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 of the invention of Group I (drawn to methods of treating) in the reply filed on 08/25/2022 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicants’ additional election of the particular SNP that is rs11552449 and the gene that is HIPK1 (see species election requirement on pages 4-5 of the Requirement of 04/25/2025) is also acknowledged.
Claims 7, 8, 14, 15 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 6, 11, and 27 are withdrawn from further consideration as they require non-elected species elements (i.e.: claim 6 is directed to a causal variant in the MINK1 gene, where the HIPK1 gene was elected; claim 11 requires a therapeutic agent that is PF06260933, thus requiring a MINK1 variant according to the teachings of the specification and the requirements of the claims; claim 27 requires a variation in the non-elected FDFT1 gene).
Election was made without traverse in the reply filed on 08/25/2025.
Claim Rejections - 35 USC § 112 – New Matter
Claims 22-26 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. This is a new matter rejection.
The instant rejection is relevant to several aspects of the rejected claims. As a first aspect, the rejected claims are directed to combinations of inhibitors directed to HIPK1 and in combination with “at least one additional inhibitor of CAMLG, CD274, CD44, CD80, CHRNE, CSK, ERBB2, FDFT1, GSK3B, HRAS, IGF1, LTA, MAPKAPK2, PTPRC, or TNF”, as recited in claim 22. But the application as originally filed does not provide for such combination of treatment supplied to a subject. Additionally, where the claims depend from claim 1, and claim 1 requires that the agent targets a gene harboring a causal variant, the rejected claims require that causal variants are detected in a plurality of genes in a subject. But the application as originally filed does not provide for causal variant in a plurality of genes in a single subject. Additionally, claim 23 requires that the elements of the combination of treatment act additively or synergistically, but there is no basis for any such requirement in the application as originally filed.
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 applicant regards as his invention.
Claims 1, 4-5, 10, 12 and 20-26 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, 4-5, 10, 12 and 20-26 are unclear over recitation of the limitation “agent which targets said gene harboring said causal variant”, as recited in claim 1. The phrase is unclear because it is not clear what is intended or required for any agent to “target” a gene. It is not clear if the claims intend to require that the agent physically contacts the target gene, or if the agent provides some alteration of a pathway in which the gene participates or alteration of some functionality of the gene. The claims are further unclear in this regard where the limitation recites “agent which targets said gene” because in the related art a “gene” is a DNA locus in a genome that encodes some resulting element. But the claims appear to be directed to agents that in fact are associated with the resulting protein that is encoded by the gene. For example, as consonant with the election, the agent “A64”is a kinase inhibitor with affinity to to the HIPK1 and HIPK2 proteins. The A64 compound does not “target” the HIPK1 “gene”, but has affinity to the protein product encoded by the gene. The claims are further unclear in this regard over recitation of “agent which targets said gene harboring said causal variant” because it is unclear if the phrase is intended to require that the agent is specifically directed to the variant form of the gene (e.g.: a mutant allele), or if the limitation is intended to require that the agent is directed to the gene regardless of whether there is a variant in the gene.
Claims 4, 5, 21 and 27 are unclear over recitation of the limitation “wherein proximal and sentinel SNPs, inferred GWAS causal variant and genes implicated in 3D epigenomics assays are selected from at least one of” followed by a listing of gene symbols, as recited in claim 4. The limitation is unclear because there is no indication as to how the limitation is applied to the claimed methods. The claims depend from claim 1, but there is no antecedent basis for any proximal SNPs, sentinel SNPs, inferred GWAS causal variant, or genes implicated in 3D epigenomics assays. The relevant portion of claim 1, from which the rejected claims depend, recites “identifying … a SLE GWAS causal variant”, but this recitation is not a requirement for any proximal or sentinel SNPs. Furthermore, the recitation in claim 1 is not directed to any “inferred GWAS causal variant”, or any implication from “3D epigenomics assays”. It is unclear if the limitation is intended to require that the methods detect a SLE GWAS causal variant in one of the recited genes. Additionally, where the list in claim 4 includes “intergenic”, such an embodiment does not appear to be consonant with the requirement in claim 1, from which the rejected claims depend, that there is a “variant in a gene”. The unclear phrase of claim 4 is further indefinite because the claim depends form claim 1, where claim 1 is directed to a ….variant in a gene” (i.e.: singular gene), but the recitation in claim 4 appears to encompass and require more than one gene (i.e. the recitation “genes … are selected from”).
Claim 20 is unclear over recitation of the limitation “wherein proximal and sentinel SNPs, inferred GWAS causal variant and genes implicated in 3D epigenomics assays are selected from at least one of” followed by a listing of gene symbols. The limitations are unclear for the same reasons as addressed above with regard to the recitation in claim 4.
Claim 21 is unclear over the recitation of various asserted therapeutic agents separated by a slash symbol (i.e.: / ), as well as the misplacement of commas throughout the claim. For example, where the claim recites “the agent is … alemtuzumab/cyclosporin A” it is unclear if the claim requires both alemtuzumab and cyclosporin A as a combination, or if the claim encompasses a method where the agent is either one of the elements individually. Furthermore, the claims erroneous commas, where for example the agents recited in the claim includes “cyclosporine, A/tacrolimus,sirolimus/ tacrolimus, methotrexate” where ““cyclosporine A/tacrolimus, sirolimus/tacrolimus, methotrexate” is consonant with the disclosure in Table 2.
Claim Rejections – Improper Markush Group
Claims 4, 5, 10, 12, 20, 21, 22, are rejected on the basis that it contains 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 genes in the limitations recited in claims 4, 5 and 20, and the alternative agents for therapeutic treatment recited in claims 21 and 22, are in each case 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 gene that is HIPK1, and thus agents that “target HIPK1” and the particular agent that is “A64”. The different gene loci are each unique, with different sequences of nucleotides required for their detection and analysis. Additionally, any asserted “causal variant” in any particular gene locus may have a different strengths of association with the SLE phenotype, indicating that each individual locus, may be used to determine risk of SLE with a different level of reliability.
Similarly, the different recited agents have different chemical structures, some being small molecules, some being proteins, some being antibodies, and each targets a different gene product, thus potentially altering different biological processes in a cell.
To overcome this rejection, Applicant may provide claims directed to a particular element(s) consonant with the election, which in the instant case is the gene HIPK1 and the agents that target HIPK1 including the particular agent that is A64, as consistent with the teachings of the specification.
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 1, 4, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more.
The claim(s) recite(s) the naturally occurring relationship between variant gene content and increased risk or presence of SLE, which is a law of nature judicial exception. The claims further recite steps of “identifying” a “causal variant”, which is an abstract idea judicial exception, a mental processes of the evaluation of information to reach a conclusion.
This judicial exception is not integrated into a practical application. Although claim 1 recites “treating said patient with an effective amount of at least one agent which targets said gene harboring said causal variant”, the recited treatment in the rejected claims is at such a high level of generality that it is a mere invitation to “apply” the judicial exceptions. Additionally, where the claims generically encompass any variant in any gene, and treatment with any agent that “targets” the gene, the administering step is not considered significantly more because the claims thus generically encompass gene targets for which there are no known agents that reverse the functional consequences of variants in the genes related to SLE pathology (see the additional discussion of this issue in the rejection of claims made under 35 USC 112(a) presented later in this Office Action). Because of these generic aspects of the claims (i.e.: detect a causal variant in any gene, treat with any agent that “targets” that gene), the claims are considered to require limitations that attempt to cover any solution for treating SLE with no restriction on how the result is accomplished and no particular 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). Treatments encompassed by the rejected claims were not known in the prior art. The treating step cannot be considered a practical application of the judicial exceptions as the treating step 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 (to alleviate SLE disease symptoms) as fully encompassed by the rejected claims was known. The addition of a highly general treating step that encompasses agents/treatments not supported in the disclosure or prior art by any actual drugs 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 steps in addition to the judicial exceptions are data gathering steps recited at an extremely high level of generality. The prior art indicates that detecting variant content in TFH cells was well understood, routine and conventional in the related art (Weinstein et al (2014) citation 22 on the IDS of 04/05/2023; Wells et al (2018)). And, as discussed above, the treatment steps that amount to instruction to “apply” the judicial exceptions.
Therefore, following all of this, the claims are rejected because they do not amount to significantly more than the recited judicial exceptions.
Claim Rejections - 35 USC § 112 - Enablement
Claims 1, 3-5, 7, 9-11, 16-18, and 20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification provides an analysis of genetic variation and 3-dimensional epigenomic maps of the interactions between open chromatin and promoters in a CD4+ T cells and follicular helper T cells (TFH) from human tonsils to identify asserted disease-associated regulatory regions and the genes they influence (e.g.: Example, pages 40-50). The specification asserts that various genomic positions, identified with SNP content, are associated with promoters relevant to the SLE phenotype (e.g.: Table 1), and discloses several drug asserted to modulate genes associated with the genomic positions (e.g.: Table 2).
The claims generically encompass any variants in any genes that are identified in the claims as “a SLE GWAS causal variant in a gene” as well as any treatment with any “agent which targets said gene harboring said causal variant”. Considering generically encompassed gene variants, while the specification discloses several SNP positions, it is noted that he relationship between any particular variant and SLE is not predictable a priori, it must be discovered using case and control samples. 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)).
Even considering the claims in the scope of the election, that is particular SNP that is rs11552449 and the gene that is HIPK1, and thus an agent that “targets” HIPK1, there is a considerable gap between the teachings of the specification, the knowledge of the related art, and the requirement of the claims. Initially it is noted that neither the instant disclosure, nor the related art, teach causal variants in the HIPK1 gene. The specification provides (Table 1) that rs11102701 and rs11552449 are, a sentinel SNP (i.e.: the SNP with the most significant association in a region) and a proxy SNP (a different SNP that is inherited with the sentinel SPN sue to linkage disequilibrium), respectively. But neither SNP is in fact in the HIPK1 gene. Both SNPs are in the DCLRE1B gene (rs11102701 is in an intron, and rs11552449 is a missense SNP) (see the information from dbSNP provided on NC_000001.11:113771194..113990258 Homo sapiens chromosome 1, GRCh38.p14 Primary Assembly). There is no disclosure of a variant meeting the structural and functional requirements of the claims consonant with the Applicants’ election.
And so, having considered the discrepancies between the requirements of the claims, the disclosure of the application, and the teaching of the related art, it is concluded that it would require undue experimentation to practice the instant invention as currently claimed.
Furthermore, with regard the claims as they require treating with an “agent which targets said gene harboring said causal variant” it is relevant such limitations generically encompass any gene and any agent, and as such include treatments for SLE comprising treating with agents that are unknown. This is extremely relevant in view of the fact that the instant disclosure asserts that genes are related to SLE based on an analysis of “open chromatin-promoter connectomes” (e.g.: p.49 of the specification), and thus asserting that the genes themselves are relevant to treatment of SLE. However, it is known tin the art that “assigning specific regulatory elements to the genes they control is not straightforward since they can be millions of base pairs apart (Orozco et al. Front Cell Dev Biol. 2022 Oct 20;10:995388).” Orozoco teaches that enhancer sequences, which can activate or increase expression of a gene can be located in the intron of a gene and can operate over very large genomic distances to control the expression of a gene millions of base pairs away (Section 1.1.1). Similarly, Shaid et al. emphasizes “the importance of caution when considering the lead SNP as likely causal, and the importance of fine mapping to identify causal variants.” It cannot be assumed that just because rs11102701 and rs11552449 were identified as a SNPs associated with SLE by GWAS, that they are in fact causal of SLE such that any gene in the same locus is a suitable target for disease treatment. In this regard the breadth of treatment with an agent which “targets” the gene is noted. Such an agent may have any effect on the gene (e.g.: increase or decreased gene expression; be an agonist or antagonist for the gene product; be an inhibitor or enhancer of the gene function). This is particularly relevant where the instant specification discloses inhibits of target genes, but the related art of Zhang et al (2011) teaches that a loss of gene function in comes cases contributes to SLE pathology. Thus, without particular guidance about specific SNPs in particular genes and the function of the genes related to SLE pathology, it is highly unpredictable how to even select a drug that would target a gene and alleviated SLE disease symptoms.
The specification discloses (p.40), as consonant with the election, an example where human primary CD4+ T cells were cultured under TFH condition for 5 days in the presence of the HIPK kinase family inhibitor A64 trifluoroacetate, and that such treatment reduces IL-21 production (Fig 17F) and does not affect IL-2 secretion (Fig 18D). However, it is unclear if this such treatments are specifically relevant to any version of the HIPK1 that harbors some particular variant. This is particularly relevant where the specification asserts that HIKP1 is a gene “implicated by 3D epigenomics”, but the relevant SNPs are not within the gene (as detailed above).
Thus, having carefully considered all of these factors, it is concluded that it would require undue experimentation to practice the claimed invention.
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
The Examiner has identified the following citation/reference that is relevant to the instantly claimed subject matter:
Andrew D Wells , Matthew Johnson , Elisabetta Manduchi , Carole Le Coz , Michelle Leonard , Sumei Lu , Kenyaita Hodge , Neil Romberg , Alessandra Chesi , Struan Grant, "A high-resolution, genome-scale promoter interactome in human T follicular helper cells implicates novel causal genes at SLE GWAS loci" The Journal of Immunology, Volume 200, Issue Supplement_1, May 2018, Page 174.29, Immunology 2018™ Meeting Abstracts
The authorship of the cited Abstract includes inventors of the instant application, and appears to be an abstract related to the Annual Meeting of the American-Association-of-Immunologists (AAI). Austin, TX, USA. May 04 -08, 2018.
The Examiner requires additional information in order to make further determinations about the patentability to the instant claims. In response to this requirement, please provide answers and relevant information to each of the following:
1. Applicant is required to provide a copy of any material presented in association with the abstract (e.g.: poster presentation materials, slides).
2. Were any genes or SNPs recited in the claims, including those relevant to the election (rs11102701, rs11552449 , HIPK1) included in any part of any presented materials?
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement.
Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.58. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Conclusion
No claim is allowed.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683