) that are in LD with the SNPs of Cluster 2 that are disclosed in Table 1. But the particular disclosure in specific SNPs in Table A does not inform the skilled artisan of any other “equivalent” alleles. The nature of alleles is that they are variant structures, and in the present state of the art, the structure of one allele does not provide guidance to the existence or structure of other alleles. In other words, the existence and structure of other alleles are not predictable from the particular species disclosed in the specification. In this regard it is relevant to point out that Wall (2003) teaches that linkage disequilibrium (LD) refers to the fact that particular alleles at nearby sites can co-occur on the same haplotype more often than is expected by chance (page 587, 1st column, 1st paragraph). Wall teaches that patterns of LD are known to be noisy and unpredictable as pairs of sites tens of kilo bases apart might be in complete LD, whereas nearby sites from the same region can be in weak LD (page 587, 2nd column, last paragraph). Wall teaches that population history, population size, and population structure lead to differences in LD (page 588, 1st column, top). Wall teaches, “Measuring LD across a region is not straightforward" (box 1, last paragraph, page 588). Wall teaches it is difficult to compare results from different LD studies directly because of the variation in study design and methods of analyzing the data (page 591, 2nd column, 1st full paragraph). Thus , Wall teaches that LD is not predictable. The breadth of the claims in view of the particular teachings of the application as originally filed is notable where specification teaches that even SNPs in the same genomic location do not share the same related functionality (p. 71): Surprisingly, the results show that two SNPs (rs 1 475658_T 10 and rs13298116_T) in segment 11 showed strong enhancement effect on IL33 promoter activity under basal conditions. The effect was not necessarily segment-specific, as rs1929995 C in segment 11 did not induce any increase in NanoLuc luciferase activity under basal, or cytokine stimulation condition (Figure 9). Thus where the claims encompass a large variety of possible alleles while only disclosing a few particular SNPs, and also require a functional association of the “equivalent” alleles with asthma it an IL-33-mediated disorder , it is relevant to point out that given the establish ed volatility is establishing such associations, the particular disclosures of the specification are not a description of the encompassed subject matter. Even in cases where an association between a particular gene and a phenotypic state is known to exist, such as with the LPL gene and heart disease risk or the beta-globin gene and sickle cell anemia, researchers have found that when using polymorphism analysis it was difficult to associate SNPs with disease states or to even identify key genes as being associated with disease ( Pennisi (1998)). An association between genotype and phenotype is not apparent from any detected allele a priori, but must be established by statistical analysis in each case. Another instance of a gap between the teachings of the application as originally filed and the subject matter encompassed by the claims is the recitation in the claims which broadly requires “ an I L-33 axis binding antagonist ”. In this regard, the specification provides an indication of the breadth of targets encompassed by the broadly recited agent : Free IL-33 associates with a heterodimeric IL-33 receptor complex composed of suppression of tumorigenicity 2 (ST2) protein and interleukin-1 receptor accessory protein (IL-1 RAcP ) to activate the AP-1 and NF-KB pathways through the adaptor protein myeloid differentiation primary response 88 (MyD88) and possibly MyD88-adapter-like (Mal) protein. IL-33 stimulates 20 numerous cell types, including innate lymphoid type II cells (ILC2), mast cells, basophils, eosinophils, and dendritic cells, to promote an immune response . And while the specification assert s that a variety of different types of agents are included in the I L-33 axis binding antagonist s of the claims (e.g.: specification at pages 51-62), the only type of binding agent that is disclosed with a practical application related to asthma treatment is an IL-33 antibody or the antigen biding portion of the antibody . Furthermore, neither the specification nor the related art teach a method of treatment (e.g.: how much of a substance; treatment duration; methods of administration) that is in fact suitable for amelioration of any symptoms using other I L-33 axis binding antagonist . It is noted that while the application asserts that antagonist identification may be an inventive method (e.g.: p. 58 ), a general assertion of how to potentially identify treatments that might be used in the claimed methods is not sufficient to establish that Applicants were in possession of the invention as broadly claimed. 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. In the rejection of claims as anticipated by the prior art, the claims are compared to the prior art as consonant with the election (i.e.: the particular SNP that is rs1475658). Claim(s) 3 and 47 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Ran et al (2020) as cited on the IDS of 07/17/2023 . In the rejection of claims as anticipated by the prior art, the required practical limitations of the claimed methods are noted. The claim requires only the single step of “identifying from a sample obtained from the patient the genotype of at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele at a polymorphism in linkage disequilibrium therewith” (as consonant with the election, the claim require identifying the genotype at rs1475658 in a sample from a patient). The preamble of claim 3 recites “a method for determining whether a patient is at increased risk of asthma”, but there is no particular step recited to making a determination . A nd where claim 3 recites “the patient is at increased risk of an IL-33-mediated disorder if the genotype of the patient comprises” a recited genotype, such a limitation is only a recitation of an asserted property of a genotype, not any step that distinguishes the claimed methods from the cited prior art. Ran et al teaches the detection of genotypes at rs1475856 in human subjects (e.g.: Table I on page 4) , consonant with the required identifying step of the rejected claims. 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. Claim (s) 1, 3-6, 8, 10, 43, and 45-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ran et al (2020) as cited on the IDS of 07/17/2023, in view of Cohen et al (WO 2016/156440, Oct. 6, 2016) . Relevant to the limitations of the claimed methods, with regard to genotype content in a patient (claim 1), and identifying genotype content in s patient (claim 3), Ran et al teaches the detection of genotypes at rs1475856 in human subjects (e.g.: Table I on page 4) , consonant with the election and relevant to the limitations of claims 1, 3, 6, 8 and 10 . Further relevant to the claims, Ran et al teaches that rs1475658 is associated with the IL-33 gene, and that T allele of rs1475856 is overrepresented in subject with allergic rhinitis (AR) (e.g.: Table I; Table II); Ran et al further teaches IL ‑ 33 has been indicated to be an important factor driving asthma, and that the commonly observed comorbidity of asthma and AR in the clinic suggests the presence of shared genetic risk factors and biological mechanisms between these diseases (e.g.: p.1, left col) . Furthermore, the teachings of Ran et al include a total of 769 patients with AR (453 men and 316 women) aged between 10 and 65 years (e.g.: p.2 – Subjects), where such a population includes subjects with an age that would be characterized as early onset asthma (e.g.: under age 18, relevant to claims 5 and 47) Ran et al does not teach treatment of a subject suffering from asthma with an IL-33 binding antagonist that is an anti-IL-33 antibody (as encompassed by the limitations of claims 1, 43, 45 and 47) or an antibody comprising SEQ ID NOs: 37-42 (relevant to claim 46). However, the use of such antibodies in the treatment of asthma was known in the prior art and is taught by Cohen et al. Cohen et al teaches anti IL-33 antibodies, including (e.g.: p.217) the antibody identified as 33_640087-7 which includes SEQ ID NOs: 543-545 and 548-550 of the prior art application (which are the same as SEQ ID NOs: 37-42, respectively, of the instant application, as recited in claim 46). Cohen et al teaches that the antibody functional against IL-33 binding (e.g.: Figs 45; Fig 49 ) , and teaches that the antibody can be used in the treatment of asthma (paras 671, 686; claims 46-52 on page 246). It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have detected genotypes associated with AR as taught by Ran et al in a subject with asthma based on the expressed teachings of Ran et al that asthma is a typical comorbidity with AR, and based on the teachings of Ran et al that IL-33 has genotypes associated with both asthma and AR. It would have been obvious to treat asthma subject with the genotype taught by Ran using the anti-IL33 antibodies o f Cohen et al based on the expressed teachings of Cohen et al that such antibodies abrogate the function of IL-33, that IL-33 is associated with the asthma phenotype (e.g.: para 5-8), and that the antibodies can be used to treat a subject with an inflammatory condition such as asthma. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT STEPHEN THOMAS KAPUSHOC whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-3312 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F, 8am-5pm . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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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. FILLIN "Examiner Stamp" \* MERGEFORMAT Stephen Kapushoc Primary Examiner Art Unit 1683 /STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683