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 .
Status of Claims
Applicant' s amendment filed 11/07/2025 is acknowledged. Claims 1-3, 5, and 9-10 have been amended. Claims 44 and 45 have been added. Claims 37 and 43 have been cancelled. Claims 1-12, 17-19, 21-23, and 44-47 are pending in the instant application and claims 1-3, 5, 9-10, 12, 17-19, 21-23, and 44-47 are the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
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/Restriction
The newly added claim 45 reads on the election of the drug carbamazepine, which is known in the art to treat the disease/condition of: epilepsy, neuropathic pain, and mood disorders.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Previous Rejection
Status of Prior Rejections/Objections:
The 112(b) rejections to claim(s) claims 1, 5, 9-10, and 37 are withdrawn in view of the amendments to or cancellation of the claims. See new 112(b) necessitated by amendments.
The 112(a) written description rejection to claims 1-3, 5, 9, 10, 12, 17-19, 21-23, 27, and 43 are withdrawn in view of the amendment to claim 1 or cancellation of the claim.
The prior art rejection(s) under 35 USC 103 are withdrawn in view of the amendments to the claims:
Claims 1-3, 5, 12, 17, and 19-22 over Liu
Claims 9-10, 18, and 23 over Liu in view of Fang
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/07/2025 was filed after the mailing date of the non-final Office Action on05/09/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1 is objected to because of the following informalities:
Claim 1 recites “Tables 1-4” and individually “Table 1 is …” to “Table 4 is …”. This has the potential to create confusion if amended going forward because the specification also has tables, and should be changed to another grouping name (e.g., “Set”).
Appropriate correction is required.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claim 1, the claim recites “assaying for one or more genetic markers … wherein the one or more genetic markers are in [LD] with an HLA allele associated with the ADR and selected from HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01” and “assessing the risk of the … ADR … in response to the drug, wherein a high risk is assessed when the one or more genetic markers are present in the sample and a low risk is assessed when the one or more genetic markers are absent in the sample”.
The “one or more genetic markers” are interpreted to be a group for the purposes of assessment, i.e., if “the one or more genetic markers” includes at least two and at least one is present and at least one is absent, neither a high nor a low risk would be assessed for the purposes of the claim.
Additionally, the claim defines that “the one or more genetic markers” are in LD with an HLA allele, that that HLA allele is associated with the ADR, and that the ADR is in response to the drug.
Further, the subject is interpreted to be a human subject as genetic markers correspond to sites in the human genome and the multi-ethnic populations comprise human populations.
Claim Rejections - 35 USC § 112(a)
Claim 46 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. This is a new matter and written description rejection.
Regarding claim 46, the newly entered claim recites “wherein the risk of the ADR in the subject … is determined with an average of 99% sensitivity and 99% specificity across the multi-ethnic populations”.
Claim 1 recites “the multi-ethnic populations comprise an African American population, a European population, a Hispanic population, an East Asian population, and a South Asian population”.
The specification recites the term “average” only in the context of a “normal dosage” and having an “average level of risk for ADR” (pg. 13, para 5). The provisional applications to which the instant application claims priority fail to recite the term (62/884,661 and 62/858,326) or recite it in the same context (62/915,171).
Further, the disclosure fails to establish a direct numeric link between the HLA risk alleles and/or SNPs in multi-ethnic populations and risk of particular ADRs so as to enable calculations of sensitivity and specificity, let alone provide such exemplary calculations in averaged across the multi-ethnic populations. The specification recites only calculating an “HLA risk score for a subject” including across multi-ethnic populations based on the SNPs (pg. 10, para 1). Such a determination or data sufficient for the artisan to make such a determination was likewise not found in the provisionals to which priority is claimed.
To satisfy the written description requirement, the specification must describe the invention in sufficient detail that one skilled in the art can reasonably conclude that the applicant had possession of the claimed invention at the time of filing.
Under the interpretation that the claim requires an average of sensitivity and specificity of at least two discrete sub populations of the multi-ethnic populations (see discussion in the 112(b)), the previously filed disclosures lack a recitation of such an averaging. Likewise, under the interpretation that the sensitivity and specificity are determined for the risk of the ADR, the disclosure fails to provide any examples of calculations of sensitivity of specificity of the risk of the ADR in the subject for multi-ethnic populations (i.e., beyond the calculation of the sensitivity and specificity of HLA risk alleles) sufficient to make a determination of sensitivity .
Accordingly, the claim adds new matter that was not disclosed in the specification as filed, and now changes the scope of the instant disclosure. Such limitations recited in the present claim, which did not appear in the instant specification or in the provisional applications introduce new concepts and do not comply with the written description requirements of 35 USC 112.
Claims 1-3, 5, 9-10, 17-19, 21-23, and 44-47 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.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, a “Satisfactory disclosure of a “representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.”
Regarding claims 1-3, 5, 9-10, 17-19, 21-23, and 44-47, the amended claims recite a method that comprises “assessing the risk of … ADR … wherein the assessing comprises determining the risk of the ADR concordant across muti-ethnic populations”.
The specification recites that “The genetic markers described herein can be … concordant across multi-ethnic populations” (pg. 10, para 2). It further recites “The Sema4 … panel described herein … are very concordant across multi-ethnic populations” (pg. 17, para 3, “Summary”), which is interpreted to refer to the panel of 18 proxy SNPs described above the “Summary” (pg. 17, para 1-2). It then recites a limited number of individual SNPs in Table 7 that have sensitivity, specificity, PPV, and NPV values for each SNP in Example 2, some of which have similar values across the sub populations and some of which do not. For example, the HLA-B*15:02 probes do not have values provided for populations other than East and South Asians. It is noted that the number of SNPs in Table 7 is not 18 and it is not clear which SNPs, if any, that are disclosed elsewhere correspond to the panel of 18 described as “very concordant”.
In contrast, the genetic markers of Tables 1-4, which lack a disclosure outside of the small subset included in Table 7, for sub populations of multi-ethnic populations are claimed. The for this larger set, the specification recites only that “a series of polymorphic markers were identified in LD with four pharmacogenetic HLA alleles” and that “haplotype analysis using this … HLA panel could be a cost-effective … screening test to predict … HLA carrier status across multi-ethnic populations” (pg. 17, para 3 “Summary”).
As noted in the 112(b) below, even among the disclosed genetic markers that have data across multiple multi-ethnic populations, some display a level of variability in risk “concordance” across multi-ethnic populations, e.g., the HLA-B*58:01 SNP rs79815527_A that has variability in PPV for the HLA allele (0.88 in African Americans, 0.63 in Hispanics, and >0.97 in the three other groups), which would correspond to a further level of variability in the level of risk of ADR.
Further, the claims fail to recite calculations for groups of more than one genetic marker, which are included in the claim, and further broaden the scope and level of variability.
Thus, while the claims recite the broad class of one or more of the sets of markers of Tables 1-4, the specification only describes a possible level of concordance for the subset of the genetic markers in Table 7.
Erlichster (Erlichster, 2019; as cited in the IDS dated 08/17/2023 and below in the art rejections) teaches a similar analysis wherein 378 prospective and 67 reported tag SNPs were validated using multi-ethnic populations of 1000 Genomes resulting in only 45 being validated across such multi-ethnic populations (Fig. 1), indicating a high level of variability in tag SNPs/proxy-SNPs.
Therefore, under the interpretation of the claim that the determining “the risk of the ADR is concordant across multi-ethnic populations”, the artisan would expect a high level of variability in genetic markers and the ability to determine concordance across multi-ethnic populations. The Applicant has failed to describe a sufficiently representative number of genetic markers or combinations of genetic markers to represent the entire genus of the genetic markers claimed, and for certain alleles has failed to provide data for any exemplary genetic markers that appears to satisfy the limitation.
Thus, the specification has not described the invention in sufficient detail that the skilled artisan would reasonably conclude that the applicant has possession of the claimed invention at the time of filing. For this reason, the claims do not comply with the written description requirements of 35 USC 112.
Claim Rejections - 35 USC § 112(b)
Claims 1-3, 5, 9-10, 12, 17-19, 21-23, and 44-47 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.
Regarding claim 1, first, the claim recites, in (b), “the subject”, “the adverse drug reaction”, and “the drug”. There is insufficient antecedent basis for these limitations in the claim; the preamble which previously recited these terms was removed in the amendments. For clarity, it is suggested the claims recite “in response to a drug associated with the ADR” rather than “in response to the drug”.
The claim also recites “determining the risk of the ADR concordant across multi-ethnic populations”.
Second, it is unclear whether the claim limitation is intended to require “determining the risk of the ADR is concordant across multi-ethnic populations” (i.e., establishing that the subset risk of ADR is concordant for the chosen set of one or more genetic markers) or “determining the risk of the ADR across multi-ethnic populations” (i.e., only a further step of determining across diverse populations, e.g., as part of a pipeline).
Third, the term “concordant” is a relative term which renders the claim indefinite under the interpretation. The term “concordant” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
In the instant case, Example 1 recites 18 proxy-SNPs identified in a multi-ethnic subset of 1000 Genome subjects for the four pharmacogenetic HLA risk alleles, wherein the “majority” had 100% sensitivity and 99% specificity for the four pharmacogenomic HLA alleles in the Asian, European and Hispanic populations. However, the panel SNPs had proxy-SNPs with 98% sensitivity and specificity for HLA-A *31:01 and HLA-B*58:01 in the African population. This section is silent about the other two alleles and the markers thereof.
The summary of Example 1 recites that the “Sema4 pharmacogenetic HLA panel markers” are “very concordant across multi-ethnic populations” but does not describe the degree of concordance for individual genetic markers of the panel or in what number of populations are required to make this determination. As this is presented as “panel markers” without further data or description, it is also unclear whether the concordance is being assessed collectively across all markers for particular HLA alleles, individually, or some combination thereof and how this might inform assessment of “concordance” for a single SNP marker, as included in the claims.
Example 2 provides an analysis of multi-ethnic populations and provides data for each of the proxy-SNPs (Table 7), wherein SNPs appear to have been included if they met a threshold in at least two populations. However, the risk is not described as being concordant so it is unclear whether the ranges of sensitivity/specificity/PPV/NPV are intended to be used as a bases for determining concordance.
For this reason, the metes and bounds are unclear to one of skill in the art.
Claims 2-3, 5, 9-10, 12, 17-19, 21-23, and 44-47 are indefinite for depending from claim 1 and not rectifying the deficiency.
Regarding claim 45, the claim recites “such as bipolar”. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 46, the claim recites “the risk of the ADR … is determined with an average of 99% sensitivity and 99% specificity across the multi-ethnic populations”.
Claim 1 recites “the multi-ethnic populations comprise an African American population, a European population, a Hispanic population, an East Asian population, and a South Asian population”.
It is not clear from the claim in view of the specification if the artisan is intended to calculate an average each of the populations (e.g., (AA + Eu + His + EA + SA)/5 ) for the individual population sensitivity and specificity values or merely calculate the sensitivity and specificity for the combined multi-ethnic population comprising the multi-ethnic populations, as was performed in Example 1 of the specification.
Further, it is not clear from the claim in view of the specification if the artisan is intended to calculate the sensitivity and specificity for the risk of the ADR (e.g., determining the sensitivity/specificity of detecting SJS for carbamazepine if one or more genetic marker in LD with B*15:02 is present) or any sensitivity and specificity (e.g., 99% sensitivity and 99% specificity for the HLA risk allele across the multi-ethnic population).
Claim Rejections - 35 USC § 103
Claim(s) 1-3, 5, 9-10, 12, 17, 19, 21-23, and 44-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Erlichster (Erlichster M, et al. Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction. Pharmacogenomics J. 2019 Jun;19(3):230-239. Epub. 2018 Aug. 10 [supp.]; as cited in the IDS dated 08/17/2023) in view of Abi-Rached (Abi-Rached L, et al. Immune diversity sheds light on missing variation in worldwide genetic diversity panels. PLoS One. 2018 Oct 26;13(10):e0206512 [supp.]; as cited in the IDS dated 11/07/2025) and Leckband (Leckband SG, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013 Sep;94(3):324-8. Epub 2013 May 21.).
Regarding claims 1-3, 5, 9-10, 12, 17, 19, 21-23, and 44-47, Erlichster teaches a method comprising:
assaying for at least rs10484555_C (Tables 5 and 6; instant claims 1 and 5);
assessing a risk of ADR in a subject based on the presence/absence of the genetic marker (pg. 237, Discussion, para 3: “confident screening of HLA risk alleles … confidently predict a reduced ADR risk for most negative individuals”; pg. 230, col 2, para 1: “predictive value of HLA-ADR associations”; see also, Table 6);
stratifying treatment using the HLA biomarkers (pg. 237, Discussion, para 1) to reduce ADR incidence (pg. 238), whereby drug exposure [i.e., administering or not administering] guided by genetic makeup is a promising approach in precision medicine (pg. 230, para 1).
Erlichster teaches rs10484555 is a SNP tag for B*15:02 (Table 5), wherein SNPs may act as highly accurate “tags” for the inference of HLA genotypes due to strong linkage disequilibrium between the HLA variants and the SNPs (pg. 231, col 1, para 1) [i.e., rs10484555 is in LD with B*15:02]]. Erlichster teaches that B*15:02 is associated with the ADRs Stevens-Johnson Syndrome and toxic epidermal necrolysis with drugs comprising carbamazepine (Table 1; instant claims 12 and 17).
Erlichster teaches carbamazepine is capable of treating epilepsy, neuropathic pain, and mood, evidenced by Leckband. While Erlichster does not explicitly teach carbamazepine is capable of such, it is inherently taught because Leckband teaches that the drug is FDA approved for these conditions ((pg. 325, Background, para 1; instant claims 44-45).
Erlichster teaches determining which of the tag SNPs were suitable across ethnic backgrounds by evaluating the performance of each in the 1000 Genomes datasets (pg. 235, Validation of tagging SNPs, para 1), including assessing the performing of each of the top tagging variants in each super-population to remove any possible bias due to the weighting of ethnicity in the validation cohort (pg. 235, col 2, para 2; pg. 233, Tag validation method), wherein this set comprised rs10484555 (pg. 235, col 2, para 2; Supplementary table 5; Table 5).
Erlichster teaches assessing the ability of the tagging SNPs to detect the HLA allele [i.e., determine the risk of the ADR] in the multi-ethnic populations of:
said 1000 Genomes cohort, wherein the multi-ethnic populations comprise: Ad-Mixed American [i.e., Hispanic], East Asian, European, and African (pg. 232, Data processing—validation dataset; Supplementary Table 5); and
a combined multi-ethnic population comprising samples from the Pan-Asian, T1DGC, and 1000 Genomes datasets (Supplementary Table 3), wherein the Pan-Asian dataset comprises samples from the Indian datasets [i.e., South Asian] from the Singapore Genome Variation Project (pg. 232, Data processing—5 discovery datasets)
Erlichster also teaches rs140855588_G as the highest specificity tag for B*15:02 with 100% sensitivity in the 1000 Genomes Dataset and the following as equivalent SNPs (Supplementary Table 6):
rs151107659, rs371096447, rs185615899, rs144012689, rs186302377, and rs186302377 (instant claims 1, 5, 9, and 10); and
rs190335533, rs149481627, rs183151869 (instant claims 1, 5, and 9).
Erlichster teaches that these SNPs were identified in the validation cohort and may be viable tags for assessment in future validation studies (pg. 237, Discovery of tagging SNPs in the 1000 genomes dataset), and have a predicted clinical performance of 100% sensitivity, 100% specificity, and 100% PPV (Supplementary Table 7; see pg. 237, Discovery of tagging SNPs in the 1000 genomes dataset).
Erlichster teaches the assaying methods may comprise PCR amplification, selective hybridization, selective hybridization, and/or sequencing (Table 2; instant claims 19 and 21).
Erlichster teaches that the genetic markers are SNPs (entire document, e.g., pg. 233, Estimation of clinical performance of tag SNPs; instant claim 22).
Erlichster teaches that the frequency of multiple HLA-B variants of interest was below 1% in multiple populations, suggesting that these variants may be difficult to tag using polymorphism selected for inclusion on commercial genotyping platforms (pg. 234, Frequency of ADR-associated alleles in the discovery and validation datasets, spanning pg. 235). Erlichster teaches that multiple tagging SNPs may further improve the specificity of the tag SNP approach (pg. 237, col 2, para 3; instant claim 23) and applying a specificity threshold for clinical utility of tagging SNPs (pg. 237, Discussion, para 3).
Erlichster teaches performing an average of HLA typing accuracy (pg. 232, Tag SNP discover). Erlichster teaches a sensitivity of 100% and specificity of 99% across the 1000 Genomes dataset (Supplementary Table 4), 100% sensitivity in all populations in which the allele is present in 1000 Genomes and >99% specificity in 3 or four multi-ethnic populations (Supplementary Table 5), 100% sensitivity and 100% specificity of rs140855588 and equivalent SNPs across the 1000 Genomes datasets (Supplementary Table 6). Erlichster teaches that perfect sensitivity across all ethnic super populations is guaranteed due to a 100% sensitivity in the combined populations, it is possible that a given tag may have reduced specificity in a particular ethnic super-population (pg. 235, col 2, para 2).
Erlichster teaches setting thresholds for SNPS at 100% sensitivity and >95% specificity (pg. 233, Tag validation method; instant claim 46). Erlichster teaches there are situations where this specificity is insufficient (pg. 237, Discussion, para 3).
Erlichster teaches that the inability of proposed SNP tags to function across different populations is a key barrier to the clinical relevance of this genotyping approach, mandating multiple tags for each allele to account for patient background, and that the misclassification of patient background in a clinical context is not uncommon (pg. 231, col 2, para 1). Erlichster teaches setting a sensitivity threshold of 100% (pg. 231,
Erlichster does not explicitly teach that the African population comprises African Americans, and due to differing sample numbers, inherency cannot be clearly established. Erlichster does not explicitly teach assessing the risk of ADR across the South Asian populations for the additional genetic markers.
While Erlichster teaches stratifying treatments based on the genetic markers, it fails to explicitly teach which genetic makeup to stratify by (i.e., how many markers).
Erlichster fails to explicitly teach assessing comprising determining with an average of 99% sensitivity and 99% specificity across multi-ethnic populations and determining the risk of the ADR at least in part on a positive PPV or a negative PPV.
Abi-Rached teaches that the 1000 Genomes AFR (African) super population code comprises Americans of African Ancestry (Supplementary Table 1). It is also noted that the AMR (Ad Mixed American) super population code consists of those of Mexican Ancestry, Peruvians, Columbians, and Puerto Ricans (Supplementary Table 1).
Leckband teaches that the HLA-B*15:02 genotyping results are presented as positive if one or two copies of HLA-B*15:02 are present or negative if no copies of HLA-B*15:02 are present (pg. 325, Genetic test interpretation). Leckband teaches that there is no intermediate genotype of phenotype (pg. 325, Genetic test interpretation) and stratifying into carrier with a significantly increased risk or non-carrier with a normal/reduced risk (Table 1).
Leckband teaches use of carbamazepine for at least 3 months (pg. 326, Therapeutic recommendations, para 2; instant claim 2). Leckband teaches that patients who have been taking carbamazepine for longer than 3 months without developing cutaneous reactions regardless of HLA-B*15:02 status are not at zero risk (pg. 326, Therapeutic recommendations, para 2, spanning pg. 327) and recommending alternative treatments (pg. 327, Potential benefits and risks for the patient, para 1; instant claim 3).
Leckband teaches that regional and ethnic distribution of the HLA-B*15:02 allele and the genetic risk of carbamazepine-associated SJS/TEN is higher in several Asian countries including Vietnam, Cambodia, the Reunion Islands, Thailand, some parts of India, Malaysia, and Hong Kong (pg. 326, Linking genetic variability to variability in drug-related phenotypes, para 3).
Leckband teaches linking genetic variability to variability in drug related phenotypes (pg. 326, Linking genetic variability to variability in drug-related phenotypes, para 1 and title) and further estimating the risk of an ADR, given the presence of HLA-B*15:02, in a particular ethnic population of Han Chinese based on the PPV and NPV (pg. 326, Linking genetic variability to variability in drug-related phenotypes, para 3; instant claim 47).
Leckband teaches the importance of considering the HLA-B*15:02 allele carrier status regardless of self-reported ethnicity (pg. 326, Linking genetic variability to variability in drug-related phenotypes, para 3). Leckband teaches the HLA-B gene encodes a cell surface protein involved in presenting antigens to the immune system (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to assess the risk of the ADR in a multi-ethnic population comprising African Americans (instant claim 1) in the method of using SNPs for at least HLA-B*15:02 of Erlichster because Abi-Rached teaches that AFR is a genus comprising African Americans, motivated by the teachings of Erlichster that assessing tagging variants in multi-ethnic sub populations (e.g., “super population”) helps to remove possible biases of the weighting of ethnicity in cohorts and/or the teachings of Erlichster and Leckband to assess risk regardless of self-reported carrier status due errors in self-reported ethnicity. Additionally, it would be obvious for the same reasons to assess the additional or alternative markers in a multi-ethnic population comprising South Asians, as taught by Leckband.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to stratify drug exposure based on the presence or absence of at least one genetic marker including rs10484555 for HLA-B*15:02’s corresponding risk of carbamazepine-induced SJS/TEN (instant claim 1) in the method of Erlichster in view of Abi-Rached in view of the teachings of Leckband that there is no intermediate genotype/phenotype, motivated by the desire address the genetic risk of SJS/TEN, as taught by Erlichster and Leckband. That is to say, it would be obvious to perform, for example, further testing as taught by Erlichster, rather than to administer the drug or not administer if a result showed a mixed grouping of genetic markers present and absent in view of Leckband. It further would have been obvious to substitute and/or add additional tagging SNPs (instant claims 5, 9-10, and 23) from the list of the highest specificity tagging SNPs of Erlichster such that “high” and “low” risk is assessed when all of the genetic markers are present or absent respectively, motivated by their high predicted clinical performance taught by Erlichster and the teaching of Erlichster that multiple SNPs can help account for patient background and improve at least specificity.
Additionally, it would have been obvious to the ordinary artisan before the effective filing date to continue to treat or not treat in a further step of treating or not treating (instant claims 2 and 3), once the genetic markers had been assayed and risk had been assessed, given that the markers represent alleles of somatic genes [i.e., would not be expected to readily change], as taught by Leckband, it would be obvious to continue to treat the patient with either carbamazepine if no B*15:02 genetic markers identified and a low risk was assessed and no SJS/TEN developed or to continue to treat the patient with the alternative treatment rather than the ADR-associated drug carbamazepine, motivated by the teachings of Leckband that treatments typically span multiple months.
Also, it have been obvious to the ordinary artisan before the effective filing date to have utilized genetic markers with a 99% sensitivity and 99% specificity across the multi-ethnic populations (instant claim 46), wherein utilizing the multi-ethnic populations of the claims would be obvious for the same reasons as above, as Erlichster teaches identifying tags with 100% sensitivity—wherein such would mean 100% sensitivity across each ethnic super population, i.e., the average would be expected to be the same—and at least 95% specificity and multiple markers with specificity at or around 99% overall or across multiple sub-populations. The choice of such threshold variables are determined to be a matter of routine experimentation based on the desires of the artisan for a threshold, e.g., for the number of SNPs in the analysis as Erlichster teaches utilizing additional SNPs to increase specificity and multiple SNPs at various specificity levels that the artisan could choose among if such is determined to be insufficient for the situation. See MPEP 2144.05(II).
Further, it is noted that as Erlichster also discusses possible biases of weighting of ethnicity in a validation cohort and performing an average for HLA genotyping across a dataset. Thus, it also would have been obvious to the artisan before the effective filing date of the claimed invention to re-weight an “average” sensitivity and specificity calculation motivated by the desire to reduce such a possible bias.
Finally, it would have been obvious to the ordinary artisan before the effective filing date of the claimed invention to the utilize the PPV and/or NPV (instant claim 47) to determine the probability of an ADR, as taught by Leckband for the Han Chinese population, in the combined method, motivated by the desire to link genetic variability to variability in drug-related phenotypes, as taught by Leckband.
There would have been a strong expectation of success as all are directed to genetic testing and assessment of HLA status.
Claim(s) 18 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Erlichster (Erlichster M, et al. Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction. Pharmacogenomics J. 2019 Jun;19(3):230-239. Epub. 2018 Aug. 10; as cited in the IDS dated 08/17/2023) in view of Abi-Rached (Abi-Rached L, et al. Immune diversity sheds light on missing variation in worldwide genetic diversity panels. PLoS One. 2018 Oct 26;13(10):e0206512 [supp.]; as cited in the IDS dated 11/07/2025) and Leckband (Leckband SG, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013 Sep;94(3):324-8. Epub 2013 May 21.) as applied to claim 1 above, and further in view of Fang (US 2016/0376656 A1; published 12/29/2016).
Regarding claims 18 and 19, in the method of Erlichster in view of Abi-Rached and Leckband, Erlichster teaches fails to teach specific samples.
Fang teaches detecting the HLA-B*15:02 allele comprises obtaining a sample, determining the presence of rs144012689 minor allele in the sample (claim 1), wherein the samples may be any type of body sample may be used without limitation including whole blood and saliva (para [0044]; instant claim 18).
It is also noted that while Erlicher teaches PCR amplification as part of the broader assaying, for the purposes of compact prosecution Fang explicitly teaches amplification as part of the assay (para [0047]; claim 3; instant claim 19). Fang teaches that its novel TaqMan genotyping assay comprising amplification has a 100% sensitivity and 100% specificity making it valuable and clinical desirable (para [00238]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to choose from among the various samples of Fang, including whole blood and saliva, in the combined method as such were taught to be equivalent substitutes for the same purpose. See MPEP 2144.06. It further would have been obvious to utilize amplification in combined method, motivated by the ability to perfectly detect the SNP using the method TaqMan method of Fang. There would be a strong expectation of success as Fang is also directed to B*15:02 detection methods.
Response to Arguments
Applicant’s arguments, see pg. 16-18, filed 11/07/2025, with respect to the rejection(s) of claim(s) 1-3, 5, 12, 17, 19-22 under Liu have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Erlichster, Abi-Rached, and Leckband, as necessitated by amendments.
Conclusion
No claims are 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.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636