DETAILED ACTION
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 .
The Amendments and Remarks filed 11/14/25 in response to the Office Action of 8/15/25 are acknowledged and have been entered.
Claims 1, 3, 8-11, 14-16, and 18 are pending.
Claims 1 and 14 have been amended by Applicant.
Claims 1, 3, 8-11, 14-16, and 18 are currently under examination.
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 Office Action contains a new rejection Necessitated by Amendments.
Rejections Withdrawn
The rejection under 35 U.S.C. 103 is withdrawn; however, a new rejection under 35 U.S.C. 103 necessitated by amendments is set-forth below.
New Rejections
Claim Rejections - 35 USC § 103
Claim(s) 1, 3, 8-11, 14-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Francies et al (Methods in Molecular Biology, 2019, 156: 339-351; first published online 9/15/16; see https://link.springer.com/protocol/10.1007/7651_2016_10) in view of Sandercock et al (Molecular Cancer, 2015, 14(147): 1-18), Wei et al (Acta Pharmac Sinica, 2015, 36: 241-251), Abou-Alfa et al (JAMA, 2010, 304(19): 2154-2160), Dai et al (Molecular Cancer Therapeutics, 2016, 15(12): 2966-1976), Seo (Current Cancer Therapy Reviews, 2015, 11: 82-93), Li et al (Cancer Letters, 2012, 318: 154-161), Affo et al (Annu Rev Pathol Mech Dis, 2017, 12: 153-186), Huch Ortega et al (WO 2015/173425 A1; 11/19/15), and Plotnikov et al (Cell, 1999, 98: 641-650).
Francies et al teaches method of determining drug sensitivities of human organoid cultures comprising obtaining cancer cells, establishing a cancer culture with the cells, mixing the cancer culture with a culture medium (“BME-2”) forming mini cancers, growing the mini cancers, dividing the mini cancers into one or more samples (including 322 samples, as illustrated by Figure 2), adding one or more agents to the one or more samples, analyzing cell viability of mini cancers treated with the one or more agents and cell viability of reference mini cancer cells treated negative controls and DMSO/vehicle only (“without addition of one or more agents”) (Figures 1-2 and pages 344-346, in particular). Francies et al further proposes performing individualized patient cancer through modeling of drug sensitivity in patient-derived cancer organoids (second full paragraph on page 340, in particular). BME-2 of Francies et al comprises the polymers collagen and heparin (as evidenced by https://www.sigmaaldrich.com/US/en/technical-documents/protocol/cell-culture-and-cell-culture-analysis/mammalian-cell-culture/membrane-extract-type-2). Further, Francies et al teaches extracellular matrix components (including the extracellular matrix (ECM) polymers collagen and heparin sulfate proteoglycan) of BME-2 are found in an interface between a number of cell types and adjacent stroma (see Notes on page 347, in particular).
While Francies et al teaches methods of determining drug sensitivities of the mini cancers by measuring cell “viability”, Francies et al does not specifically mention “growth” inhibition or “invasion” inhibition, Francies et al does not describe a chemotherapy as being identified for treatment of a subject, Francies et al does not teach the cancer cells as liver cancer cells, Francis does not mention endothelial cells or fibroblasts, and Francies et al does not teach the recited cell culture media. Further, Francies does not specifically describe cells as “autologous.” However, these deficiencies are made up in the teachings of Sandercock et al, Wei et al, Abou-Alfa et al, Dai et al, Seo, Li et al, Affo et al, Huch Ortega et al, and Plotnikov et al.
Sandercock et al teaches analyzing effects of treating cancer cell organoids with therapeutic agents, wherein the effects include per-organoid size (same as “growth”) and invasion inhibition (right column on page 6 and Figure 3, in particular).
Wei et al teaches therapeutic effects of the agent sorafenib on liver cancer cells include inhibition of proliferation and inhibition of invasion (Abstract, in particular).
Abou-Alfa et al teaches synergistic therapeutic benefit from administering liver cancer patients a combination of the agent sorafenib and the chemotherapeutic doxorubicin (Abstract, in particular).
Dai et al teaches co-administration of the agent ascochlorin in combination with the chemotherapeutic doxorubicin can enhance the therapeutic inhibition of invasion, therapeutic inhibition of metastasis, and therapeutic inhibition of liver tumor growth, as compared to administration of doxorubicin alone (Figure 5, Abstract, and page 2967, in particular).
Seo teaches fibroblasts, extracellular matrix, and endothelial cells in the liver cancer tumor microenvironment (TME) influence liver cancer cells in vivo (see last paragraph of left column on page 83 and right column on page 84, right column on page 87, paragraph spanning columns of page 84, and Figure 1, in particular). Regarding cancer-associated fibroblast cells and HCC (the most common type of liver cancer), page 83 of Seo et al teaches “…cancer-associated fibroblasts (CAFs),which are a specialized group of fibroblasts in cancer, can significantly promote the growth and invasion of tumor cells in various cancers….CAFS are extremely critical components of the HCC microenvironment because most HCC cases are derived from fibrosis and cirrhosis…Chuang et al demonstrated that co-culture of HCCs and CAFs in vitro can enhance proliferation, migration, and invasion of HCCs….” Regarding endothelial cells, page 84 of Seo et al teaches “…endothelial cells form a continuous and uniform monolayer in normal tissues and express various receptors of angiogenic factors…Activation of receptors in endothelial cells trigger several signal cascades to regulate survival, proliferation, and invasion…The growth of liver cancer requires the formation of new blood vessels, and VEGF is critical factor in angiogenesis. VEGF expression is up-regulated in most of human HCC…VEGF affects endothelial cells to promote neovascularization in HCC, and the VEGF/VEGFR network may stimulate the growth of liver tumor cells.” At the left column on page 88 of Seo, endothelial cells co-cultured with HCC tumor cells and fibroblasts are taught to include human umbilical vascular endothelial cells (HUVECs). Seo further teaches generating multicellular tumor spheroid models (MCTS) comprising liver tumor cells, the extracellular matrix polymer collagen, and other cells of the tumor microenvironment (including fibroblasts and endothelial cells) that “remarkably recapitulate the 3D cellular environment and has pathophysiological relevance like in vivo tumors” as a tool to mirror tumor complexity and heterogeneity for anticancer research (page 88 and Figure 1, in particular). Seo further teaches such models “will offer a new paradigm for high-throughput drug screening and will significantly improve the efficacy of identifying new drugs for liver cancer treatment” (page 88, in particular). The left column on page 83 of Seo further teaches cancer associated fibroblasts affect tumor progression through enhancement of expression of factors that include bFGF (bFGF is the same as “FGF2”). Seo et al further cites studies using patient-derived (“autologous”) HCC-associated human fibroblasts (first full paragraph of the right column on page 83 citing Li et al and see “isolation of fibroblasts and cell culture” on page 155 of Li et al, in particular) and teaches studies using human endothelial cells (see HUVECs at right column on page 89, in particular).
Affo et al teaches the extracellular matrix (ECM) polymer collagen (of Francies et al and the multicellular tumor spheroid models (MCTS) of Seo comprising liver tumor cells) is found to be increased within the liver cancer tumor microenvironment (TME) and increases in such ECM components result in phenotypic and behavioral changes in epithelia, tumor, and stomal cells (see first paragraph on page 160 and last paragraph on page 161, in particular).
Huch Ortega et al teaches components of media used to culture liver cells include: HGF, FSK, FGF10, gastrin (same as “Gastrin I”), NAC (N-Acetylcysteine), B27 supplement, N2, Nicotinamide, Wnt3A-conditioned media (same as “Wnt CM (home-made prepared as described in [Barker and Huch 2010]).”, R-spondin1-conditioned media (same as “RSPO1 conditioned media”), EGF, Noggin, A83-01, FGF10, and Y27632 (see Example 12, in particular). Huch Ortega et al further teaches such components further include a prostaglandin pathway activator such as PGE2 (lines 5-6 on page 84 and paragraph spanning pages 19-20, in particular). Regarding “FGF2”, Huch Ortega et al teaches including a FGF in the media that “is preferably an FGF able to bind FGFR2 or FGFR4” (lines 1-10 on page 11, in particular). While Example 12 of Huch Ortega et al uses FGF10 in the media as an FGF able to bind FGFR2 or FGFR4, Plotnikov et al teaches FGF2 is an FGF known to bind FGFR2 (first full paragraph of right column on page 641, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to provide individualized liver patient cancer care through modeling of drug sensitivity in human patient-derived cancer organoids by performing a combined method comprising the method of Francies et al wherein the cells of the human organoid cultures include human cells from a biopsy (“autologous”) of a patient with liver cancer (as opposed to colorectal or esophageal cancer cells), the mini cancers are assayed for inhibition of growth of the mini cancers and inhibition of invasion alongside the inhibition of viability of Francies et al, wherein the agents include sorafenib, ascochlorin, and doxorubicin, and wherein a combination of (i) sorafenib and doxorubicin or (ii) ascochlorin and doxorubicin is chosen and administered to treat liver cancer patients with mini-cancers exhibiting inhibition of viability, growth, and/or invasion in response to treatment with (i) sorafenib and doxorubicin or (ii) ascochlorin and doxorubicin, as compared to reference mini cancer cells treated negative controls and DMSO/vehicle only (“without addition of one or more agents”) because Francies et al proposes performing individualized patient cancer through modeling of drug sensitivity in patient-derived cancer organoids, the method of Francies et al models drug sensitivity in cancer organoids, inhibition of viability, growth, and invasion are therapeutic responses from agents taught to be measured in cancer cells organoids, including autologous fibroblastast from the patient and human endothelial cells and extracellular matrix provides an organoid culture with parameters found in vivo because Seo teaches fibroblasts, extracellular matrix, and endothelial cells in the liver cancer tumor microenvironment (TME) influence liver cancer cells in vivo, and cited art teaches liver cancer patients can be provided therapeutic benefit from the administration of the combination of (i) sorafenib and doxorubicin or (ii) ascochlorin and doxorubicin.
Further, should a subject of the combined method stop responding or have a recurrence of cancer, one of skill in the art would have been motivated to repeat the combined method and administer any additional agent identified as inhibiting viability, growth, and/or invasion of mini cancers of the patient because cancers are known to become non-responsive and are known to recur and the combined method identifies agents that demonstrate therapeutic benefit to subjects with cancer.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein just any amounts of just any combination of cells and/or other components found in the human patient’s liver cancer tumor microenvironment TME (including a combination cells consisting of a 1:1 ratio of “autologous” cancer-associated fibroblasts from the patient and human vascular endothelial cells of Seo and/or li et al and including the ECM polymer collagen of Affo et al and Francies et al) of the biopsy are added to the cancer culture of liver cancer cells (equivalent of mixing a cancer culture with a “matrix” and forming complex mini-cancers, wherein the matrix comprises a combination of the ECM polymer collagen and cells found in the liver cancer TME) prior to forming the mini cancers because Affo et al teaches the extracellular matrix (ECM) polymer collagen (of Francies et al and the multicellular tumor spheroid models (MCTS) of Seo comprising liver tumor cells) is found to be increased within the liver cancer tumor microenvironment (TME) and increases in such ECM components result in phenotypic and behavioral changes in epithelia, tumor, and stomal cells, Seo teaches such cells of the TME influence liver cancer cells in vivo (see last paragraph of left column on page 83 and right column on page 84, right column on page 87, paragraph spanning columns of page 84, and Figure 1, in particular), Seo teaches models comprising both liver tumor cells and other cells of the TME “remarkably recapitulate the 3D cellular environment and has pathophysiological relevance like in vivo tumors” as a tool to mirror tumor complexity and heterogeneity for anticancer research, and Seo teaches such models “will offer a new paradigm for high-throughput drug screening and will significantly improve the efficacy of identifying new drugs for liver cancer treatment”.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the cultured liver cells of the combined method are not maintained in the colorectal or esophageal cancer cell culture medium of Francies et al, but are maintained in a cell culture media that comprise just any combination of components of the liver cell culture media of Huch Ortega et al (including those recited by instant claims) because Huch Ortega et al teaches each component of instant claims culture medium as components of media used to culture liver cells and explains how each component functions.
Further, one of ordinary skill in the art would have been motivated, with an expectation of success, to perform the combined method wherein the cell culture media used to maintain the cultured liver cells of the combined method comprises an FGF that is FGF2 because Huch Ortega et al teaches including a FGF in media used to culture liver cells that “is preferably an FGF able to bind FGFR2 or FGFR4” (lines 1-10 on page 11, in particular) and Plotnikov et al teaches FGF2 is an FGF known to bind FGFR2 (first full paragraph of right column on page 641, in particular). It is further noted that FGF2 would predictably be present in the media of the combined method because the culture of the combined method comprises cancer associated fibroblasts and Seo teaches cancer associated fibroblasts affect tumor progression through enhancement of expression of factors that include bFGF (bFGF is the same as “FGF2”).
Further, one of skill in the art would recognize that combined methods wherein the only cells co-cultured with the liver cancer cells are cancer-associated fibroblasts and endothelial cells would produce a reduced-variability drug response profile relative to a matrix containing additional tumor microenvironment cell types because such additional tumor microenvironment cell types represent additional variables.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
It is acknowledged that page 25 of Huch Ortega et al teaches that in some embodiments FGF2 is absent from an expansion media; however, such a teaching does not “teach away” from the use of FGF2 in media of the combined method. A “prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Also, see MPEP 2123.
Conclusion
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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/SEAN E AEDER/ Primary Examiner, Art Unit 1642