DETAILED ACTION
This action is in reply to papers filed 3/1/2024. Claims 2-21 are pending and examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240200023A1, Published 6/20/2024.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 13 is 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.
Claim 13 recites the limitation "the at least two populations of tumor cells" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 13 is separately rejected as being indefinite. This is because the claim recites, inter alia, “…and wherein the at least one population of non-cancerous tissues cells comprises astrocytes, glial cells and endothelial cells.” Note that claim 13 depends on claim 11 which already recites the ‘one or more separate populations of cells…..comprises astrocytes.” It is thus unclear whether the method of claim 13 requires two astrocyte populations- the astrocytes population of claim 11 and the astrocytes population in claim 13.
Clarification is requested.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Prior Art Rejection 1
Claim(s) 2-3, 9-11 and 20-21 are rejected under 35 U.S.C. 103(a)(1) as being unpatentable over Fang et al. (PgPub US20140155292A1, Published 6/5/2014) and Golebiewska et al. (Brain, Volume 136, Issue 5, May 2013, Pages 1462–1475).
Fang teaches that the inability to develop more successful therapies is hampered by insufficient knowledge about the interactions between the multiple cellular components involved in the angiogenesis process and the inability to evaluate angiogenic potential in individual patients. Hence, one of the major problems confronting clinicians today is the ability to assess angiogenic/antiangiogenic therapy effectiveness in a mixed cell environment, such as the mixed cell environment responsible for angiogenesis. Fang teaches the disclosed assays are particularly suited to the investigation of angiogenesis especially in a mixed cell environment, such as a mixed cell environment approximating in vivo conditions (Pg. 11, para. 146).
Towards this end, and with regards to claim 2, Fang teaches three-dimensional models for the study of the complex interactions between different at least three cell types (Pg. 12, para. 156) in a three-dimensional environment. Fang teaches that because the different cell types used are labeled with different fluorescent proteins it becomes easier to image in real time the evolution of the model. It becomes also possible to sort apart the cells and do gene expression analysis on them (Pg. 2, para. 31; Fig. 14) (which reads on labeling the one or more separate populations of cells with a detectable compound to provide one or more labelled populations of cells with each of the one or more labeled populations of cells having a different detectable signal; and combining the one or more labelled populations of cells to form an organoid as recited in claim 2). Also, these 3D models allow for screening of drugs (antiangiogenic, antitumoral, etc) in a more complex in vitro system (which reads on contacting at least one test compound to the organoid; and determining growth, metastasis, and/or amount of cells in the organoid, thereby determining a treatment and/or treatment regimen for the subject as recited in claim 2 and claim 20) (Pg. 3, para. 31, last sentence). Fang teaches a test agent exhibiting such an activity is identified as an inhibitor of angiogenesis and would be of use in treating a disease or condition in which normal angiogenesis is increased, for example cancer (as in claim 21) (Pg. 13, para. 166).
However, Fang fails to teach a tissue sample comprising tumor cells from the subject (as further in claim 2).
Before the effective filing date of the claimed invention, Golebiewska et al. taught
glioblastoma multiforme (as in claim 3) , a grade IV glioma is a deadly tumour for which no curative treatment is available. Typical features of glioblastoma include aggressive proliferation, a strong invasive capacity and extensive angiogenesis within the tumour core. Moreover glioblastoma is known as a highly heterogeneous tumour, both at the cellular and genetic level. Like many solid tumours, brain tumours contain not only neoplastic cells but also a variety of stromal cells. For malignant gliomas, there is conflicting data in the literature with regard to the presence of the side population phenotype, e.g. while efflux properties in glioma cell lines have been described in some reports, they were not confirmed in others. Thus the nature and identity of the side population phenotype in human brain cancer remains elusive (Pg. 1463, paragraph bridging Col. 1-2).
Continuing, Golebiewska teaches that in glioblastoma the blood–brain barrier is disrupted in the tumour core, which is characterized by aberrant vessel morphology and vessel leakiness. The invasive component of the tumour is, however, largely protected from circulating drugs by an intact blood–brain barrier. There is currently little known about efflux properties within glioma vessels. Another unresolved question is whether and how anti-angiogenic agents influence the efflux properties of tumour endothelial cells, and whether a ‘normalized’ vasculature is more or less selective for drug penetration (Pg. 1463, Col. 2, para. 1).
Thus, towards this end, Golebiewska sought to elucidate the phenotypic and functional characterization of the side population phenotype. Golebiewska teaches the side population of the stromal compartment in glioblastoma xenografts contains endothelial cells and A2B5+ astrocytes (as further in claim 2, claim 9, claim 10 and claim 11) (paragraph bridging Pg. 1469 and 1470). Golebiewska teaches the efflux properties of endothelial cells are retained in glioblastoma multiformes following anti-angiogenic treatment, suggesting that drug penetration through the blood–brain barrier may still be hampered by a functional drug-effluxing endothelium. Golebiewska teaches efficient drug delivery is a major concern in glioblastoma treatment, in particular with regard to the highly invasive component of glioblastoma, which is largely shielded by an intact blood–brain barrier. Given the protective role of drug efflux transporters of endothelial cells in the brain, Golebiewska suggests transiently modulating transporter function on endothelial cells may improve drug delivery to target invasive glioblastoma cells (Pg. 1474, Col. 1, para. 1; Abstract).
When taken with the teachings of Golebiewska et al., wherein Golebiewska teaches side populations of GBM have not been fully elucidated, one of ordinary skill in the art would have found it prima facie obvious to modify the teachings of Fang et al. such that the generic cells in their 3D model is substituted for GBM cells and GBM side population cells (astrocytes and endothelial cells) as set forth in Golebiewska et al. The skilled artisan would have been motivated to make such a modification because Fang teaches their model can be used to screen for antiangiogenic therapeutics and Golebiewska teaches targeting endothelial cells as a means of improving drug delivery to target invasive glioblastoma cells.
Thus, the combination would have been prima facie obvious.
Prior Art Rejection 2
Claim(s) 4, 8 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (PgPub US20140155292A1, Published 6/5/2014) and Golebiewska et al. (Brain, Volume 136, Issue 5, May 2013, Pages 1462–1475) as applied to claims 2-3, 9-11 and 20-21 above, and further in view of Sottoriva et al. (Proc Natl Acad Sci U S A. 2013 Feb 14;110(10):4009–4014.)
The teachings of Fang et al. in view of Golebiewska et al. are relied upon as detailed above. However, neither Fang nor Golebiewska teach the glioblastoma cells comprise at least
two different glioblastoma subtypes or are representative of different glioblastoma subtypes (as in claim 4).
Before the effective filing date of the claimed invention, Sottoriva et al. teach glioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure (Abstract).
To characterize intratumor variation at the level of transcription, Sottoriva used microarrays to profile gene expression levels in 51 tumor fragments from 10 patients, 8 of whom were common to the copy number set (Table S1). Hierarchical clustering confirmed patient-specific cancer profiles, with most samples from the same tumor falling into the same cluster, with only three exceptions (sp42T4, sp54T3, and sp56T3). Sottoriva assigned each sample to one of four subtypes: “proneural,” “neural,” “classical,” and “mesenchymal” using the Verhaak classifier. Each subgroup has a characteristic copy number profile, different survival, and variable response to treatment; hence, this classification is believed to be relevant for patient stratification and thus therapy design. Sottoriva found that in 6 of 10 cases (sp42, sp49, sp52, sp54, sp55, and sp56), the fragments from the same tumor mass were classified into at least two different GB subgroups (Fig. 3 A and B) (as in claim 4, claim 8 and claim 12). This indicates that tumor clones with different phenotypic profiles coexist within the same malignancy (Pg. 4011, paragraph bridging Col. 1 and Col. 2).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention , it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Fang et al. in view of Golebiewska et al., wherein the combination teaches a 3D glioblastoma model comprising fluorescently labeled glioblastoma cells and fluorescently labeled side population cells, with the teachings of Sottoriva et al., wherein Sottoriva teaches intratumor heterogeneity likely is the key to understanding treatment failure of glioblastomas. That is, one of ordinary skill in the art would have used the teachings of Sottoriva to identify and then subsequently fluorescently label the subgroups within the glioblastoma of Fang et al. in view of Golebiewska. The skilled artisan would have found it prima facie obvious to do so because Sottoriva states plainly that the intratumor heterogeneity of glioblastoma is likely is the key to understanding treatment failure. Accordingly, to understand treatment failure, the modification would have been prima facie obvious.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 3
Claim(s) 5-7, 14-15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (PgPub US20140155292A1, Published 6/5/2014) and Golebiewska et al. (Brain, Volume 136, Issue 5, May 2013, Pages 1462–1475) as applied to claims 2-3, 9-11 and 20-21 above, and further in view of Fehlauer et al. (Oncology reports 15.1 (2006): 97-105.) and Elhag et al. (Anticancer Res. 2015 Mar;35(3):1263-9.).
The teachings of Fang et al. in view of Golebiewska et al. are relied upon as detailed above. However, neither Fang nor Golebiewska teach the glioblastoma cells are selected from the group consisting of U138MG, U373MG, U87MG, A172 glioblastoma cell lines (as in claim 5).
Before the effective filing date of the claimed invention, Fehlauer notes that in glioma research, four different in vitro culture systems are often used. These include characterized permanent cell lines grown as monolayer, monolayer cultures of single cells with an early or late passage number after initial isolation of uncharacterized cell suspensions, three-dimensional tissue cultures as spheroids derived from a cell line known as cell line spheroids (CLS), and spheroids derived from fresh biopsy-tissue known as organotypic multicellular spheroids. However, Fehlauer notes most experimental data on the response of glioblastoma to irradiation are based on monolayer cultures (paragraph bridging Pg. 102 and Pg. 103; Abstract).
Fehlauer notes that a major advantage of cell lines is that they can be easily obtained, cultured, treated and analyzed with conventional endpoints, such as clonogenic assay. Furthermore, the control and treated samples have the same initial characteristics. Thus, any effects can be attributed to treatment (Pg. 103, Col. 1, para. 1).
Thus, towards this end, Fehlauer used two human glioma cell lines, including the human U87MG cell line (as in claim 5) (Pg. 98, Col. 1, para. 1), cultured as spheroids (as in claim 14 and claim 15) (Pg. 97, Col. 2, last paragraph) to determine the radiosensitizing effect of gemcitabine.
Elhag et al. evaluated the effects of silibinin, a natural plant component of milk thistle seeds, to potentiate toxic effects of chemotherapy drugs such as temozolomide, etoposide and irinotecan on U87 and A172 (PTEN) -mutated) glioma cell lines (as in claim 5, claim 6 and claim 7). Elhag teaches the PTEN mutation makes the cell lines suitable to study aggressive gliomas (Abstract; Pg. 1267, Col. 1, para. 1).
When taken with the teachings of Fang et al. in view of Golebiewska et al. , wherein the combination teaches a 3D glioblastoma model comprising side population cells, one of ordinary skill in the art would have found prima facie obvious to substitute the biopsy tissue of Golebiewska for the U87 or A172 cell lines taught in Fehlauer or Elhag, respectively. A reasonable expectation of success is found in Fehlauer et al. who teach both biopsied tissue and cell lines can be used to derive three dimensional tumor spheroids. Moreover, the skilled artisan would have found it prima facie obvious to use a PTEN mutated U87 and A172 cell line because Elhag teaches the PTEN mutation makes the cell lines suitable to study aggressive gliomas.
Thus, for this purpose, the modification would have been prima facie obvious.
Prior Art Rejection 4
Claim(s) 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (PgPub US20140155292A1, Published 6/5/2014) and Golebiewska et al. (Brain, Volume 136, Issue 5, May 2013, Pages 1462–1475) as applied to claims 2-3, 9-11 and 20-21 above, and further in view of Avci et al. (IEEE Transactions on NanoBioscience, vol. 14, no. 7, pp. 790-796, Oct. 2015).
The teachings of Fang et al. in view of Golebiewska et al. are relied upon as detailed above. However, neither Fang nor Golebiewska teach organoid comprises a core and a shell
that surrounds the core, wherein the core comprises the tumor cells, and the shell comprises at least one population of non-cancerous tissue cells.
Before the effective filing date of the claimed invention, Avci et al. studied a 3D in vitro tumor model with an increased complexity by co-culturing U87 GBM cells as tumor cell origins
and human umbilical vein endothelial cells (HUVEC) as endothelial cell origins, at a 1: 1 ratio (as in claim 19), within a 3D PEGDA-based hydrogel microwell platform to simulate in vivo microenvironment of GBM tumors and investigate whether endothelial cells influence GBM tumor growth and progression (Pg. 781, Col. 1, para. 1; Abstract). As shown in Fig. 2A, at a 1: 1 ratio, the core of the spheroid comprises tumor cells (Blue tracker) and shell of the spheroid comprises endothelial cells (Red tacker) (Pg. 792, Fig. 2) (as in claim 16).
When taken with the teachings of Fang et al. in view of Golebiewska et al. , wherein the combination teaches a 3D glioblastoma model comprising side population cells, including endothelial cells, one of ordinary skill in the art would have found it prima facie obvious to apply the teachings such that the endothelial cells surround the core of glioblastoma cells in the 3D model. The skilled artisan would have found it prima facie obvious to do so in order to mimic the in vivo tumor microenvironment, as set forth in Golebiewska et al.
Allowable Subject Matter
Claims 17 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
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