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 .
This Office Action is in reply to Applicants’ correspondence of 03/18/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 08/25/2022 Applicants elected the invention of Group I (drawn to methods of treating), and the particular SNP that is rs11552449 and the gene that is HIPK1; the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 6, 7, 8, 11, and 27 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on page 2 of the Office Action of 12/18/2025.
Election was made without traverse in the reply filed on 08/25/2025.
New Claim Rejections - 35 USC § 112 - Indefiniteness
Necessitated by Claim Amendments
Claims 5 and 21 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 5 and 21 are each unclear over recitation of the phrase “the methods of claim 4” because claim 4 is a cancelled claim and as such the intended required/encompassed limitations of the rejected claims are entirely unclear.
Withdrawn Claim Rejections - 35 USC § 112 – New Matter
The rejection of claims under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as set forth on page 3 of the Office Action of 12/18/2025, is withdrawn in light of the amendments to the claims and Applicants’ arguments (p.9-10 of the Remarks of 03/18/2026).
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 4-6 of the Office Action of 12/18/2025, are withdrawn in light of the amendments to the claims.
Maintained Claim Rejections – Improper Markush Group
Modified as Necessitated by Claim Amendments
Claims 1, 10, 12, 20, 22, 24-26 and 28 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.
Response to Remarks
Applicants have traversed the rejection of claims, drawn to different proximal and sentinel SNPs identify SLE GWAS causal variants in different genes and combinations thereof. Applicants’ arguments (p.10-11 of the Remarks of 03/18/2026) have been fully and carefully considered but are not persuasive to withdraw the rejection.
Applicants initially argue that the Markush group of claim, which recites in the alternative approximately 350 different gene symbols, as well as the term “Intergenic”, is a proper Markush group because each of the elements each possess a property in common which is mainly responsible for their function in the claimed invention, and it is clear from the prior art that all members possess this property. This argument is not persuasive. Applicants point to the disclosure of Table 1 of the specification as evidence that all of the genes are a proper Markush group of elements with a common property. This argument is no persuasive because Table 1 does not in fact provide evidence of a common property (e.g.: a single structural similarity) that is shared among the different elements which is responsible for their function (e.g.: an indication of the increased risk of SLE) in the claimed methods. Each gene is composed of a different nucleotide sequence in a different chromosomal locus, and encodes a different polypeptide that may have a different function in a cell. The assertion that the different element share the sample “property” is not supported by the disclosure of the Table. Consider first the elected gene HIPK1; Table 1 does not disclose any particular variant in the gene that is a “causal variant” but instead discloses that rs11552449 is a “proxy SNP” and rs11102701 is a “sentinel SNP” of several “implicated” genes including HIPK1 located at chr1: 113,929,192-113,977,869). Here it is noted that the proxy and sentinel SNPs are in fact in the DCLRE1B gene locus; and the specification does not disclose any particular variants in HIPK1 that are either causative of SLE, or in fact linked to the disclosed proxy and sentinel SNPs. Consider next the claims as they encompass a different gene such as PHRF1, which is in a different locus on a separate chromosome (chr11: 576,220-612,222). Table 1 discloses entirely different proxy and sentinel SNPs, which are themselves in different gene loci that are not PHRF1. So there is in fact no disclosure of some common structure that is possessed by all of the different genes, where the common structure is associated with SLE. Furthermore, it is not accepted based on the prior art that in fact all of the different genes have variants that are causal of SLE. Arguing that all of the genes have a common structure that is “genetic alterations” is not persuasive because such an asserted structure (i.e.: a variation) is presented in essentially every gene in the human genome, but most of these variations are no associated with SLE; additionally the presence of a variation in any gene is not a common structure when considering other different genes because the “variation” is some change that is particular to the reference sequence of a given gene, that reference sequence is specific to that given gene as is not common to any other different gene. Applicants’ reliance on this rationale to support that argument that all of the different encompassed therapeutics are also part of a proper Markush group is similarly not persuasive. An agent that modulates the activity of HIPK1 dose not require any common structure with an agent that modulates, for example, PHRF1.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims under 35 U.S.C. 101 as set forth on pages 8-10 of the Office Action of 12/18/2025, are withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 112 – Enablement
Modified as Necessitated by Claim Amendments
Claims 1, 10, 12, 20, 22, 24-26 and 28 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 drugs asserted to modulate genes associated with the genomic positions (e.g.: Table 2).
The claims generically encompass any “SLE GWAS causal variant” in any of the genes recited in the claims as well as any treatment with any “agent that modulates any activity of the gene”. 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 “modulates” 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.
Furthermore, the claims recite that “detection of a proximal SNP and a sentinel SNP identify said causal variant in the gene”. The claims thus require the detection of content in one part of the genome to deduced that some other particular variation elsewhere in the genome is present. But the use of one genetic marker to make a conclusion about any other different marker at a different positionin the genome (e.g.: using linkage disequilibrium) is known to be unpredictable. The difficulty in identifying markers that are in linkage disequilibrium is demonstrated by the prior art of Wall et al (2003), which teaches (p.587 – Linkage disequilibrium) that patterns of LD are well known for being noisy and unpredictable. For example, pairs of sites that are tens of kilobases apart might be in ‘complete’ LD, whereas nearby pairs of sites from the same region might be in weak LD. Similarly, there can be tremendous differences in the extent of LD from one genomic region to another.
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.
Response to Remarks
Applicants’ have traversed the rejection of claims under 35 USC 112 for encompassing non-enabled subject matter as maintained above. Applicants have argued that the claims are amended to recited that proximal and sentinel SNPs are used to identify a causal variant that is indicative of SLE. Applicants argument is that sentinel SNPs are statistically associated with a disease, and proximal SNPs can then be used to as a filter such that putatively functional SLE variants can be distinguished from the thousands of SNPs that are implicated in a GWAS. The argument is not persuasive for the reasons set forth in the rejection. The Examiner maintains that the claims, consonant with the Election, are directed to identification of a causal SLE variant in HIPK1, but there is in fact no disclosure in the application as filed of any particular mutations in f HIPK1 that are causative of SLE. As discussed earlier in this Office Action, the application discloses a sentinel SNP and a proximal SNP that are asserted to be relevant to several genes, including HIPK1, that are “implicated” in SLE based on 3D epigenomics. But such an “implication” is not a disclosure of any particular causal variants. Additionally, as addressed in the rejection, where the claims are directed to the use of one genetic marker (i.e.: sentinel SNP; proximal SNP) to deduce the presence of a different genentic element (i.e.: a causal SLE variation), such associations are themselves unpredictable. And it can be further noted that when considering such analysis of biological analytes in case:control studies, the identification of a correlation is not the same as the identification of a cause such that a treatment can be established (e.g.: Richards (2020)).
Applicants have finally argued that the specification as filed has demonstrated that treatment with HIPK1 inhibitors inhibits IL-21 secretion, and concludes that such a teaching provides “that treatment of SLE with any one of these agents is effective for the treatment of SLE”. This argument is not persuasive. Initially the Examiner maintains that the teachings of the specification are particular to a specific treatment (i.e.: A64 trifluoroacetate), and are not a general teaching of “HIPK1 inhibitors”. Furthermore, the argument is not commensurate in scope with the claims. The claims are directed to any “causal variant” of a gene, and any treatment that “modulates” the gene. Considering only the elected HIPK1, the claims encompass any variant that could be a loss of function, or a gain of function mutation. And then the claims encompass any agent in which the modulation is either increased or decreased activity of the gene. But if, for example, a loss of function mutation is indicative of increased risk of SLE, how would an agent that inhibits the same gene be expected to alleviate the pathological symptoms of the disease. Similarly, if the subject already has a lack of activity of the gene from the presence of the variant, how would an agent that decreases activity of the same gene be expected to alleviate the pathological symptoms of the disease.
Requirement for Information
Applicants’ submission of 03/18/2026 addresses the requirement for information as set forth on pages 13-15 of the Office Action of 12/18/2025.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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