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 .
Applicant's amendments to the claims and arguments filed on 07-22-2025 have been received and entered. Claims 1, 6, 13 have been amended. Claims 8-10, 19-21 have been canceled. Claims 1-7, 11-18, 22-25 are pending and under consideration.
Priority
This application is a 371 of PCT/JP2020/003159 filed on 01/29/2020 that claim priority from foreign applications JAPAN 2019-014778 filed on 01/30/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Withdrawn-Claim Rejections - 35 USC § 101
Claims 6-7, 13-18 and 22 were rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. In view of Applicants' amendment of base claim 6 and 13, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 6-7 and 13-18 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Petersen et al (Science. 2010 Jul 30;329(5991):538-41. doi: 10.1126/science.1189345. Epub 2010 Jun 24.). In view of Applicants' amendment of base claim 6 and 13, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained in modified formed-Claim Rejections - 35 USC § 103 - Necessitated by amendments
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 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.
Claims 1-7, 11-18, 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Vega (Dissertation, August, 2018, Development and Utilization of a Bioengineered 3D Human Lung Model to Study Pathogenesis of Lung Disease, The University of Texas Medical Branch at Galveston, https://hdl.handle.net/2152.3/10717) as evidenced by WikiLectures (https://www.wikilectures.eu/w/Immunocompetent_cells) in view of Onn et al (Clinical Cancer Research, Vol. 9, 5532–5539, November 15, 2003, )
Claim interpretation:
The specification of the claimed invention teaches the idea that a cancer model having a three-dimensional structure and reproducing a naturally-occurring cancer can be produced by once recellularizing using normal cells and then seeding cancer cells, rather than by a method for producing a recellularized organ by seeding cancer cells in a decellularized organ, and found that an artificial lung that reflects the histopathological findings of naturally-occurring lung cancer, that is, that reproduces naturally-occurring lung cancer, can be produced when the lung is used as the organ (see [0008], page 4). Thus, the cancer model is interpreted to be produced by seeding/injecting cancer cells on normal cells of lung organ instead of recellularizing organ by seeding cancer cells in a decellularized organ.
The specification of the claimed invention teaches when adenocarcinoma cells were used, a nodule was found at the site where the cells were introduced, a grand duct-like structure which is a histopathologic finding of adenocarcinoma was formed, and the cells contained mucus ([0013], page 9, lines 2-6). Thus, the phenotype of a nodule, a grand duct-like structure and mucus are inherent properties of adenocarcinoma formation.
The specification of the claimed invention teaches PC-9 cells, which are adenocarcinoma cells are used, cancer cells with round nuclei and bright cytoplasm form cell aggregates with septa. However, when H520 cells, which are squamous carcinoma cells, are used, cancer cells with oval nuclei without cytoplasm proliferated to replace alveolar septa, and the pathological image was clearly different from that using PC-9 cells. Suitable cancer cells can be appropriately selected according to the type of cancer to be treated (see [0013], page 9, lines 9-17). Thus, adenocarcinoma cells have phenotype of cancer cells with round nuclei and bright cytoplasm form cell aggregates with septa, and squamous carcinoma cells have phenotype of oval nuclei without cytoplasm proliferated to replace alveolar septa.
It is noted that the specification of the claimed invention does not define the phrase “immunocompetent cells” in a limiting way. The phrase “immunocompetent cells” is only mentioned once in paragraph [0014] on page 9 : “In addition, since a recellularized organ or tissue does not contain immunocompetent cells, any cell can be easily engrafted regardless of the type of organ or tissue. Therefore, the recellularized organ or tissue to be used in the present invention is not particularly limited, and includes heart, kidney, liver, lung, pancreas, bowel, muscle, skin, breast, esophagus, trachea, tissues thereof and the like.” ([0014], page 9). According to the art, WikiLectures, Immunocompetent cells mediate the immune response by two groups: 'non-specific immunity cells' - granulocytes and macrophages and (ii) 'cells of specific immunity' - T- and B-lymphocytes. Thus, the phrase “re-cellularized organ or tissue lacks immunocompetent cells” is interpreted as lacking immune cells.
Regarding to claims 1, 2 Vega teaches development and utilization of a bioengineered 3d human lung model to study pathogenesis of lung disease (Title). Vega also teaches production of human whole organ constructs by utilizing primary cells isolated from discarded whole human lungs as a cell source to re-cellularize whole acellular human lung scaffolds with the goal of bioengineering whole pediatric lungs (Page 73, 1st para., chapter 3). Rat acellular whole lung scaffolds have been shown to support attachment of neonatal rat lung epithelial cells and microvascular lung endothelial cells, A549 cells (lung adenocarcinoma cells), rat fetal lung cells and HUVEC (Page 14, 1st para.).
It is noted that Vega generated acellular (no cell) whole lung scaffolds and recellularized whole acellular human lung scaffolds with neonatal rat lung epithelial cells and microvascular lung endothelial cells which are not immune cells/ immunocompetent cells (see the paragraph above) . The specification of the claimed invention specifically used the same type of cells for recellularization with cancer cells: “The alveolar epithelial cells and vascular endothelial cells that were perfused during recellularization were engrafted to reproduce the normal alveolar structure while maintaining the alveolar structure of the decellularized scaffold (Fig. 4). In addition, both adenocarcinoma cells and squamous carcinoma cells were engrafted on the recellularized lung (Fig. 6)” (see the instant disclosure [0056], page 27-28). Thus, there is no immunocompetent cells added to the acellular human lung scaffolds (the recellularized organ or tissue lacks immunocompetent cells). Since Vega do not seed immunocompetent cells into acellular whole lung scaffolds, person of ordinary skill in the art would not look for and add immunocompetent cells into acellular whole lung scaffolds. Furthermore, Vega teaches that “our assessments of the immunogenicity of AC (acellular scaffold) lung scaffolds revealed that scaffolds produced with 1% SDS, did not elicit the activation of T-cells or the production of proinflammatory chemokines.” (Page 71, 2nd para.). Thus, Vega concerned about immunogenicity of acellular lung scaffolds and provided guidance for assessments immunogenicity to achieve no induction of an immune response. A person of ordinary skill in the art would know to not induce an immune response by not using immunocompetent cells in acellular lung scaffolds.
Although Vega teaches the use of lung adenocarcinoma cells such as A549 cells to generate bioengineering whole pediatric lungs (Page 8, 1st para) and the method of injecting primary human alveolar epithelial cells into the human lung scaffold piece (Page 52, 2nd para), Vega does not teach introducing a cancer cell into normal cells by injection, of organ such as lung to generate cancer model. However, Onn et al cure the deficiency.
Onn et al teach development of an orthotopic model to study the biology and therapy of primary human lung cancer (Title). Human lung adenocarcinoma (PC14PE6), bronchioloalveolar carcinoma (NCI-H358), squamous cell carcinoma (NCI-H226), poorly differentiated non-small cell lung cancer (NCI-H1299 and A549), or small cell lung cancer (NCI-H69) cells in Matrigel were injected percutaneously into the left lungs of nude mice (see Abstract) (For the claimed: by injection (introducing a cancer cell into normal cells)).
Onn et al teach immunohistochemical analysis of thoracic tumors: Thoracic tumors were examined for expression of several proangiogenic factors including bFGF, IL-8, and VEGF/VPF. The pleural effusion producing adenocarcinoma (PC14PE6) tumors expressed higher levels of VEGF/VPF as compared with IL-8 and bFGF. These three factors were also expressed by the bronchioloalveolar tumors (NCI-H358), although to similar degree (Fig. 2) (Page 5537, bridging last para. from left column to right column) (For the claimed: thereby obtaining a cancer model that shows a histopathologic finding
characteristic for the cancer from which the introduced cancer cell is derived).
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Vega by injecting lung cancer percutaneously into normal cells of the lungs as taught by Onn et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Onn et al teach that the orthotopic models of human lung cancer confirm the “seed and soil” concept and likely provide more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies (see abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Onn et al concluded that they have developed in vivo models of primary lung cancer for both human NSCLC and human SCLC, which are reproducible, well tolerated, feasible, and straightforward to perform. These lung cancer models closely mimic the patterns observed for the natural progression of primary lung cancer from a single nodule to disseminated disease, and enables study of novel therapeutics and better understanding of lung cancer metastasis (See page 5538, right column, last para.).
Regarding to claims 3, 4, 11 Vega teaches table 1.1 provided commonly used cell types for production of respiratory tract models, including human lung adenocarcinoma alveolar basal cell line (A549) (Page 24, Table 1.1).
Regarding to claims 5, 12 Vega teaches upon establishing appropriate cell installation protocols for recellularization, pediatric whole acellular lung scaffolds were recellularized using primary human lung tracheal/bronchial epithelial cells, alveolar epithelial cells and endothelial cells (Page 73, 1st para., chapter 3).
Regarding to claims 6-7, 13-18, Vega teaches development and utilization of a bioengineered 3d human lung model to study pathogenesis of lung disease (Title). Vega demonstrated that whole acellular pediatric lung scaffolds and cells isolated from discarded human lungs can be used to bioengineer whole-organ constructs with functional characteristics similar to native human lungs. Small-scale human lung constructs can also be developed and used as models for repetitive standardized testing. The 3D bioengineered human lung construct is composed of human acellular lung scaffold and primary or immortalized human lung cells isolated from donor lung tissue. Vega provided data to support the ability of this 3D engineered human lung construct to be used as an in vitro model to examine early pathological changes associated with acute lung injury and initiation of pulmonary fibrosis (PF) (Abstract). Additionally, Onn et al teach that the present model recapitulates the local and regional growth pattern seen in lung cancer patients, i.e., from a solitary nodule to a diffuse thoracic disease involving both lungs and the lymph nodes (Page 5532, right column, last paragraph bridging to page 5533), and Fig. 1C: the solitary nodules surrounded by a normal lung developed several days after injection of tumor cells with Matrigel, which anchored them and prevented cell suspension spread (Page 5534).
Furthermore, The specification of the claimed invention teaches that “when adenocarcinoma cells were used, a nodule was found at the site where the cells were introduced, a grand duct-like structure which is a histopathologic finding of adenocarcinoma was formed, and the cells contained mucus” ([0013], page 9, lines 2-6). Thus, the phenotype of a nodule, a grand duct-like structure and mucus are inherent properties of adenocarcinoma formation according to the specification of the claimed invention. According to MPEP 2112 (II) inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)
Regarding to claim 21-23, as discussed above in the interpretation, the specification of the claimed invention teaches when adenocarcinoma cells were used, a nodule was found at the site where the cells were introduced, a grand duct-like structure which is a histopathologic finding of adenocarcinoma was formed, and the cells contained mucus ([0013], page 9, lines 2-6). When adenocarcinoma cells are used, cancer cells with round nuclei and bright cytoplasms form cell aggregates with septa. Suitable cancer cells can be appropriately selected according to the type of cancer to be treated (see [0013], page 9, lines 9-17). Since both Vega and Onn et al teach the use of adenocarcinoma (such as adenocarcinoma alveolar basal cell line A549 which is the same cell line used by the claimed invention), it is inherent that adenocarcinoma cells would have the same phenotypes required by the claims. Thus, it is a matter of choice for a person of ordinary skill in the art to select and use adenocarcinoma cell line such as A549 to arrive at the invention as required by the claims.
Regarding to claim 24, it should be noted that as discussed above in the interpretation, the specification of the claimed invention teaches when squamous carcinoma cells, are used, cancer cells with oval nuclei without cytoplasms proliferated to replace alveolar septa. Suitable cancer cells can be appropriately selected according to the type of cancer to be treated (see [0013], page 9, lines 9-17). Regarding to requirements of claim 24, Onn et al teach squamous cell carcinoma (NCI-H226) (see abstract), and Onn et al developed models of each of the most common lung cancer histological types including adenocarcinoma, squamous cell, bronchioloalveolar, and small cell. For each tumor type, lesions develop after direct injection of a tumor cell suspension into the thorax of the mouse, making it a reproducible technique to study either NSCLC or SCLC human tumors (Page 5532, right column, last para.). Thus, it is a matter of choice for a person of ordinary skill in the art to select and use squamous cell carcinoma to arrive at the invention as required by the claims.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Vega (Dissertation, August, 2018, Development and Utilization of a Bioengineered 3D Human Lung Model to Study Pathogenesis of Lung Disease, The University of Texas Medical Branch at Galveston, https://hdl.handle.net/2152.3/10717) as evidenced by WikiLectures (https://www.wikilectures.eu/w/Immunocompetent_cells) in view of Onn et al (Clinical Cancer Research, Vol. 9, 5532–5539, November 15, 2003, ) as applied to claims 1-7, 11-18, 21-24 above, and further in view of Murakami et al (Lung Cancer 83 (2014) 30–36, Doi: 10.1016/j.lungcan.2013.10.011).
The teachings of Vega and Onn et al above are incorporated herein in their entirety.
Regarding to claim 25, Vega and Onn et al do not teach the use of anticancer drug on a cancer model. Murakami et al teach effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model (title). Murakami et al teach Fig. 2. Effects of AZD1480 on PC-9 (adenocarcinoma cells) xenograft tumors (Page 33).
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references with treating lung cancer model with anticancer drug such as AZD1480 as taught by Murakami et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Murakami et al teach the effect of AZD1480 on survival was demonstrated (Fig. 5B). The median survival time in the AZD1480-treated group (217 days) was almost twice that in the control group (106 days) (Page 35, right column, last para). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Murakami et al were successful in using anticancer drug on lung cancer model to demonstrate the efficacy of the drug on lung cancer treatment with detailed instructions and data.
Response to Arguments
Applicant's arguments filed 07-22-2025 have been fully considered but they are not persuasive.
1. Applicant argues that Vega allegedly teaches that rat acellular whole lung scaffolds have been shown to support attachment of A549 cells, rat fetal lung cells and HUVEC, citing page 14, first paragraph of Vega. As previously explained in Applicant's submission of February 13, 2025, the A549 cells were perfused through trachea and dispersed homogeneously, extending from large to small airways, terminal bronchioles, alveolar ducts and alveoli, using ventilation with cell culture medium. Engraftment and formation of an epithelial monolayer by culture day 5 was observed throughout the entire lung constructs. Thus, A549 cells were not used as cancer cells for producing a cancer model that mimics naturally-occurring cancer tissue (e.g., formation of nodule, grand duct-like structure, accumulation of mucus, etc.). Instead, the A549 cells were employed as epithelial cells for forming an epithelial monolayer throughout the entire lung construct. Vega merely teaches use of A549 cells as a material for forming epithelial monolayer in the preparation of recellularized lung tissue. The recellularized lung containing A549 cells disclosed in Vega cannot be used as a cancer model, such as an adenocarcinoma model.
The Office cites Onn to allegedly "cure the deficiency" of Vega. Yet, one of ordinary skill would not have combined the teachings of the reference as suggested by the Office. According to the Office, Onn discloses the development of an orthotopic model to study the biology and therapy of primary human lung cancer. Onn's model is an in vivo model, whereas the system of Vega is an ex vivo model. Generation and maintenance of an ex vivo cancer model employing a recellularized organ or tissue is far removed from implantation of tumors into a living system such as described in Onn. One of ordinary skill would not have considered adjusting the teachings of Vega based on Onn to be a simple combination of "elements according to known methods to yield predictable results." The distinct systems have different considerations and technical challenges such that one of ordinary skill would not equate the two systems (Remarks, page 7).
Response to Arguments:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case:
Applicant argue that A549 cells were not used as cancer cells for producing a cancer model that mimics naturally-occurring cancer tissue. However, Vega stated that “natural lung-derived AC (acellular scaffold) lung scaffolds already contain the desired anatomical structures and morphological structures that provide an adequate 3D configuration and biological cues that facilitate production of tissue-engineered lung tissue” (Page 15, 1st para).
Applicant argue that the recellularized lung containing A549 cells disclosed in Vega cannot be used as a cancer model, such as an adenocarcinoma model. However, Vega specifically teaches “development and utilization of a bioengineered 3d human lung model to study pathogenesis of lung disease” (title), and stated that “We have developed a decellularization procedure for native human lungs to produce whole human acellular (AC) lung scaffolds that contain the desired anatomical structures and morphological structures that provide a 3D configuration and biological cues that facilitate production of tissue-engineered lung tissue ……can be used to bioengineer whole-organ constructs with functional characteristics similar to native human lungs ” (see page iv and v), and “Some studies have used transformed cell lines derived from cancerous lung tissue (e.g. A549) for development of tissue-engineered 3D lung cancer models.” (page 8, 1st para).
Applicant argue that Onn discloses the development of an orthotopic model to
study the biology and therapy of primary human lung cancer. Onn's model is an in vivo
model, whereas the system of Vega is an ex vivo model. However, Vega also teaches transplantation of the bioengineered left lung into a porcine animal model (in vivo) (see page 108-109). Vega also stated that “Our results indicated that all pigs who received a bioengineered lung transplant, had development of collateral vessels indicating the development of systemic circulation. This collateral systemic circulation aided in survival of transplanted bioengineered lungs…… Bioengineered lungs contained well-developed bronchial and alveolar epithelium. We found that the overall cell numbers present in bioengineered lungs increased in pigs survived for 10 hours to 2 months” (Page 117, 2nd para). Additionally, Onn et al teach development of an orthotopic model to study the biology and therapy of primary human lung cancer (Title). Human lung adenocarcinoma (PC14PE6), bronchioloalveolar carcinoma (NCI-H358), squamous cell carcinoma (NCI-H226), poorly differentiated non-small cell lung cancer (NCI-H1299 and A549), or small cell lung cancer (NCI-H69) cells in Matrigel were injected percutaneously into the left lungs of nude mice (see Abstract). One of ordinary skill in the art would have been motivated to combine the teaching of Vega and Onn et al because Onn et al teach that their model provides more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies (see abstract). Onn et al concluded that they have developed models of primary lung cancer for both human NSCLC and human SCLC, which are reproducible, well tolerated, feasible, and straightforward to perform. These lung cancer models closely mimic the patterns observed for the natural progression of primary lung cancer from a single nodule to disseminated disease, and enables study of novel therapeutics and better understanding of lung cancer metastasis (See page 5538, right column, last para.).
2. Applicant argues that the rationale proposed for modifying the teachings of the references is arrived upon only through use of impermissible hindsight reconstruction. In this regard, the Office alleges that one of ordinary skill would be motivated to adjust the teachings of the references as proposed by the Office because "Onn et al teach that the orthotopic models of human lung cancer confirm the "seed and soil" concept and likely provide more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology... " (emphasis in original). Action, page 13. Yet, the passage referenced by the Office merely describes a concept underlying metastases, cancer cells ("seed") travel to organs having an environment which is compatible with metastases ("soil"). There is no hint or suggestion in Onn as to what type of environment is compatible for metastases or how an environment could be recapitulated in an ex vivo model. Onn provides no predictable basis for arriving at the instantly claimed invention, even when taken with Vega.
Response to Arguments:
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, one of ordinary skill in the art would have been motivated to combine the teaching of Vega and Onn et al because Onn et al teach that their model provides more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies (see abstract). Moreover, Onn et al teach viable tumor cells were harvested and established in vitro, and viable cells were harvested and reinjected into the lungs of nude mice (Page 5536, left column, last para.). Thus, one of ordinary skill in the art would be able to harvest, establish in vitro and inject lung cancer into a lung model. Additionally, Vega already provided evidence for successful growth of a cancer cell such as A549 cells in ex-vivo environment (see Figure 3.6 on page 99), and since Onn et al also teach cancer cell such as A549 for injection for developing lung cancer model (see abstract), it is expected that cancer cell such as A549 would be able to grow and develop in ex-vivo model.
3. Applicant argues that neither Vega nor Onn (nor Murakami) discloses or suggests recellularizing an organ or tissue with normal cells such that the recellularized organ or tissue lacks immunocompetent cells and introducing a cancer cell or fibroblast into the recellularized organ or tissue via injection, and the references certainly do not suggest the inventive ex vivo cancer model that mimics an in vivo cancer model achieved by the instant invention (remarks, Page 8).
Response to Arguments:
Applicant argues that neither Vega nor Onn (nor Murakami) discloses or suggests recellularizing an organ or tissue with normal cells such that the recellularized organ or tissue lacks immunocompetent cells. This is found not persuasive because Vega teach injecting primary human alveolar epithelial cells (normal cells) into the human lung scaffold piece (Page 52, 2nd para). Additionally, as explained above in the claim interpretation, the specification of the claimed invention does not define the phrase “immunocompetent cells” in a limiting way. According to the art, WikiLectures, Immunocompetent cells mediate the immune response by two groups: 'non-specific immunity cells' - granulocytes and macrophages and (ii) 'cells of specific immunity' - T- and B-lymphocytes. Thus, the phrase “re-cellularized organ or tissue lacks immunocompetent cells” is interpreted as lacking immune cells. Additionally, it is noted that Vega generated acellular (no cell) whole lung scaffolds and recellularized whole acellular human lung scaffolds with neonatal rat lung epithelial cells and microvascular lung endothelial cells which are not immune cells/ immunocompetent cells (see the paragraph above) . Since Vega do not seed immunocompetent cells into acellular whole lung scaffolds, person of ordinary skill in the art would not look for and add immunocompetent cells into acellular whole lung scaffolds. Moreover, the specification of the claimed invention specifically used the same type of cells for recellularization with cancer cells: “The alveolar epithelial cells and vascular endothelial cells that were perfused during recellularization were engrafted to reproduce the normal alveolar structure while maintaining the alveolar structure of the decellularized scaffold (Fig. 4). In addition, both adenocarcinoma cells and squamous carcinoma cells were engrafted on the recellularized lung (Fig. 6)” (see [0056] of the instant disclosure , page 27-28). Thus, there is no immunocompetent cells added to the acellular human lung scaffolds (the recellularized organ or tissue lacks immunocompetent cells). Furthermore, Vega teaches that “our assessments of the immunogenicity of AC (acellular scaffold) lung scaffolds revealed that scaffolds produced with 1% SDS, did not elicit the activation of T-cells or the production of proinflammatory chemokines.” (Page 71, 2nd para.). Thus, Vega concerned about immunogenicity of acellular lung scaffolds and provided guidance for assessments immunogenicity to achieve no induction of an immune response. A person of ordinary skill in the art would know not to induce an immune response by not using immunocompetent cells in acellular lung scaffolds.
4. Applicant argues that Regarding claims 6 and 13, the Office has not established that the combination of teachings of the cited references render obvious an ex vivo cancer model wherein a nodule is formed at the site where the cancer cell is introduced. The Office states on page 11 that "the phenotype of a nodule, a grand duct-like structure and mucus are inherent properties of adenocarcinoma formation," but bases this assertion on the teachings of the instant specification. There is nothing in the cited references leading one of ordinary skill in the art to the particular method of generating the ex vivo cancer model of the instant invention and, as such, there is no teaching of suggestion of an ex vivo cancer model resulting from the method which comprises a nodule
In addition, one of ordinary skill would not have had a reasonable expectation of success in arriving at the instantly claimed subject matter in view of the cited references. The Office merely states that one of ordinary skill would have had a reasonable expectation of success because Onn describes various advantages of its in vivo model. Yet, as explained above, in vivo models and ex vivo models are different. It would not have been predictable based on the cited references that any advantage reported by Onn could be achieved using an ex vivo model. It was the applicant which first generated an ex vivo cancer model which mimics in vivo effects (remarks, Page 8).
Response to Arguments:
Onn et al teach that the present model recapitulates the local and regional growth pattern seen in lung cancer patients, i.e., from a solitary nodule to a diffuse thoracic disease involving both lungs and the lymph nodes (Page 5532, right column, last paragraph bridging to page 5533), and Fig. 1C: the solitary nodules surrounded by a normal lung developed several days after injection of tumor cells with Matrigel, which anchored them and prevented cell suspension spread (Page 5534).
Furthermore, The specification of the claimed invention teaches that “when adenocarcinoma cells were used, a nodule was found at the site where the cells were introduced, a grand duct-like structure which is a histopathologic finding of adenocarcinoma was formed, and the cells contained mucus” ([0013], page 9, lines 2-6). Thus, the phenotype of a nodule, a grand duct-like structure and mucus are inherent properties of adenocarcinoma formation according to the specification of the claimed invention. According to MPEP 2112 (II) inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Also, as explained above, Vega also teaches in vivo model of bioengineered lung: transplantation of the bioengineered left lung into a porcine animal model (in vivo) (see page 108-109). Vega also stated that “Our results indicated that all pigs who received a bioengineered lung transplant, had development of collateral vessels indicating the development of systemic circulation. This collateral systemic circulation aided in survival of transplanted bioengineered lungs…… Bioengineered lungs contained well-developed bronchial and alveolar epithelium. We found that the overall cell numbers present in bioengineered lungs increased in pigs survived for 10 hours to 2 months” (Page 117, 2nd para). One of ordinary skill in the art would have been motivated to combine the teaching of Vega and Onn et al because Onn et al teach that their model provides more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies (see abstract). Onn et al concluded that they have developed models of primary lung cancer for both human NSCLC and human SCLC, which are reproducible, well tolerated, feasible, and straightforward to perform. These lung cancer models closely mimic the patterns observed for the natural progression of primary lung cancer from a single nodule to disseminated disease, and enables study of novel therapeutics and better understanding of lung cancer metastasis (See page 5538, right column, last para.). Thus, it appears that the applicant was not the first generated an ex vivo cancer model which mimics in vivo effects.
According to MPEP 716.01(c), Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. The examiner can normally be reached M-F (9-5).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, PETER PARAS can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632