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 .
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.
Priority
This application, Serial No. 17/266,029 was filed on 02/04/2021, and is a 35 U.S.C. 371 national stage entry of PCT Application No. PCT/JP2019/031328 filed on 08/08/2019. Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on an application filed in Japan on 08/08/2018. Acknowledgement is also made of the English translation filed 09/03/2024 of the application filed in Japan on 08/08/2018.
Status of the Claims
Claims 1, 3-5 and 7-21 are pending, claims 9-20 are withdrawn, claim 21 is newly recited. Claims 1, 3-5, 7-8 and 21 are examined below.
Maintained Rejection
Claim Rejections - 35 USC § 102
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.
Claims 1, 3-5 and 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vlachogiannis et al., Science 359, 920–926 (2018) DOI: 10.1126/science.aao2774 (“Valeri”) as evidenced by Vlachogiannis et al. "Supplementary Materials for Patient-derived organoids model treatment response of metastatic gastrointestinal cancers" Published 23 February 2018, Science 359, 920 (2018) DOI: 10.1126/science.aao2774 (“Valeri-Supplemental”).
Regarding claims 1 and 5, Valeri teaches a culture method (“Patient Derived Organoids model treatment response of metastatic gastrointestinal cancers” Title). Note that as evidenced by Valeri-Supplemental, the Supplemental Materials of the Valeri reference which contain the Materials and Methods section, the patient-derived organoids are cultured (“Establishment and culture of PDOs from GI cancers” page 4). Valeri further teaches that wherein the method comprises: a step of three-dimensionally culturing organoids (Title). Note that as evidenced by Valeri-Supplemental, the organoids are three-dimensionally cultured (“Dissociated cells…resuspended in 120 μl of growth factor reduced (GFR) matrigel (Corning), and seeded in a well of a 24- or 48-well flat bottom cell culture plate (Corning). The matrigel was then solidified” page 4 para. 2). Note that although Valeri-Supplemental fails to use the language “three-dimensionally culturing”, the teaching of using a solid Matrigel as ECM for the culture of the cells inherently provides a 3D culture. Valeri further teaches the organoids being derived from cancer stem cells, wherein the cancer stem cells are derived from colorectal cancer, wherein the cancer stem cells were first treated with at least one anticancer agent, wherein the at least one anticancer agent is one or more anticancer agents that inhibit the growth of cancer cells (“We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials” Abstract, “PDOs presented in this study were derived from ultrasound (n = 20), computed tomography (CT)–guided (n = 7), or endoscopic (n = 2) biopsies of metastatic CRC (mCRC; n = 16), metastatic GOC (mGOC; n = 4), and metastatic cholangiocarcinoma (n = 1) patients (fig. S1). Liver, pelvic, peritoneal, and nodal metastases of chemo-refractory patients were used to establish PDOs” page 1 col. 3 para. 2). Note that although Valeri fails to use the language “derived from cancer stem cells, wherein the cancer stem cells are derived from colorectal cancer, wherein the cancer stem cells were first treated with at least one anticancer agent”, the teaching of using biopsies of chemo-refractory metastasis of colorectal cancer inherently provides the organoid being derived from colorectal cancer stem cells that were first treated with an anticancer agent because the tumor in the colorectal cancer patients are expected to contain colorectal cancer stem cells and since the patient is ”chemo-refractory” the tumor has also been treated with at least one anticancer agent. Note that the specification teaches that chemo-refractory tumors contain cancer stem cells (“As for the reason for resistance, it is assumed that anticancer agent treatment induces a group of cells that have acquired resistance and that manage to survive. However, regarding the origin of cells that acquire resistance, several different theories such as cancer stem cells (CSC) and epithelial mesenchymal transition (EMT) have been advocated” para. 3). Therefore, Valeri inherently teaches the organoids being derived from cancer stem cells, wherein the cancer stem cells are derived from colorectal cancer, wherein the cancer stem cells were first treated with at least one anticancer agent. Furthermore, although Valeri fails to use the language “wherein the at least one anticancer agent is one or more anticancer agents that inhibit the growth of cancer cells”, the teaching of the chemotherapy drugs used in the patients inherently provides the inhibiting of the growth of cancer cells. Note also that table s1 of Valeri contains the information of the chemotherapy agents used in the patients. Table s1 of Valeri has been included in the Valeri-Supplemental reference. As evidenced by Valeri-Supplemental, one of the anticancer agents used was, for example, “Oxaliplatin” (page 48), therefore this anticancer agent inherently provides the inhibiting of the growth of cancer cells (“oxaliplatin” para. 21 of instant spec.). Valeri further teaches a step of recovering the organoids from the three-dimensional culture (Title). Note that as evidenced by Valeri-Supplemental the 3D culture of the organoids involves a step of recovering the organoids from the three-dimensional culture (“Passaging of PDOs was performed using TrypLe. Briefly, PDOs were mechanically harvested (pipetting) out of matrigel” page 4 para. 3). Note that although Valeri-Supplemental fails to use the language “recovering the organoids”, the teaching of harvesting the organoids inherently provides a step of recovering the organoids.
Regarding claims 3 and 7, Valeri further teaches wherein the three-dimensional culturing step comprises allowing the organoids derived from colorectal cancer stem cells previously treated with the at least one anticancer agent to adhere to a first extracellular matrix and culturing by adding a first medium (Title). Note that as evidenced by Valeri-Supplemental, the organoids are allowed to adhere to a first extracellular matrix and are cultured by adding a first medium (“resuspended in 120 μl of growth factor reduced (GFR) matrigel (Corning), and seeded in a well of a 24- or 48-well flat bottom cell culture plate (Corning). The matrigel was then solidified by a 20-minute incubation in a 37 oC and 5% CO2 cell culture incubator, and overlaid with 500 μl of complete human organoid media” page 4 para. 2).
Regarding claims 4 and 8, Valeri further teaches wherein the organoids derived from colorectal cancer stem cells are formed by a pre-culture step of culturing one or more cancer stem cells (Title). Note that as evidenced by Valeri-Supplemental, the organoids are formed by a preculture step of culturing one or more cancer stem cells (“Biopsies were minced … Dissociated cells were collected … resuspended in 120 μl of growth factor reduced (GFR) matrigel (Corning), and seeded in a well of a 24- or 48-well flat bottom cell culture plate (Corning). The matrigel was then solidified by a 20-minute incubation in a 37 oC and 5% CO2 cell culture incubator, and overlaid with 500 μl of complete human organoid media; complete media was subsequently refreshed every two days” page 4 para. 2). Although Valeri-Supplemental fails to use the language “formed by a preculture step of culturing one or more cancer stem cells”, the teaching of seeding biopsy cells on matrigel and changing the media every two days inherently provides the organoids being formed by a pre-culture step of culturing one or more cancer stem cells because the biopsy cells contain cancer stem cells and the organoids are formed as time passes (pre-culture step).
New Rejection
Claim(s) 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mazzocchi et al. SCIENTIFIC Reports | (2018) 8:2886 | DOI:10.1038/s41598-018-21200-8 (“Mazzocchi”) as evidenced by J.-K. Lee, K.-C. Kim/Biochemical and Biophysical Research Communications 438 (2013) 647–652 . http://dx.doi.org/10.1016/j.bbrc.2013.07.128 (“Lee”).
Regarding claim 21, Mazzocchi teaches a culture method (“In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screening” Title, “3D cell culture has been shown to better reproduce in vivo effects, and as a result, are more accurate systems for in vitro cancer modeling…Additionally, integration of bioengineering…resulted in organ-on-a-chip technologies for accurate and addressable testing of compact 3D organoids in parallel” page 2 para. 2, see Figure 1 showing the tumor on a chip culture method), wherein the method comprises culturing cancer stem cells in vitro (Title, “Subject 1 was a 50-yearold male who was diagnosed with epithelioid malignant peritoneal mesothelioma” page 3 para. 2, “subject 1 tumor constructs were biofabricated and maintained for 3 days” page 5 para. 2). Note that although Mazzocchi fails to use the language “culturing cancer stem cells”, the teaching of culturing patient-derived tumor samples inherently provides the culturing of cancer stem cells because tumors tissue contains cancer stem cells according to the instant specification (“The origin of the cancer stem cells of the present disclosure is not particularly limited, but is preferably a human tumor tissue or a human cell line” para. 59). Mazzocchi further teaches incubating the cancer stem cells in the presence of at least one anticancer agent (“Organoids were then subjected to DZNep, a histone methyltransferase EZH2 inhibitor, at concentrations 0.1 μM, 1 μM, and 10 μM in cell culture media for an incubation periods of 96 hours” page 5 para. 2), three-dimensionally culturing organoids derived from the anticancer agent treated cells (an incubation periods of 96 hours” page 5 para. 2). Note that although Mazzocchi fails to use the language “three-dimensionally culturing organoids derived from the anticancer agent treated cells” the teaching of incubating the organoids with the anticancer agent for 96 hours also inherently provides the three-dimensionally culturing of the organoids derived from the anticancer agent treated cells because the incubation step of Mazzocchi also encompasses the culturing of the organoids (see Figure 1d showing the “closed loop fluidic circuit” which permits both the incubation of the anticancer agent and the three-dimensional culturing of the organoids by simply adding the drug to the circulating media), which are derived from cancer stem cells, which were treated with the anticancer agent. Note that the three-dimensionally culturing step is not limited to the exclusion of a concurrent incubation step, therefore, the adding of the drugs to the circulating media for 96 hours (4 days) provides the incubation step and subsequent culturing step. Mazzocchi further teaches recovering the organoids from the three-dimensional culture (“Drug effects were quantified by…IHC staining of Annexin V versus Ki67” page 5 para. 2, “5 μm thick organoid sections were created from paraffin-embedded constructs, and then deparaffinized for staining. IHC was used to visualize biomarkers cytokeratin 5/6 (CK5/6), calretinin, and thrombomodulin…to the sections on the slides” page 10 para. 4). Note that although Mazzocchi fails to use the language “recovering the organoids from the three-dimensional culture” the teaching of embedding the organoids in paraffin, cutting the organoids in 5 μm thick sections, mounting the sections on a slide, deparaffinizing the sections and staining the sections, inherently provides a step of recovering the organoids from the three-dimensional culture because these steps necessarily involve the recovering of the organoids from the three-dimensional culture. Mazzocchi further teaches wherein the at least one anticancer agent is one or more anticancer agents that inhibit the growth of cancer cells (“DZNep…EZH2 inhibitor” page 5 para. 2). Note that as evidenced by Lee, DZNep is an anticancer agents that inhibit the growth of cancer cells (“3-Deazaneplanocin A (DZNep), an epigenetic anticancer drug… We confirm that DZNep induced growth inhibition and increased the dead cell population of lung cancer cells” Abstract).
Response to Arguments
Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive.
Regarding the 102 rejections,
Applicant argues that “the fact that a patient received chemotherapy does not assure that the particular cells removed by biopsy and subsequently cultured were themselves exposed to, or had been directly treated by, the named anticancer agent such that the cells "were first treated with at least one anticancer agent."… Metastatic tumors are heterogeneous and biopsies sample a subset of cells which may or may not include cells exposed to or having been in contact with a particular drug. Under inherency doctrine, possibility or probability is insufficient. The Examiner must show inevitability. Valeri describes biopsy processing and culture methods (Matrigel seeding, passaging, etc.), but it does not identify or measure, for the cultured cells, the claimed antecedent step of in vitro or in vivo exposure to specific anticancer agents such that exposure is a necessary attribute of the cells used to form the PDOs. Absent such disclosure or corroborating evidence, inherency cannot be presumed” (page 7 paras. 2-4).
However, contrary to Applicant’s arguments, the fact that a patient received chemotherapy inherently provides the treating of the cancer stem cells within the cancer in the patient because the purpose of the chemotherapy is to treat the cancer in the patient. Note that the claim broadly recites “wherein the cancer stem cells were fist treated with at least one anticancer agent”. The specification fails to define the term “treating” or “treatment”. The recited treatment is not limited to a direct contacting or exposure of the anticancer agent to the cancer stem cells and thus encompasses a treatment that may be via a clinical chemotherapy intervention in vivo. Therefore, using the broadest reasonable interpretation of the claim as currently recited in light of the specification, the biopsy cells obtained from the patient who received chemotherapy would reasonably inherent the chemotherapy treatment done in vivo. Indeed, the specification seems to acknowledge that biopsy samples from patient who received chemotherapy are considered to be an example of cancer stem cells that were first treated with at least one anticancer agent (“Among these various cancer treatment techniques, the use of anticancer agents is still one of the major options. In the treatment of cancer with anticancer drugs (chemotherapy), acquisition of anticancer agent resistance by cancers is one of the major causes hindering treatment, and elucidation of the mechanism is awaited… As for the reason for resistance, it is assumed that anticancer agent treatment induces a group of cells that have acquired resistance and that manage to survive. However, regarding the origin of cells that acquire resistance, several different theories such as cancer stem cells (CSC) and epithelial mesenchymal transition (EMT) have been advocated, but there is still a great deal of ongoing debate” paras. 2-3, “In addition, the anticancer agent may be a compound administered to a living body” para. 23, “In the culture method of the present disclosure, a cancer tissue generated in a cancer lesion can be cultured after being treated with an anticancer agent. For example, a cancer tissue in a surgically-resected cancer lesion, or a structure containing cancer stem cells formed in the cancer lesion, can also be cultured using a culture method of the present disclosure” para. 38). The 102 rejection is therefore maintained. No claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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