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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 22, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on January 22, 2026. Claim 1 is presently amended. Claims 7-9, 11, 13-14, 16-21, 23-27, 29-31, 33-36, 40-49, 51, 53-57, 59-60, and 62-72 are canceled. Claims 28, 32, 37-39, 50, 52, 58, 61, and 73 were previously withdrawn from further consideration pursuant to 37 CPR 1.142(b) as being drawn to nonelected inventions. Election was made without traverse in the reply filed on December 18, 2024. Therefore, claims 1-6, 10, 12, 15, 22, and 74-75 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2020/029584, filed April 23, 2020. Applicants' claim benefit of a prior-filed application parent provisional application 62/837,525, filed on April 23, 2019, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c).
Thus, the earliest possible priority for the instant application is April 23, 2019.
Withdrawn Specification Objection
The objection to the specification has been withdrawn.
Claim Interpretation
Under the broadest reasonable interpretation consistent with the specification and understanding of a person of ordinary skill in the art, a “metastatic lesion” is any secondary anatomical site, tissue, or organ outside the primary tumor where cancer cells originating from the primary tumor have metastasized and are detectably present, such as those demonstrated to form in the lung, liver and brain in the teachings of Echeverria. This is consistent with the instant specification, See pg. 31, para. 2; pg. 40, para. 3. Additionally, “metastatic potential” or propensity is broadly understood as the relative likelihood or tendency of a cancer cell population to disseminate from a primary site and colonize one or more secondary organs, as evidenced by differential presence, abundance, or enrichment of those cells at such metastatic lesions (Instant Specification, pg. 1, para. 3; pg. 9, para. 2; pg. 26, para. 5). Also, “cancer cell lines” are reasonably interpreted to include genetically distinct cancer cell populations or cell lineages, including genetically different subclones derived from a common progenitor, as such subclones are routinely treated in the art as biologically distinct cancer populations with differing metastatic behaviors, including organ-specific metastatic propensities, consistent with the disclosure of the instant specification as well as the teachings of Echeverria.
Maintained Claim Rejections - 35 USC§ 103
Claims 1-6, 10, 12, 15, and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 10,724,099 B2, prior published US 2015/0044676 A1, Feb. 12, 2015), in view of Echeverria et al. (Nat Commun. 2018 Nov 29;9(1):5079), Marsic et al. (Mol Ther Methods Clin Dev. 2015 Oct 28:2:15041. eCollection 2015).
Regarding claim 1 and 15, Yu teaches methods utilizing a mixture including a plurality of nucleic acid-tagged or barcoded cancer cells and signals from a marker, example a selectable, detectable, and quantifiable markers of specific cells, such as in vivo evaluation of changes within a tumor following a specific treatment and the tracking of cells from a primary tumor which become metastases (column 7, lines 23-50; column 8, lines 11-57; column 9, lines 19-42; column 9, lines 65 through column 10, lines 1-3; column 12, lines 42-46).
The methods taught comprise barcoding vectors, where the DNA barcode sequences are engineered for greater sensitivity (column 7, lines 23-50). Specifically, Yu teaches the methods can be performed on any type of cells including tumor cells from different tumor types as different stages of cancer (column 9, lines 1-6). Yu also teaches that the methodology can employ a selectable and detectable marker (column 9, para. 5).
Specifically, Yu teaches barcoded cancer cells with selectable and detectable markers for tracking tumorigenic potential where the cells are comprised of a plurality of genetically heterogenous cell types, including cells from different tumor types, different tissues, different genetic backgrounds, different subjects, different stages of cancer, and multiple various cancer or tumor cell lines (column 2, lines 1-53; column 4, para.1; column 9, para. 1; column 19, para. 1).
While Yu does teach the measuring of optical fluorescence by imaging methods (column 15, para. 3), imaging the cells and their descendants subsequent to delivery to locate where in the body the cell and/or its descendants are present is not taught.
However, the ordinary artisan would have understood the prior art recognizes imaging of cells and their descendants to locate where in the body metastatic cells are present, further in view of Echeverria.
Echeverria teaches high-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer by genomic sequencing and high-complexity barcode mediated clonal tracking to reveal robust alterations in clonal architecture between primary tumors and corresponding metastases (Abstract). The ordinary artisan would readily appreciate the relationship between cell lines and cell colonies, as both represent populations of cells derived from a single progenitor cell and maintained in culture for extended periods. Accordingly, cell lines are generally understood in the art to be clonal populations, meaning they originate from a single cell. This recognized congruence between “cell lines” and “cell colonies” renders the teachings of the prior art directly applicable to the claimed subject matter, now explicitly reciting cell lines.
Additionally, Echeverria teaches the isolation of spatially distinct metastatic lesions, where tumor cells were engineered to express click beetle red luciferase (CBRLuc) and mCherry, then engrafted into the MFPs of recipient mice. Bioluminescence imaging (BLI) of secondary organs revealed the presence of tumor cells in physiologically relevant sites including lung, liver, brain, and bone (pg. 2, last para. and Fig. 1- 3). Echeverria explicitly states, “In this study, barcoding was employed to map primary tumor lineages in multiple metastatic sites in vivo with clone-level resolution (pg. 12, column 1, para. 2).”
Before the effective filing date, it would have been obvious to the ordinary artisan, to have used the known technique of real-time bioluminescence imaging (BLI) of barcoded metastasized cells for cancer cell clonal metastatic localization, as taught by Echeverria, to improve the similar methods applied to multiple cell lines, as taught by Yu, in the same way. Moreover, Echeverria provides express motivation in concluding the evolution of single-cell sequencing and imaging technologies will afford the opportunity to investigate mechanisms enabling rare MFP tumor cell populations to colonize secondary organs and will inform strategies to preclude the preferential outgrowth of these clones in multiple organ sites (pg. 12, column 2, para. 3).
The combined teachings of Yu and Echeverria do not expressly teach the limitation that barcode, detectable marker, and selectable marker are all encoded by a single transcript.
However, Marsic teaches a method of biodistribution analysis utilizing a vector encoding a single transcript a barcode, a detectable marker suitable for in vivo imaging; the detectable marker (luciferase) suitable for cell selection and/or sorting (mApple) (abstract; Fig. 1; pg. 1, column 2, first para.). Prior to the effective filing date, the ordinary artisan would have found it prima facie obvious to have applied the known technique of vector design incorporating these components into a single transcript, as taught by Marsic, to the known method of metastasis cell tracking, as taught by Yu, ready for improvement to yield the predictable result of characterizing the metastatic potential of a mixture of cancer cells and cell lines.
Regarding the limitation of “quantifying the abundance of each barcode for each cell line in a tissue or organ where the cancer cells and/or their descendants are present in order to characterize thereby characterizing the metastatic potential of each cancer cell line targeting the tissue or organ, wherein the metastatic potential of a cell line targeting the tissue or organ is defined as enrichment of barcodes for the cell line in the tissue or organ relative to the composition of the mixture of cancer cells prior to the delivery to the non-human subject,”
Yu teaches the method called PRISM, which use multiplexed, mixed cell populations or populations comprising genetically heterogeneous cancer cells, to assess response in vivo and in vitro allowing use of screening methods to efficiently and cost-effectively determine relative reaction of a mixture of cell populations to conditions. Additionally, Yu teaches methods use pools of barcoded cells and barcode signals as quantifiable markers of specific cells or cell lines, such as evaluation of ecological changes within a tumor following a specific treatment and the tracking of cells from a primary tumor which become metastases (column 8, lines 52-57; column 13, Example 1; column 16, Example 2).
Echeverria teaches the analysis of data, including barcodes and omics level datasets, obtained from the method provide compelling evidence that lung, liver, and brain metastases were derived from a shared genomic lineage and identify 18 potential driver mutations of multi-organ metastasis, equivalent to a genetic basis for metastatic potential (pg. 10, column 2, first para.). Furthermore, Echeverria teaches high-resolution barcode-mediated clonal tracking in patient derived xenograft models, demonstrating that the abundance of specific barcodes correlates with the metastatic potential of different cell clones. The study shows that certain high abundance subclones preferentially seed multiple organ sites, including lung, liver, and brain, indicating that barcode frequency directly reflects metastatic potential.
Thus, in addition to Yu, Echeverria applies the concept of relative abundance or ‘enrichment’ and demonstrates that barcode abundance is not random, but instead reflects the metastatic fitness of specific clones, as subclones with higher barcode representation in metastases consistently dominates across multiple organ sites. Given that barcode sequencing is a standard method for tracking tumor heterogeneity, an ordinary artisan would recognize that variations in barcode frequency implicitly indicate different metastatic potential. Furthermore, since clonal selection, cell line maintenance, and expansion are well characterized processes in cancer biology, it would be an expected result that cells with greater metastatic potential would leave a more pronounced barcode signal in downstream metastatic sites. The study also highlights that certain clones exhibit preferential organ tropism, reinforcing that barcode frequency or abundance is an effective predictor of metastatic potential (pg. 7, column 2, para. 2; pg. 9, column 1, para. 1).
Thus, applying barcode abundance as a quantitative measure of metastatic fitness would have been a logical and predictable optimization of the existing mythologies. Since Yu and Echeverria both teach barcode tracking was known and used to monitor clonal cell line dynamics in metastatic progression, and explicitly correlate barcode abundance with metastatic potential, an ordinary artisan would have had both a motivation and a reasonable expectation of success in using barcode abundance to assess metastatic potential.
Regarding claim 2, the combined teachings of Yu, Echeverria, and Marsic render claim 1 obvious. Yu additionally teaches where cells proliferated for ranges between 12 days to several weeks (column 16, Example 2, lines 41-51). Echeverria also makes clear that these assays are taught for account for tracking tumor proliferation assays, in vivo, or in a subject (pg. 2, column 1, para. 3-4). The methods are clearly taught to account for metastasis and allow for the metastatic cells to proliferate in vivo.
Regarding claim 3, the combined teachings of Yu, Echeverria, and Marsic render claim 1 and 2 obvious. Yu additionally teaches, after several weeks, mice were sacrificed and tumors excised. Tumors were sectioned into 4-5 adjacent fractions, genomic DNA was harvested, and the relative abundance of each cell line in each portion was determined by PRISM: for each sample, the fluorescent signal for each cell line was converted to cell number using the signal from the cell mixture used for injection, and these cell numbers were used to calculate the relative contribution of each cell line to the tumor (column 16, lines 50-58). Echeverria additionally teaches the surgical resection or isolation of cells from the subject and characterization of the identity of the cells and their abundance (Fig 1-3).
Regarding claim 4, the combined teachings of Yu, Echeverria, and Marsic render claim 1-3 obvious. Yu additionally teaches a method of cell sorting. Specifically, the use of the Becton Dickinson LSR II flow cytometer, a common cell sorter and laboratory technique used to analyze and characterize individual cells in a sample (column 18, line 54).
Echeverria additionally teaches the sorting of cells using FACS for sorting mCherry-positive tumor cells isolated from in vivo metastasis models (Fig. 1). Specifically, Fig le states:
“PIM00 1-P tumor cells were engineered to express click beetle red luciferase (CBRLuc) and mCherry. Following lentiviral transduction, mCherry-positive tumor cells were sorted by F ACS and engrafted into the MFP of a NOD/SCID mouse. Tumors were isolated and re-passaged into recipient mice and mCherry positivity was confirmed at each passage by flow cytometry.”
Echeverria further teaches in vivo isolation by macro-dissection of tumor cells using bioluminescence imaging of PIM 1-CBRLuc MFP tumor cells were isolated, barcoded, and engrafted into MFPs of mice, and mouse cell depletion was validated by FACs of stained cells (Fig. 3; pg. 6, column 1, para. 1; pg. 14, column 1, para. 2). Given that FACS is a widely used method for separating cell populations based on marker expression, it would have been obvious to one of ordinary skill in the art to apply the same F ACS-based sorting technique to the isolated cells post-extraction. One of ordinary skill in the art would recognize that once tumor cells are extracted from the subject, they can be further purified using established techniques like FACS to ensure that only those expressing the barcode, imaging marker, or selection marker are retained for downstream applications. Since Echeverria already teaches the in vitro isolation and FACs-based selection in vitro/in vivo, extending FACS-based post-extraction sorting represents a routine and expected step in maintaining a purified cell population.
Regarding claim 5, the combined teachings of Yu, Echeverria, and Marsic render claim 1 and 2 obvious. Yu additionally teaches the methods of detection include a step of amplifying the nucleic acid tags. Nucleic acid amplification methods include, without limitation, polymerase chain reaction (PCR) and its variants such as in situ polymerase chain reaction and quantitative polymerase chain reaction (column 10, lines 54-59) and sequencing (column 10, lines 5-8 and lines 50-53; column 20, Example 5). Again, Yu explicitly teaches the application of the methods in vivo and to multiple cell lines (column 1, para. 5; column 4, para. 2; column 7, lines 40-67; column 9, para. 3)
Regarding claim 6 and 22, the combined teachings of Yu, Echeverria, and Marsic render claims 1 obvious. Yu teaches the application of high-throughput sequencing-based detection methods (column 10, para. 2). Echeverria additionally teaches the application of RNA sequencing to the methodology (Fig. 2), and the use of single-cell sequencing technology (pg. 12, column 2 para. 3). On pg. 12, Echeverria explicitly states:
“Further, the evolution of single-cell sequencing and imaging technologies will afford the opportunity to investigate mechanisms enabling rare MFP tumor cell populations to colonize secondary organs and will inform strategies to preclude the preferential outgrowth of these clones in multiple organ sites (column 2, para. 3).”
Moreover, the methods taught by Echeverria are applicable to single cells as Echeverria teaches the dissociation of the tumor into single cells throughout the reference; expressly demonstrating that the assay is effective when moving from in vitro applications to in vivo applications, and repeated:
“The viable mCherry-positive fraction was collected and an aliquot was analyzed on the FACS sorter in a post-sort purity check, which confirmed that the sorted population contained no mCherry-negative cells. 50,000 viable mCherry-positive tumor cells were washed and engrafted into the MFP of one NOD/SCID mouse as described above in the presence of EG fibroblasts. Half of the EG fibroblasts were irradiated with 4 Gy and mixed with non-irradiated fibroblasts. Once the tumor reached 1000mm3, it was harvested, dissociated into single cells and immediately re-transplanted into 9 recipient mice (one million cells each). This process was repeated on second-passage CBRLuc labeled tumor cells (pg. 13, para. l)."
The term passaged or re-passaged is inclusive of an in vivo passaging assay, where the experimental results are provided at each passage by flow cytometry. Echeverria teaches the distinct transcriptomes or transcriptomic data of subclones, reading on the limitations of the claim (pg. 10, column 1, Section: Shared molecular features in multi-organ metastases; Fig. 7).
Echeverria teaches RNA sequencing and explicitly discusses single-cell sequencing as a tool for studying metastasis. It also describes dissociating tumors into single cells and sorting then via FACS, as a standard technique for isolating cells for RNA sequencing. Given that RNA sequencing is already applied in Echeverria and that prior art describe RNA sequencing methods, an ordinary artisan would have had clear motivation and a reasonable expectation of success in applying single-cell RNA sequencing to generate transcriptomes for individual cells. Since sequencing is already being used bulk populations, refining it to the single-cell level would have been an expected optimization, not an inventive step. Thus, it would have been prima facie obvious for the ordinary artisan to have carried out RNA sequencing on a single cell, thereby generating a transcriptome for each cell with a reasonable expectation of success as motivation already existed in the prior art, see pg. 15, column 2, para 4-5 for a description of RNA sequencing methods.
Regarding claim 10, the combined teachings of Yu, Echeverria, and Marsic render claim 1 obvious. Additionally, Echeverria teaches isolation of spatially distinct metastatic lesions tumor cells engineered to express click beetle red luciferase (CBRLuc) and mCherry, then engrafted into the MFPs of recipient mice. Bioluminescence imaging (BLI) of secondary organs revealed the presence of tumor cells in physiologically relevant sites including lung, liver, brain, and bone (pg. 2, last para. and Fig. le, f).
Regarding claim 12, the combined teachings of Yu, Echeverria, and Marsic render claim 1 obvious.
Additionally, Yu teaches the methodology of detecting a level of the exogenous nucleic acid tag in each cell type of the sample, wherein the level of the exogenous nucleic acid tag correlates to the number of living cells, and comparing the number of living cells in the sample to the test condition to a reference number of cells (column 2, line 40 through column 3, line 10). Yu additionally teaches the correlation between methods including PRISM and OPTICAL to evaluate sensitivity and specificity of barcode reads and fluorescent markers (column 5, lines 36-53). In fact, cell line responses in mixture determined by PRISM were found to correlate well with two independently validated measures of optical response (CTG or OPTICAL) performed with the same cell lines examined individually (column 7, lines 40-47). Thus, Yu teaches correlating barcode expression with fluorescence markers using PRISM and OPTICAL techniques, establishing a basis for barcode-marker correlation.
Additionally, the methods taught by Echeverria similarly confirm that the relationship or correlation of barcode reads and fluorescent detection of sorted cells was taught and utilized to track metastasis of subclones within the subject and yield information on polyclonal seeding of metastases, without the selective pressure of a therapy. The entire publication of Echeverria is devoted to supporting that the assay is effective at maintaining a precise and valid correlation between the identity of the cellular subclones as they metastasize by employing the utility of the barcode and detectable marker (pg. 12, Section: Discussion). Please see pg. 2, column 2, para. 2 for an assessment and demonstration of the maintenance of mutant allele frequencies stability during the in vivo serial passaging process.
Hence, the prior art discusses three different methods for assessing cell viability, PRISM for barcode quantification, CellTiter-Glo for ATP measurement, and OPTICAL for fluorescence detection post-isolation, but none of these techniques perform in vivo correlation, as required by claim 12. The references also failed to correlate the barcode, imaging marker, and selection marker simultaneously, addressing only pairwise correlations for general viability assessments.
Furthermore, an ordinary artisan would have recognized that correlating these markers in vivo would have been an expected optimization based on routine practices in high-throughput linage tracing and in vivo imaging studies. Given that researchers routinely co-express barcodes with imaging and selection markers in tumor tracking models, it would have been a logical extension to apply Yu's barcode-fluorescence correlation methods in an in vivo setting, as suggested by Echeverria's in vivo tracking methodologies. Additionally, claim 12 is broad because it does not specify the degree, direction, or statistical significance of the correlation between the barcode, imaging marker, and selection marker. Correlation is statistical terms can range from -1 (perfect negative correlation) to + 1 (perfect positive correlation), with 0 indicating no correlation. Yet, the clam does not define whether the relationship must be strong, weak, positive, or negative.
This means that even a minimal or incidental correlation, whether biologically meaningful or not, would still fall within the scope of the claim, making general observations such as those taught above indistinguishable from the claim's correlation limitations. Moreover, the claim only requires the detectable marker to be suitable for in vivo imaging or cell selection or sorting. Pairwise correlations between different viability indicators (such as those disclosed in Yu and Echeverria) could be interpreted as falling within the claim scope, even if they do not represent a meaningful or functional relationship in vivo. This is because real-world biological systems often contain complex, nonlinear interactions, and the claim does not require a specific statistical confidence threshold (e.g., p-value or R2 value), the claim could be met by correlations that occur randomly without any causal relationship. Thus, the broad scope of the claim further contributes to its obviousness, as even routine experimental variability in marker expression could inadvertently satisfy the claim.
***
Claim 1-6, 10, 12, 15, 22 and claims 74-75 remain rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 10,724,099 B2, prior published US 2015/0044676 A1, Feb. 12, 2015), in view of Echeverria et al. (Nat Commun. 2018 Nov 29;9(1):5079), Marsic et al. (Mol Ther Methods Clin Dev. 2015 Oct 28:2:15041. eCollection 2015), and further in view of Fidler et al. (J Natl Cancer Inst. 1976 Nov;57(5):1199-202.).
The teaching of Yu, Echeverria, and Marsic, as applied to claims 1-6, 10, 12, 15, 22, are set forth above.
Regarding claims 74-75, the combined teachings of Yu, Echeverria, and Marsic render claim 15 obvious.
Furthermore, Yu teaches barcoded cell lines are individually frozen and later thawed to generate mixtures of equal numbers of barcoded cell lines, and injection in equal proportions (column 4, lines 52-57; column 6, lines 42-45).
Although Yu, Echeverria, and Marsic do not expressly teach intracardiac injection of cancer cells, Fidler clearly teaches that tumor cells can be delivered into mice via intracardiac injection and that such a route of administration is a well-established and predictable technique to disseminate tumor cells systematically. Specifically, Fidler demonstrates that intracardiac injection of variant tumor cell lines results in reproducible and quantifiable metastatic colonization across multiple organs, thereby providing direct motivation to employ intracardiac administration when modeling systemic cancer dissemination (Abstract; pg. 1199, column 12, bridging para.; pg. 1201, Discussion Section).
Before the effective filing date, one of ordinary skill in the art would have found it obvious to incorporate the intracardiac route, as taught by Fidler, in order to refine or expand upon the systemic tumor models taught by Yu, Echeverria, and Marsic. The application of this route of administration represents a known and predictable alternative to intravenous injection for achieving systematic delivery of cancer cells, and the substitution of intracardiac injection for intravenous injection constitutes nothing more than the use of a known method to achieve a predicable result.
Response to Applicants' arguments as they apply to the rejection of claims 1-6, 10, 12, 15, 22, and 74-75 under 35 USC§ and 103
Applicant's arguments filed January 22, 2026, have been fully considered but they are not
persuasive.
At pages 8-15 of the remarks filed January 22, 2026, Applicants essentially argue the
arguing:
Applicant argues the examiner relies upon unreasonable hindsight reasoning and points to discrepancy of the instant claims’ recitation of “metastatic potential” versus “metastasis” and “cell lines” versus clonal lineage, “subclones,” or genomic lineage.
Applicants’ arguments are not persuasive because they rely primarily on linguistic distinctions and incorrect definitional reframing, rather than on substantive methodological differences between the claimed steps and the teachings of the prior art. In particular, Applicants argue that the cited references do not expressly use the term “metastatic potential” or define it in terms of “propensity,” and further attempt to distinguish cell lines from genetically distinct subclones or clonal lineages. However, under the broadest reasonable interpretation, metastatic potential is reasonably understood by an ordinary artisan as the relative tendency or likelihood of cancer cells to metastasize to secondary organs, which the prior art demonstrates through differential organ colonization, enrichment, and abundance of genetically distinct cancer populations. For instance, Echeverria teaches the methods utility in characterizing cancer cells from distinct metastatic lesions, in different organs, throughout such as lungs, for instance see pg. 2, column 2, last para.
Likewise, the asserted distinction between cell lines and subclones or cells of different genetic lineage is semantic rather than substantive, as the prior art teaches genetically heterogenous cancer cell populations of different lineage that exhibit differing organ-specific metastatic behavior, for instance see Echeverria, Fig. 3a. Applicants do not identify any claim-recited step that is absent from, or performed differently than, the combined teachings of the prior art, and instead focus on narrowing interpretations based on terminology rather than on concrete procedural limitations.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, Yu does indeed teach towards methodological utility for metastasis cell tracking, as acknowledged by the applicants. While the applicant asserts Yu mentions metastasis cell tracking a single time, the Examiner respectfully submits that patents are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). With
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that, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. See MPEP § 2123: Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989); Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). Moreover, the teachings of Echeverria are directed to characterizing the metastatic potential of genetically and phenotypically distinct cells, cell lines, cell lineages, cell clones, and cell subclones in individually isolated metastatic lesions, as demonstrated in Fig. 3a, and taught throughout Echeverria, for instance See pg. 2 column 1, para. 3-4.
Conclusion
Claims 1-6, 10, 12, 15, 22, and 74-75 are rejected. No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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/J.D.L./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699