Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
1. The amendment filed 10/07/2025 has been entered. Claims 1 – 5 remain pending and are under consideration.
Priority
2. This is a divisional application of U.S. Patent Application No. 13/519,059, filed June 25, 2012, which is the U.S. National Stage of International Application No. PCT/JP2010/073266, filed December 24,
10 2010, which in tum claims the benefit of Japanese Patent Application No. 2009-295426, filed December 25, 2009.
Withdrawn Specification Objection
3. The objection to the specification is withdrawn in view of Applicant’s amendment to the specification.
Withdrawn Claim Objections
4. The objection to claim 3 is withdrawn in view of Applicant’s amendment to the claim.
5. The objection to claim 4 is withdrawn in view of Applicant’s amendment to the claim
Withdrawn Claim Rejections
6. The rejection of claims 1 – 5 under 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of Applicant’s amendment to the claims to recite “mouse model”.
7. The rejection of claims 1 – 2 and 4 under pre-AIA 35 U.S.C. 102(a)(b) is withdrawn in view of Applicant’s amendment to recite “the mouse model comprises fibroblasts derived from the human tumor tissue in a tumor stroma”.
8. The rejection of claims 1 – 3 and 5 under pre-AIA 35 U.S.C. 102(a)(b) is withdrawn in view of Applicant’s amendment to recite “the mouse model comprises fibroblasts derived from the human tumor tissue in a tumor stroma”.
9. The rejection of claims 1 – 5 under pre-AIA 35 U.S.C. 103(a) is withdrawn in view of Applicant’s amendment to recite “the mouse model comprises fibroblasts derived from the human tumor tissue in a tumor stroma”.
Claim Interpretation
10. For the purpose of applying prior art, claim 2 is interpreted as the non-human animal model of claim 1 where the human cancer tissue has cancer stem cells.
11. For the purpose of applying prior art, claim 3 is interpreted as the non-human animal model of claim 1 where the human cancer tissue has cells that undergo EMT.
12. For the purpose of applying prior art, claim 4 is interpreted as the non-human animal model of claim 1 where the human cancer tissue has resistance to an anti-cancer agent.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
13. Claim 1 – 5 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Fujii (Fujii et al., Pathology International, 58:559-567, 2008; previously cited), hereinafter Fujii which is cited on the IDS filed 11/22/2022 as evidenced by Dalerba (Dalerba, Piero, et al. Proceedings of the National Academy of Sciences 104.24 (2007): 10158-10163; previously cited), hereinafter Dalerba which is cited on the IDS filed 11/22/2022 as evidenced by Vincan (Vincan, Elizabeth, et. al. Clinical & experimental metastasis 25.6 (2008): 657-663; previously cited), hereinafter Vincan in view of Qian (Qian, Li-Wu, et al. Cancer letters 190.1 (2003): 105-112), hereinafter Qian in view of Miyamoto (Miyamoto, Hidenori, et al. Pancreas 28.1 (2004): 38-44.), hereinafter Miyamoto.
Regarding claim 1 and 5, Fujii teaches a NOG mouse model (“mouse model” of claim 1) obtained by transplanting into a NOG mouse a NOG established cancer cell line established by transplanting human tumor tissue from lung, breast, pancreas, stomach or large intestine (“colon cancer”, “stomach cancer”, “breast cancer”, “lung cancer”, “pancreatic cancer” of claim 5) into a NOG mouse (“NOG-established cancer cell line” of claim 1) (Abstract; page 559, right col. last paragraph; page 560, left col. and right col. paragraph 1 – 2; Table 1 – 2; page 561, right col. last paragraph; page 565, right col. paragraph 1 – 2; page 566, left col. paragraph 3 and right col. paragraph 1). Fujii teaches well-, moderately, and poorly differentiated tumor tissue lines of adenocarcinoma of the large intestine were established and respective ductal, papillary, and nest-like structures were observed similar to the original surgical specimens and mesenchymal tumor tissue lines also showed the characteristics of the original tumors (“hierarchical organization or cancer progression of a human cancer tissue” of claim 1) (page 563, left col. paragraph 1; Figure 1 – 3). Fujii does not teach the NOG mice comprise fibroblasts derived from the human tumor tissue in a tumor stroma of claim 1.
Regarding claim 2, Fujii teaches an established tissue line preserves the characteristics of a specific tumor type in vivo in the NOG mouse and therefore can be widely utilized as a human tumor model that preserves the biological characteristics of the original tumor (page 566, left col. paragraph 3). Fujii teaches colorectal tumors were the most readily established epithelial tumor type (page 562, left col. paragraph 1; page 565, right col. paragraph 1-2). Colorectal tumor tissue either from primary tissues from surgical specimens or xenografts established in immunodeficient mice contains cancer stem cells that can be detected by the expression of surface markers such as EpCAM and CD166 and isolated and their tumorigenicity evaluated in mice as evidenced by Dalerba (Abstract; page 10158, right col. paragraph 2; page 10159, left col. paragraph 2 – 3). Therefore, Fujii’s NOG mouse model of colorectal cancer meets the limitations of claim 2.
Regarding claim 3, Fujii teaches an established tissue line preserve the characteristics of a specific tumor type in vivo in the NOG mouse and therefore can be widely utilized as a human tumor model that preserves the biological characteristics of the original tumor (page 566, left col. paragraph 3). Fujii teaches colorectal tumors were the most readily established epithelial tumor type (page 562, left col. paragraph 1; page 565, right col. paragraph 1-2). Colorectal cancer cells undergo EMT during the progression of the disease where tumor cells with more mesenchymal properties are interspersed with the stroma (page 658, left col. paragraph 2; page 660, left col. paragraph 1). Therefore, Fujii’s NOG mouse model of colorectal cancer meets the limitations of claim 3.
Fujii does not teach the NOG mice comprise fibroblasts derived from the human tumor tissue in a tumor stroma of claim 1 or the mouse models enable assessment of a cause of anti-cancer agent resistance of claim 4. However, Fujii teaches although partial loss of interstitial tissue was observed in most of the established tissue lines, the interstitium was relatively well preserved (page 563, left col. para. 1). Fujii teaches while 6 primary pancreas tumor tissue engrafted, no pancreas tumor tissue originating from a metastatic site (other than lymph node) engrafted in NOG mice (Table 1 – 2). Fujii teaches that human solid tumors can be successfully engrafted into the NOG mouse and that tissue lines with the characteristics of the original tumors can be established (Abstract). Fujii teaches with the third-generation tissue specimens there were no changes in differentiation compared to the first-generation xenograft tissue (page 562, right col. last para.). Fujii teaches the engraftment of surgically excised human tumor tissues into immunodeficient mice is an alternative model that better preserves the characteristics of the original tumor and established tissue lines derived from such tissues would enable use on demand and provide a powerful tool in the field of tumor biology (page 564, left col. para. 1). Fujii teaches tumor models play a key role in efficacy studies for the development of anti-tumor therapeutics (page 1, right col. paragraph 1). Fujii teaches understanding the biological characteristics of a tumor model is essential for utilization of the model research (page 560, left col. paragraph 1).
Regarding claim 1, Qian teaches co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts that produce HGF could initiate an apparent invasion-stimulating response in c-Met producing pancreatic cancer cell lines (Abstract; page 110, right col. para. 1). Qian teaches primary fibroblasts were isolated from pancreatic cancer patients where the diagnoses were invasive ductal carcinoma (page 106, right col. para. 2). Qian teaches co-culturing of fibroblasts f1 that secrete HGF significantly increased the invading cell number of pancreatic cancer cell lines that overexpress c-Met but not in pancreatic cancer cell lines that weakly express c-Met (page 109, right col. para. 2; Figure 2; Table 1). Qian teaches co-culturing fibroblasts f2 that do not secrete HGF did not significantly increase the number of invading pancreatic cancer cells in c-Met overexpressing pancreatic cancer cell lines (page 109, right col. para. 2; Figure 2; Table 1). Qian teaches the mutual interaction between pancreatic cancer cells and orthotopic tumor-derived fibroblasts have not been clarified yet (Abstract). Qian teaches the results may help unveil the more complicated mutual modulation in vivo between pancreatic cancer and host mesenchymal tissues (Abstract). Qian teaches the adenocarcinomas of the pancreas often exhibit a strong stromal reaction and it is not clear if this process benefits the host to localize the tumor or protects the tumor (page 105, right col.; page 106, left col. para. 1). Qian teaches HGF is a stromal-derived cytokine that elicits strong mitogenic activities on pancreatic cancer cells in vivo and in vitro and the HGF receptor c-Met is expressed in various malignant cells including pancreatic carcinoma (page 106, left col. para. 2). Qian teaches fibroblasts have been shown to be deeply involved in tumor proliferation as they hold an ability to produce cytokines that influence their neighboring cells including malignant cells (page 110, right col. para. 1). Fujii does not teach the mouse models enable assessment of a cause of anti-cancer agent resistance of claim 4. One would have been motivated to combine the teachings of Fujii and Qian because Fujii teaches no pancreatic tumor tissue from metastatic sites engrafted and Qian teaches paracrine HGF from tumor stroma affects the tumor’s behavior such as invasion and metastasis (page 106, left col. para. 2).
Regarding claim 4, Miyamoto teaches pancreatic cancer is one of the major causes of cancer-related deaths and it is known that pancreatic cancer is resistant to chemotherapy and that cancer cells are surrounded by extracellular matrix (ECM) proteins including collagen I and IV, fibronectin, and laminin (Abstract). Miyamoto teaches pancreatic cancer cell lines adhering to ECM proteins show decreased cytotoxicity of anticancer drugs (Abstract; Figure 1 – 6; Table 2; page 43, right col. last para.; page 44, left col. para. 1). Miyamoto teaches the expression of ECM proteins in pancreatic cancer specimens could provide valuable information to aid anticancer drug cytotoxicity (Abstract; page 44, left col. para. 1). Miyamoto teaches pancreatic cancer has the potential to produce ECM proteins and is composed of infiltrating adenocarcinoma surrounded by stroma containing fibroblasts (page 38, right col. para. 3; page 42, right col. para. 2). Miyamoto teaches these fibroblasts may transform into an activated myofibroblast-like state and synthesize collagen, fibronectin, and laminin (page 42, right col. para. 2). Miyamoto teaches one of the difficulties in the treatment of pancreatic cancer is likely due to the composition of ECM proteins deposited by pancreatic cancers (page 44, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Fujii regarding a mouse model of human cancer with the teachings of Qian regarding fibroblasts derived from human tumor tissue enhance cancer cell invasion with the teachings of Miyamoto regarding pancreatic cancer is resistant to chemotherapy and ECM protein involvement to arrive at the claimed model where the model comprises fibroblasts derived from the human tumor tissue in a tumor stroma. One would have been motivated to combine the teachings of Fujii, Qian, and Miyamoto in a mouse model of cancer to investigate the role of tumor stroma on anti-cancer drug resistance as Fujii teaches the engraftment of surgically excised human tumor tissues into immunodeficient mice is an alternative model that better preserves the characteristics of the original tumor and established tissue lines derived from such tissues would enable use on demand and provide a powerful tool in the field of tumor biology and Qian teaches the mutual interaction between pancreatic cancer cells and orthotopic tumor-derived fibroblasts have not been clarified yet and Qian teaches the adenocarcinomas of the pancreas often exhibit a strong stromal reaction and it is not clear if this process benefits the host to localize the tumor or protects the tumor and Qian teaches the results may help unveil the more complicated mutual modulation in vivo between pancreatic cancer and host mesenchymal tissues and Miyamoto teaches the expression of ECM proteins in pancreatic cancer specimens could provide valuable information to aid anticancer drug cytotoxicity and Miyamoto teaches one of the difficulties in the treatment of pancreatic cancer is likely due to the composition of ECM proteins deposited by pancreatic cancers. One would have a reasonable expectation of success in combining the teachings as Fujii teaches that human solid tumors can be successfully engrafted into the NOG mouse and that tissue lines with the characteristics of the original tumors can be established and Qian teaches fibroblasts have been shown to be deeply involved in tumor proliferation as they hold an ability to produce cytokines that influence their neighboring cells including malignant cells and Miyamoto teaches pancreatic cancer has the potential to produce ECM proteins and is composed of infiltrating adenocarcinoma surrounded by stroma containing fibroblasts.
Applicant’s Arguments/ Response to Arguments
14. Applicant Argues: On page 5, para. 3 – 5 and page 6 – 7, Applicant traverses the rejection of claims 1 – 3 and 5 because the cited art does not teach the new limitation of amended claim 1.
Response to Argument: The previous rejection of the claims has been withdrawn and a new rejection is set forth above. Fujii teaches although partial loss of interstitial tissue was observed in most of the established tissue lines, the interstitium was relatively well preserved (page 563, left col. para. 1) but does not teach human fibroblasts in the mouse tumor stroma. However, Fujii does teach the presence of human fibroblasts derived from the human tumor tissue in the first-generation xenografts (page 563, left col. last para. and right col. para. 1; page 566, left col. para. 5). In the new rejection, Qian teaches co-cultivation of pancreatic cancer cells with pancreatic patient tumor-derived fibroblasts that produce HGF could initiate an apparent invasion-stimulating response in c-Met producing pancreatic cancer cell lines (Abstract; page 110, right col. para. 1; page 106, right col. para. 2). Qian teaches co-culturing of fibroblasts f1 that secrete HGF significantly increased the invading cell number of pancreatic cancer cell lines that overexpress c-Met but not in pancreatic cancer cell lines that weakly express c-Met (page 109, right col. para. 2; Figure 2; Table 1). Qian teaches the mutual interaction between pancreatic cancer cells and orthotopic tumor-derived fibroblasts have not been clarified yet (Abstract). Qian teaches the results may help unveil the more complicated mutual modulation in vivo between pancreatic cancer and host mesenchymal tissues (Abstract). Qian teaches the adenocarcinomas of the pancreas often exhibit a strong stromal reaction and it is not clear if this process benefits the host to localize the tumor or protects the tumor (page 105, right col.; page 106, left col. para. 1). Qian teaches HGF is a stromal-derived cytokine that elicits strong mitogenic activities on pancreatic cancer cells in vivo and in vitro and the HGF receptor c-Met is expressed in various malignant cells including pancreatic carcinoma (page 106, left col. para. 2). Qian teaches fibroblasts have been shown to be deeply involved in tumor proliferation as they hold an ability to produce cytokines that influence their neighboring cells including malignant cells (page 110, right col. para. 1). Therefore, one of ordinary skill in the art would have been motivated to include human tumor stroma containing fibroblasts in the mouse model to establish a mouse model of metastatic pancreatic cancer because Fujii teaches while 6 primary pancreas tumor tissue engrafted, no pancreas tumor tissue originating from a metastatic site (other than lymph node) engrafted in NOG mice (Table 1 – 2).
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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