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 03/16/2026.
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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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 08/22/2025 Applicants elected the particular species of: TET2-CHIP mutation; and the particular SNP that is rs2296311, and the Examiner rejoined the particular SNPs that are rs2887399 andrs11846938. The election has been treated as an election without traverse (MPEP § 818.01(a)).
Withdrawn Claim Objections
The objection to claim 15, as set forth on pages 2-3 of the Office Action of 12/16/2025, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness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112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on page 3 of the Office Action of 12/16/2025, is withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 12-19 and 21-25 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, 5, 13-16, 18, 84 and 86 are unclear over recitation of the phrase “comprising an rs2887399 single nucleotide polymorphism” and the phrase “comprising an rs11846938 single nucleotide polymorphism”, as recited in claim 1. A single nucleotide polymorphism is a position of variable nucleotide content that is present in a population of genomes, the concept of a SNP represents a difference in a single DNA nucleotide at a specific position among the genomes of a group of individuals. Thus, where the claims are directed to the treatment of a particular subject, the phrases as recited in claim 1 are not consonant with the art recognized meaning of a “single nucleotide polymorphism”. The claims may be made more clear in this regard if amended to require that particular allele content is, or is not, present in the subject of the method.
Claim 13 is unclear over recitation of the phrase “administering a therapeutic … when the subject does not have a TCL1A” variant, because the recitation of the term “when” appears to make the “administering a therapeutic” step conditional upon the presence of some particular genetic content (i.e.: the subject does not have a TCL1A variant). It is unclear if the claim is in tended to require that the particular genetic content is in fact require to be in the treated subject, or if the claim only requires that if the content is present, then the required dose is administered.
Claim 14 is unclear over recitation of the phrase “administering a therapeutic … when the subject has a TCL1A” variant, for the same reasons as detailed above.
Claim 18 is unclear over recitation of the phrase “comprising an rs2296311 single nucleotide polymorphism” for the same reasons as detailed above.
Claims 19, 21, 22, 24, 25, 85 and 87-89 are unclear over the use of the inclusive conjunction “and” (line 20 of claim 19) between the clauses related to administering a standard dosage and administering a less than standard dosage. The text of the claim appears to require both different administrations, though the different administrations are presented as requiring mutually exclusive parameters of either the absence or the presence a TCL1A variant nucleic acid. It is unclear how the claim is intended to require both administrations.
Claims 19, 21, 22, 24, 25, 85 and 87-89 are unclear over recitation of the phrases “comprising an rs2887399 single nucleotide polymorphism, an rs11846938 single nucleotide polymorphism” and “comprise an rs2887399 single nucleotide polymorphism or an rs11846938 single nucleotide polymorphism”, as recited in claims 19 and 21, for the same reasons as detailed above.
Claim 24 is unclear over recitation of the phrase “comprising an rs2296311 single nucleotide polymorphism” for the same reasons as detailed above.
Claim 25 is unclear over recitation of the phrase “the TCL1A antagonist comprises” because there is no antecedent basis in either claim 25, or in claim 19 from which claim 25 depends, for any “TCL1A antagonist”.
Claims 90-92 are unclear over recitation of the phrase “the subject is TCL1A rs2887399 reference; and the subject is TCL1A rsl1846938 reference”, as recited in claim 90. It is unclear if the claims intend to require that the a subject with homozygous reference alleles is the “reference” subjects, or if a heterozygous subject with one reference allele is considered a “reference” subject.
Claim 91 is unclear over recitation of the phrase “the subject is TCL1A rs2296311 reference”. It is unclear if the claims intend to require that the a subject with homozygous reference alleles is the “reference” subjects, or if a heterozygous subject with one reference allele is considered a “reference” subject.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims made under 35 USC 102 as set forth on page 4 of the Office Action of 12/16/2025, is withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Claim Amendments
Claim(s) 1, 5, 13-16, 19, 21-22, 25, 84-90 and 92 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jaiswal et al (US PG Pub 2024/0067970, effective filing date 01/25/2021).
Relevant to the limitations of claims 1, 19, and 90 Jaiswal et al teaches that increased expression of TCL1A is associated with CHIP (e.g.: para 0007), and teaches methods of treating CHIP comprising administration of an agent that inhibits expression or activity (i.e.: an antagonist) of TCL1A (e.g.: claim 1 on p.62) and teaches RNA agents to decrease expression or activity including antisense and RNAi agents (e.g.: claim 2 and 3 on p.62) (relevant to claims 5, 25 and 87). The reference further teaches the detection of TET2 driver mutations (e.g.: claim 9 on p.62), and teaches that TCL1A is of particular relevance to TET2-CHIP (e.g.: Figures 2 and 3).
Jaiswal et also teaches genotyping for alleles of both rs2887399 and rs11846938 (e.g.: claims 7 and 8 on p.62; para 0067-0068), and specifically teaches that the alt-allele of the human (relevant to claims 84 and 85) rs2887399 prevents accessibility of chromatin at the TCL1A promoter, leading to reduced expression of TCL1A RNA (para 0008), and that individuals treated to CHIP may be genotyped for SNP rs2887399 prior to treatment, and found to have the reference allele (e.g.: para 0010; 0020), and teaches that rs11846938 is 10 base pairs away from rs2887399 and can also be used for genotyping where the two SNPs are strongly in linkage disequilibrium (e.g.: para 0068).
Jaiswal et al further teaches the analysis of homozygous and heterozygous genotypes of TCL1A rs2887399 related to the CHIP phenotype and the presence of TET2 mutations (e.g.: paras 0152-0153, 0179), relevant to claim 15, 16, 88 and 89.
With regard to the limitations of the claims requiring that the subject does not have a variant TCL1A comprising an rs2887399 or an rs11846938 SNP, such a requirement would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims. The skilled artisan would recognize that because the prior art suggests genotyping a sample for both SNPs, and that the two SNPs are strongly in linkage disequilibrium, and the prior art specifically addresses treatment of subjects that are reference for rs2887399, the combination of teachings in the prior art would therefore include the treatment of a subject that is reference for rs11846938 in addition to reference for rs2887399.
With regard to the limitations of claims 86 and 92, where Jaiswal et al teaches that expression of TCL1A is associated with increased clonal expansion (e.g.: para 0008), 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 administered a TCL1A antagonist to a subject with CHIP that does not have a loss of function mutation in TCL1A. The skilled artisan would recognize that applying the required treatment (i.e.: an antagonist of TCL1A) would require a functional target (i.e.: a functional encoded TCL1A protein) in order for that directed therapy to have a biological effect.
Jaiswal et al does not exemplify the administration of particular dosage amounts (e.g.: standard, or less than standard) dependent upon TCL1A genotypes. However, Jaiswal et al does teach dosing regimens with different dosages (e.g.: para 0060), as well as treatments with agents other than TCL1A antagonists (e.g.: para 0118-0119) and combinations of treatments (e.g.: para 0077-0078), and teaches that TCL1A genotypes may be heterozygotes, alt-homozygotes and ref-homozygotes (e.g.: para 0196).
Where claims encompass the administration of treatments in a “standard dosage” in combination with a TCL1A antagonist, 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 provided such administration of treatments to a subject based on the teachings of Jaiswal et al. The skilled artisan would have been motivated provide a standard treatment in combination with a TCL1A antagonist based on the expressed teachings of Jaiswal et al that a given therapeutic agent has a recommended dosing regimen (e.g.: para 0060; a standard dosage), and that therapeutics may include agents known in the art (e.g.: para 0118) in combination with a TCL1A antagonist (e.g.: claim 10 on page 62). Where Jaiswal et al teaches that increased expression of TCL1A is associated with increased clonal expansion, and the presence of an “alt-allele” (where an alt-allele may be a variant) of a particular SNP (i.e.: the T allele of rs2887399) leads to reduced TCL1A expression and reduced CHIP (para 0008; Fig 2B; Fig 4), it would be obvious to administer a standard dosage of, for example, Aranesp to any subject (e.g.: subject with the presence of a T allele at rs2887399, or subjects without the T allele at rs2887399) with CHIP (relevant to the requirements of claims 12-16, and claims 19-21). It would be further obvious to administer a TCL1A antagonist to a subject with at least one reference (i.e.: non-variant, non-alt-allele) copy of the TCL1A gene (i.e.: subjects where the variant is absent, or heterozygous subjects with one copy of the variant present) based on the expressed teachings of Jaiswal et al that the presence of the alt-allele (i.e.: T allele) at human SNP rs2887399 prevents accessibility of chromatin at the TCL1A promoter, leading to reduced expression. The skilled artisan would recognize that at least one wild type copy of the TCL1A gene leads to increased CHIP (e.g.: Fig 2B), and would be subject to treatment with an antagonist (e.g.: para 0009; Fig 4). The skilled artisan would have a reasonable expectation of success because Jaiswal et al teaches that drugs that increase hematocrit are suitable for treatment of CHIP (e.g.: para 0118), and that antagonists of TCL1A can be used to alter level of gene function (e.g.: para 0069-0074). Similarly, where Jaiswal et al teaches that expression of TCL1A is associated with clonal expansion the skilled artisan would recognize that if there is a disruption in the expression of TCL1A activity due to an alteration in TCL1A that results in a loss of function, then a lower dosage (relevant to claims 14, 15, 16 and 22) of a treatment may be appropriate because a biological cause of the pathology (i.e. TCL1A expression causative of CHIP) is already addressed by a biological mutation of the causative gene. In this regard it is noted that the cited prior art teaches that mutations such as frameshift mutations in TCL1A can reduce expression of TCL1A (e.g.: para 0009; para 0096).
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 103 as obvious in view of the cited prior art. Applicants’ arguments (p.11-13 of the Remarks of 03/13/2026) have been fully and carefully considered but are not found to be persuasive to withdraw the rejection as set forth above.
Applicants have initially argued that the amended claims require that “the subject does not have a TCL1A variant nucleic acid molecule comprising an rs2887399 single nucleotide polymorphism; and the subject does not have a TCL1A variant nucleic acid molecule comprising an rs11846938 single nucleotide polymorphism” (e.g.: as recited in claim 1). Applicants argue that the cited prior art does not disclose the rs11846938 reference allele with CHIP. This argument is not persuasive because, as set forth in the rejection, the skilled artisan would recognize that because the prior art suggests genotyping a sample for both SNPs, and that the two SNPs are strongly in linkage disequilibrium, and the prior art specifically addresses treatment of subjects that are reference for rs2887399, the combination of teachings in the prior art would therefore include the treatment of a subject that is reference for rs11846938 in addition to reference for rs2887399.
Applicants have next argued that the claims include aspects of detecting TCL1A genes with or without particular disruptive mutations, and that the prior art does not provide for the recited molecules. This argument is not persuasive when considering the totality of the teachings of the prior art. The prior art makes it clear that TCL1A is functionally associated with the development of CHIP, that expressed TCL1A is a therapeutic target for the treatment of CHIP, and that abrogation of TCL1A function by mutations such as frame shift mutations has a role in CHIP development. As such the examiner maintains, as set forth in the rejection, that skilled artisan would have found ample motivation in the teachings of the cited prior art to have applied treatments for CHIP that are modified based on the presence or the absence of a reference/functional/wild-type TCL1A gene product. The recitation of particular classes of mutations that are known to the skilled artisan to result in alterations of gene product functionality (e.g.: stop-gain; start-loss, frameshift) does not create a method that is inventive in view of the teachings of Jaiswal.
New Claim Rejections - 35 USC § 103
Necessitated by Claim Amendments
Claim(s) 18, 24, and 91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jaiswal et al (US PG Pub 2024/0067970, effective filing date 01/25/2021) as applied to claims 1, 5, 13-16, 19, 21-22, 25, 84-90 and 92 above, and further in view of Submitted SNP(ss) Details: ss3240379 (2001).
Jaiswal et al renders obvious the methods claims 1, 19 and 90, from which instantly rejected claims 18, 24 and 91, respectively, depend, including the treatment of CHIP in human subjects.
Jaiswal et al does not specifically address the treatment of CHIP in a subject “wherein the subject does not have a TCL1A variant nucleic acid molecule comprising an rs2296311 single nucleotide polymorphism”, as recited in the rejected claims.
However, the allele content and allele frequencies of rs2296311 were known in the prior art and are taught by ss3240379.
The Submitted SNP(ss) Details for ss3240379 teach that the polymorphic content is the refSNP (rs#) rs2296311 and that the major allele frequency is approximately 94% and the minor allele frequency is approximately 6%.
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 for the skilled artisan practicing the methods rendered obvious by Jaiswal et al (i.e.: the treatment of CHIP in a subject) to have included in such methods a subject that meets the limitations of the rejected claims. The skilled artisan in possession of the teachings of ss3240379 would understand that in fact most human subjects have the major allele at the SNP position rs2296311, and thus may be considered to not have a TCL1A variant nucleic acid molecule comprising an rs2296311 single nucleotide polymorphism.
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
Prosecution Insights