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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/14/2025 has been entered.
This Office Action is in reply to Applicants’ correspondence of 07/14/2025.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put this 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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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 NON-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 08/05/2024, Applicants elected without traverse the particular elements that are: single nucleotide variants (e.g.: relevant to claim 214); and lung cancer (e.g.: relevant to claim 219, in part) is acknowledged.
As set forth on pages 2-3 of the Office Action of 10/11/2024, the species election requirement as it was made between the elected “lung cancer” and the cancer that is “a gastric cancer” (relevant to claim 219) is withdrawn, and claim 219 has been examined as it encompasses either a lung cancer or a gastric cancer.
Claims 215-217 and 232 (directed to variants that are fusions or translocations) remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on page 3 of the Office Action of 10/11/2024.
Election was made without traverse in the reply filed on 08/05/2024.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Claim Amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 210-214, 218-223, 226 and 231 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schutte et al (2016) in view of Nam et al (2017; as cited on the IDS of 04/13/2023) and Lee et al (2015).
Relevant to the method of claim 210, Schutte et al teaches culturing tumor organoids derived from cells of a tumor sample (e.g.: p.16 - Establishment of PDO cell cultures) (relevant to step a), and teaches determining a reference genomic variant profile comprising genomic variants of the tumor cells and determining organoid variant profiles from cells of the organoid (e.g.: p.14 – Targeted sequencing; Whole genome sequencing; Whole exome sequencing; Whole transcriptome sequencing; Comparison of corresponding patient tumours and models; Figure 2) (relevant to steps b and c). Relevant to the “confirming” of step d of claim 210, Schutte et al teaches that “the genetic profiles of the models were generally concordant with their matched donor tumours” (p.2, right col), and further teaches that when considering genetic variants such as SNVs and Indels between tumors and organoids, most of the samples were greater than 65% concordant (e.g.: Fig 2c).
Relevant to the limitations of claim 211, Schutte et al teaches that within a tumor there may be intra-tumour heterogeneity (ITH) with different mutations found in distant regions of the tumour (e.g.: p.2 – right col).
Relevant to the limitations of claim 212, Schutte et al teaches the analysis of nucleic acids from primary tumors and patient derived organoid cultures (PDO) (e.g.: p.2 - Molecular landscapes of the OT tumours and derived models; p. 13 – Methods).
Relevant to the limitations of claims 213, 214 and 218, Schutte et al teaches the analysis of tumor:organoid genetic concordance using somatic variants including single nucleotide variants and a plurality of at least 20 genomic variants (e.g.: p.2 - Molecular landscapes of the OT tumours and derived models; Fig. 2).
Relevant to the limitations of claims 220-223, Schutte et al teaches detecting the level somatic variants that are discordant between patient derived tumor samples and PDO cells, and teaches that some samples have less than 5% discordance (e.g.: Fig. 2c; Fig. 3d).
Relevant to the limitations of claims 226 and 231, Schutte et al teaches providing organoid cells with therapeutic treatments (e.g.: Fig 1), and evaluating a property of the exposed tumor organoid cell line (e.g.: Figs 7 and 9; p.9 - Comparative drug responses between PDX/PDO sibling pairs; Molecular classifiers of drug response).
Schutte et al does not teach culturing tumor organoids in an organoid culture medium having less that 500 ng/mL R-spondins (relevant to step a of claim 210). But the use of media that lack R-spondins in the culturing of organoids was known in the prior art and is taught by Nam et al.
Nam et al teaches the results of a screen to find a R-spondin-1 substitute compound that is able initiate small intestinal organoids without the use of the R-spondin-1 protein. Nam et al demonstrates that organoids can be grown in the absence of R-spondin using a replacement compound identified as RS-242604 (e.g.: Abstract; Fig 1).
Schutte et al teaches that “the genetic profiles of the models were generally concordant with their matched donor tumours” and teaches that the variants present in organoids and tumors were generally concordant, as detailed above. Schuute does not specifically exemplify a comparison of organoid and tumor genetic profiles that includes a measure of the variant allele frequency (VAF) in nucleic acid samples from the organoid and original source tumor. However, the use of VAF in nucleic acid samples as a measure of sample concordance between tumors and cultures of patient derived tumor cells was know in the prior art and is taught by Lee et al.
Lee et al teaches the determination of VAF in patient derived cell cultures (p.25621 – Targeted sequencing) using variations detected in 381 cancer related genes (e.g.: p.25623 - PDCs were reflective of genomic alterations in parent tumors and clinical phenotypes in response to targeted agents; Fig 3; Table 2). Lee et al teaches that that genomic alterations were highly concordant between primary tumors and the progeny PDCs with an average VAF correlation of 0.878, and several samples with correlations higher than 95% (see for example S-1, which is a gastric cancer as noted in Supplementary Table S3 relevant to claim 219).
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 substitute the R-spondin-free media of Nam et al in the methods of creating tumor organoids of Schutte et al. The skilled artisan would have been motivated to use a medium lacking R-spondin based on the expressed teachings of Nam et al that substituting RS-246204 in place of R-spondin-1 can be a part of a cost-efficient culturing method of organoids.
It would have further been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used the VAF concordance-based methods of Lee et al to compare genetic profiles of tumor models such as organoids with their source tumor tissues. The skilled artisan would have been motivated to use the VAF concordance-based methods of Lee et al based on the expressed teachings of Lee et al that such methods can establish that a paired primary tumor/PDC are highly concordant, and that determining genetic concordance has important implications in the development of appropriate model systems for drug discovery and screening. The teachings of Lee et al are thus relevant to the teachings of Schutte et al which provides that developing organoid models that recapitulate the genetic features of the donors provide an important tool for offering a better molecular understanding disease and development of systems for linking molecular profiles with drug sensitivity patterns to identify novel biomarkers of drug treatment sensitivity.
With regard to the limitations of 211, where the prior art teaches the desirability of concordance between a source tumor and a patient derived tumor cell model (e.g.: Lee et al: p.25691 - Abstract), and the prior art teaches that a tumor may display intra-tumour heterogeneity (e.g.: Schutte et al: p.2 - Molecular landscapes of the OT tumours and derived models; p.13 - Discussion), 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 created and organoid, and determined a tumor reference profile, using cells from a plurality of regions of the tumor. The skilled artisan would recognize that using cells from a plurality of regions of the tumor would provide an accurate representation of the genetic landscape of the whole tumor including possible intra-tumour heterogeneity.
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 103 as rendered obvious by the cited prior art as maintained above. Applicants’ arguments (p. 7-10 of the Remarks of 07/14/2025) have been fully and carefully considered, but are not found to be persuasive to withdraw the rejection.
Applicants have noted that step d) of claim 210 recites confirming at least 65% concordance in the clonal diversity similarity between tumor tissue the organoid cultured form the tumor tissue using measure of variant allele frequency (VAF). Applicants have argued that there is no teaching that applying measures of VAF, as taught by Lee et al (cited in the rejection), to the organoids and tumors of Schutte et al (which teaches tumor/organoid pairs with greater than 65% concordant variations) would result in the confirmation of 65% concordance using the VAF measure. The argument is not persuasive. Initially it is noted that Schutte et al teaches (e.g.: p.12 – SciClone) that the investigation of tumour clonality in patient, PDX, and PDO samples of the same donor was performed using the program sciClone, in which SNVs were scored scored and data was clutered based on variant allele frequencies of all informative SNVs that have a minimum coverage of 48 reads for patient samples and 24 reads for PDX and PDO models. Thus, in determining concordance, the teachings of Schutte include a measure of VAF which represents the proportion of sequencing reads covering a specific genomic location that carry a particular mutation as part of the measure of concordant or discordant fractions of the samples. Lee et al further demonstrates the particular application of VAF measurements to establishing clonality among samples (i.e.: primary tumors and the progeny PDCs). Where the measures of Schutte et al are related to VAF, the skilled artisan would reasonable expect using VAF measures specifically (as taught by Lee et al) would provide similar values of clonal concordance as those provided by the sciClone based measurements used in Schutte et al.
Applicants have further argued that while Nam teaches the use of an R-spondin alternative (thus providing for a media that has less that 500ng/mL R-spondins) in the initiation of small intestinal organoids, the references lack a particular suggestion that using such a media would provide the same level of concordance in clonal diversity as the organoids provided by Schutte et al. this argument is not persuasive. As noted in the rejection, Schutte et al teaches (e.g.: Fig 2c) that different tumor/organoid pairs may have different levels of concordance; but Schutte et al makes it clear that developing organoid models that faithfully recapitulate the genetic features of the donors (i.e.: a higher level of concordance is a desired feature in organoid models) provide an important tool for the investigation of cancer treatments. As such the Examiner maintains that it would be obvious to the skilled artisan to analyze concordance in a tumor/organoid pair where the organoid is made in a media with less than 500ng/mL R-spondins, and perform VAF analysis to confirm that there is a high level of concordance between the tumor and the organoid of the pair.
Further in support of the maintained rejection, it is noted that the prior art of Urbischek et al (2019) teaches that organoids can be formed in media with 1mg/3L (i.e.: 333ng/mL, relevant to the limitations of claim 210) of R-spondin 1 (e.g.: p.2 - Production of R-spondin 1; Table 2). And the prior art of Gendoo et al (2019) teaches high levels of concordance in matched ‘trios’ of primary tumour, PDX, and PDO, where the PDO (organoids) are developed in media with less than 500ng/mL of R-spondins (Gendoo et al references Boj et al (2015) (e.g.: p. 20 – Model system derivation) for the methods of producing organoids; Boj et al teaches that media for developing organoids includes RSPO1-conditioned medium at 10% v/v (p.335 - Human Pancreatic Tumor and Normal Organoid Culture), and the data sheet for the R-Spondin1 Expressing 293T Cell Line teaches that conditioned media contains 12 µg of protein in 75 mL of FC-RSpo1-HA expressing 293T cell supernatant).
Where traversal of the following rejections is based upon the same arguments, the following rejections are maintained.
Claim(s) 227, 228 and 230 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schutte et al (2016) in view of Nam et al (2017; as cited on the IDS of 04/13/2023) and Lee et al (2015) as applied to claims 210-214, 218-223, 226 and 231 above, and further in view of Vlachogiannis et al (2018; citation A69 on the IDS of 04/13/2023) including the Supplementary Materials.
Schutte et al in view of Nam et al and Lee et al renders obvious methods including culturing tumor organoids in a medium having less than 500ng/mL R-spondins, determining genomic variant profiles from nucleic acids (relevant to the instant rejection of clam 228) comprising variant allele fractions in the source tumor and the organoid, and confirming at least 65% concordance in the variant allele fraction between the tumor and the organoid. Schutte et al teaches providing organoid cells with therapeutic treatments (e.g.: Fig 1), and evaluating a property of the exposed tumor organoid cell line (e.g.: Figs 7 and 9; p.9 - Comparative drug responses between PDX/PDO sibling pairs; Molecular classifiers of drug response), relevant to claims 226 from which the instantly rejected claims depend.
Further relevant to the rejected claims, Schutte et al teaches that organoids can serve as models for the analysis of response to therapy treatment (e.g.: Fig 9), and that genetic changes or differences can indicate response to drug treatment (e.g.: p.9 - Comparative drug responses between PDX/PDO sibling pairs).
Relevant to the instant rejection, Vlachogiannis et al teaches (e.g.: Fig 2, Fig. S1) obtaining a sample from a subject (e.g.: archival FFPE; tumor biopsy from liver or bowel) and determining a reference genetic profile from the sample (relevant to claim 116 and 117) of relative variant allele frequency (e.g.: Fig 2F; Fig S11). The reference further teaches determining genetic profile from organoids (e.g.: Fig 2F; Fig S11; Fig S3), and evaluating the reference and organoid profiles (e.g.: the chart in Fig 2F displays FFPE, biopsy, and organoid VAF for comparison). Vlachogiannis et al teaches
analysis of genomic variant profiles, and comparisons of the profiles, in organoids after exposure to a therapeutic agent.
Vlachogiannis et al teaches (e.g.: p.39-40 of the Supplemental material) performing ex-vivo clinical trials where a culture of patient-derived organoids is exposed to cetuximab and the variant allele frequency (VAF) is measured in the organoids.
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 combined the teachings of Vlachogiannis et al to perform a post-treatment genomic variant profile analysis of a PDO sample using the organoids (i.e.: grown in a medium having less than 500ng/mL) and the comparison (i.e.: variant allele frequency concordance) rendered obvious by Schutte et al in view of Nam et al and Lee et al. The skilled artisan would be motivated to perform pre- and post-treatment genomic variant profile analysis of PDOs based on the expressed teachings of Vlachogiannis et al that PDOs can be used as drug screening tools to match responses to clinical treatment, and that particular genomic variants may be associated with response or resistance to particular treatments (e.g.: p.6, left col.; Fig. S1). The skilled artisan would thus understand that comparing genomic variant profiles among tumors, pre-treated and post-treated PDOs could provide for the determination of a treatment course suitable for effective treatment of the primary tumor in the patient (e.g.: Figs S9 and S10). The skilled artisan would recognize that determining a change in a genomic variant profile in a treated PDO that is indicative of a beneficial response to a treatment would indicate that the tumor may be responsive to the same treatment, and thus assigning that treatment modality to the subject may alleviate the pathological effects of the tumor in the subject.
Relevant to the rejection of claim 230, the prior art teaches providing a measure of variant allele frequencies in samples from tumor tissues, PDOs established from the tumors, and PDOs treated with therapeutic agents, and teaches that various particular mutations are associated with the tumor phenotype, and with response to or resistance to treatment with various therapeutic agents. Where the claims require analysis of a threshold (e.g.: a change between pre-treatment and post-treatment (claim 230)), the comparing of VAFs in genomic profiles from the different samples, and the use of any of the particular VAFs as a threshold, would be recognized by the skilled artisan as a result-effective variable where different thresholds may increase the sensitivity or specificity of cancer detection in different types of cancerous tissues. Thus, in regard to the limitations of the claims, where the comparing of VAFs is provided in the cited prior art, and the VAFs are recognized as a results-effective variable, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the method. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. It would have been prima facie obvious to one of ordinary skill in the art as of the effective date of the methods of the instantly rejected claims to have compared the VAFs identified in the samples of the methods rendered obvious by Vlachogiannis et al to thresholds levels in order to achieve a desired level of sensitivity or specificity in determining, for example, response to treatment, or likelihood of response to treatment.
Claim 229 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schutte et al (2016) in view of Nam et al (2017; as cited on the IDS of 04/13/2023) and Lee et al (2015) as applied to claims 210-214, 218-223, 226 and 231 above, and further in view of Vlachogiannis et al (2018; citation A69 on the IDS of 04/13/2023) including the Supplementary Materials as applied to claims 227, 228 and 230 above, and further in view of Bronkhorst et al (2016; citation A94 on the IDS of 04/13,2023).
Schutte et al in view of Nam et al, Lee et al, and Vlachogiannis et al renders obvious the methods of claim 227, from which instantly claim 229 depends.
Schutte et al in view of Nam et al, Lee et al, and Vlachogiannis et al does not address the analysis of organoid nucleic acids isolated from a culture medium (as require by the instantly rejected claim), but such methods were known in the art and are taught by Bronkhorst et al (e.g.: p.158 - Extraction of cell-free DNA).
It would have been prima facie obvious to one of ordinary skill in the art as of the effective date of the methods of the instantly rejected claims to have performed the methods of Schutte et al in view of Nam et al, Lee et al, and Vlachogiannis et al using cell-free DNA obtained from a culture medium as taught by Bronkhorst et al. The skilled artisan would have been motivated to use cell-free DNA obtained from a culture medium based on the expressed teachings of Bronkhorst et al that such DNA may be suitable for analysis by amplification- and sequence-based methods (e.g.: p.158 - Quantification of cell-free DNA; p.164), and the skilled artisan would recognize that using DNA from a culture medium may be more efficient as it would not require additional steps related to isolating the DNA from cells.
Conclusion
No claim is allowed.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683