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 .
Claims 1-20, of record 11/14/2023, are pending and subject to prosecution.
Priority
The applicant’s claim for foreign priority to application 202211066571.6, filed 9/1/2022 in China, is not accompanied by a certified copy of the foreign application. The earliest priority date to which the instant application is entitled is therefore considered to be 8/27/2023.
Drawings
The drawings are objected to because the text in fig. 1, 7, 10, 17, and 21-22 is too small or blurry to be reproduced and because reference characters must be legible. See 37 CFR 1.84(l) and 37 CFR 1.84(p). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term NSG, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 8-10 and 17 are objected to because of the following informalities:
In claim 8, the commas in line 2-3 should be deleted. Additionally, the article “a” should be inserted in front of “solid tumor tissue”.
In claims 9-10, the phrase “said sorting” in line 2 should be followed by “method”.
In claim 17, the article “a” should be deleted in line 1.
Appropriate correction is required.
Claim Interpretation
The limitation “immunoregulating drug” in claims 16 and 19 is not defined in the instant specification. The broadest reasonable interpretation of this limitation is therefore considered to be any agent capable of modulating an immune response.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “fresh tumor tissues”. The instant specification does not define “fresh”, and it is unclear whether “fresh” relates only to any primary cells or whether it relates to a particular timing following removal from a subject. Because the metes and bounds of the claim are not clear, the claim is indefinite. Dependent claims 2-20 are included in the rejection.
Claim 12 recites “a percentage of enriched cells”. It is unclear whether the enriched cells are encompassed by the cells of claim 1 or whether they are required in addition to the cells of claim 1.
Claim 14 contains the trademark/trade name NSG. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an immunodeficient mouse and, accordingly, the identification/description is indefinite.
Claim 17 recites the limitation “wherein a flow cytometry measures cellular expression of 7AAD…”. 7-AAD is a fluorescent DNA-intercalating dye that is not expressed by cells, therefore a skilled artisan would be unable to determine the metes and bounds of the claim. Further, the instant specification recites the use of antibodies to 7-AAD (See ¶0096 of the application’s PG Pub), however, an internet search does not reveal the existence of antibodies targeting 7-AAD.
Claim 19 is directed to a method but recites no active steps. The claim is indefinite because it attempts to claim a process without setting forth any steps involved in the process. It would be remedial to amend the claim to recite a method of generating an animal model for the rapid screening of an immunoregulating drug, comprising implanting the capsule of claim 1 into an immunodeficient mouse.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7-10, 13-14, 16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (US 20190154663 A1) in view of Pu et al. (Journal of Translational Medicine, 2018).
Regarding claims 1-4, 8-10, 13, and 19: Wen et al. teach a method for screening drugs comprising implantation of fresh, primary tumor cells into an animal (See Abstract). The primary tumor cells can be obtained from a patient sample, such as a tumor biopsy sample or a surgically removed sample (See ¶0034 and 0048). The tumor cell can be derived from any type of tumor, including tumors of the blood system (See ¶0035). The sample can be implanted in a tubular device (which reads on “capsule tube”) comprised of PVDF having a 500000 Da MWCO (which reads on “average protein permeability of the capsule tube is around 300-1,000 kDa, or 500-700 kDa”) (See ¶0017 and 0041). The device can be implanted subcutaneously and can be implanted into mice (See ¶0041 and 0043). In an embodiment, the tumor cells are digested and passed through a mesh screen (which reads on “single cell suspension”) (See ¶0036 and 0050-0051). The digested cells were sorted using anti-CD45 and anti-fibroblast magnetic beads prior to implantation (See ¶0036 and 0053). The drugs screened by this method included everolimus (which reads on “immunoregulating drug”) (See fig. 9). The animal for implantation can be a nude or SCID (which reads on “immunodeficient”) mouse (See ¶0004). Wen et al. do not expressly teach the presence of immune cells in the cell sample.
Pu et al. teach the composition of patient-derived tumor xenografts transplanted into immunodeficient mice (See Abstract). Tumor-infiltrating lymphocytes—B cells and CD4+ and CD8+ T cells—from patients were detected in the clinical samples following transplantation and persisted through passaging on multiple animals (See Abstract, table 1, and fig. 1). Pu et al. suggest that the xenografts comprising tumor and stromal cells as well as immune cells may preserve the immune microenvironments of human cancers and might be used for evaluating anticancer immunotherapies and the functionality of immune components within tumor microenvironments (See page 7, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Wen et al. to comprise the inclusion of tumor-infiltrating lymphocytes in the implantable device. One would be motivated to make this modification because Pu et al. teach that their presence in xenografts may preserve the tumor microenvironment and enable evaluation of anticancer therapies and functionality of immune components (See page 7, col. 1, full ¶1 and page 10, col. 1, full ¶2). There would be a reasonable expectation in making this modification because immune cells present in tumor tissues could be readily included with tumor cells in an implantable device.
Regarding claim 14: Following the discussion of claims 1-4, 8-10, 13, and 19, Wen et al. teach the use of immunodeficient mice as the animal receiving the transplanted cells but do not teach NSG mice.
Pu et al. teach transplantation of patient-derived xenografts into NSG mice (See page 2, col. 2, full ¶1).
It would have been obvious to one having ordinary skill in the art to further modify the method of Wen et al., modified by Pu et al., to comprise the use of NSG mice. One would be motivated to make this modification because its use by Pu et al. suggests that it is appropriate for implanting human tumor tissue for analysis. There would be a reasonable expectation of success in doing so because NSG mice could be readily used.
Regarding claim 16: Following the discussion of claims 1-4, 8-10, 13, and 19, Wen et al. teach a method of screening the efficacy of chemotherapeutic drugs by implanting patient tumor cells in a device into mice (See Abstract). The drug can be in the form of a solid, semisolid, or liquid (See ¶0038). Following implantation and drug treatment, the implants were recovered for analysis of the cells by ATP quantification CellTiter-Glo assay (which reads on “detecting molecular biological information” and “total cell viability… is detected by a chemiluminescence method”) (See ¶0059-0061). Wen et al. do not expressly teach analysis of immune cells by flow cytometry.
Pu et al. teach flow cytometry for characterizing tumor-infiltrating lymphocytes recovered from xenografts (See fig. 1-4).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Wen et al. to comprise flow cytometry for the recovered immune cells, such as is taught by Pu et al. One would be motivated to make this modification because Pu et al. teach that it can be used to determine immune cell subtypes (See page 4, col. 2, full ¶1). There would be a reasonable expectation of success in doing so because immune cells recovered from the implanted device could be readily characterized by flow cytometry.
Regarding claim 18: Following the discussion of claims 1-4, 8-10, 13, 16, and 19, Wen et al. teach that the candidate drug can be administered orally (which reads on “oral gavage”) or by intravenous or subcutaneous injection (See ¶0014 and 0039).
Claims 1-5, 7-10, 13-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (US 20190154663 A1) in view of Pu et al. (Journal of Translational Medicine, 2018), further in view of Hollingshead (WO 1994025074 A1).
The teachings of Wen et al. and Pu et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 5: Following the discussion of claims 1-4, 7-10, 13-14, 16, and 18-19, Wen et al., modified by Pu et al., render obvious the implantation of tumor and immune cells in a PVDF capsule. Wen et al. teach pretreatment of the PVDF by immersion, rinsing, and high-pressure sterilization (which reads on “autoclaving”) (See ¶0058) but do not expressly teach activation or flushing with water.
Hollingshead teaches the transplantation of cells such as tumor xenografts in a semi-permeable microencapsulation device (See page 1, line 7-14 and page 6, line 1-12). The device can comprise PVDF fibers prepared by autoclaving, incubating in 70% ethanol (which reads on “activating”), and a sterile water rinse (See page 6, line 28-33 and page 7, line 20-29).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Wen et al., modified by Pu et al. to comprise the PVDF capsule pretreatment method taught by Hollingshead. One would be motivated to make this modification because its use by Hollingshead suggests that it is an appropriate method for preparing PVDF encapsulation devices for the implantation of cells. There would be a reasonable expectation of success in doing so because the capsule of Wen et al. could be readily prepared by activation in ethanol and rinsed with water.
While Hollingshead does not expressly teach the use of ultrapure water, deionized water is used for flushing and preparing other types of tubing (See page 7, line 32-34 and page 8, line 5-6) and could be readily substituted as the source of sterile water. The use of sterile deionized water would read on “ultrapure water”.
Regarding claims 15 and 20: Following the discussion of claims 1-4, 7-10, 13-14, 16, and 18-19, Wen et al., modified by Pu et al., render obvious the implantation of tumor and immune cells in a PVDF capsule but do not expressly teach the implantation of multiple capsules in an animal.
Hollingshead teaches that multiple cell lines or types (which reads on “cells that can be derived from different patients”) can be implanted into a single animal and that an animal can receive multiple implants (which reads on “the number of capsule tubes is 2-8”) (See page 10, line 17-28).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Wen et al., modified by Pu et al., to comprise multiple implants in one animal, such as is taught by Hollingshead. One would be motivated to make this modification because Hollingshead et al. teaches that this approach can be used to screen chemotherapeutic agents against multiple cell lines in a single animal and requires a smaller quantity of the agents than has been historically required (See page 2, line 12-14 and line 30-35 and page 3, line 1-3). There would be a reasonable expectation of success in doing so because multiple capsules could be readily implanted into each mouse.
Claims 1-10, 13-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (US 20190154663 A1) in view of Pu et al. (Journal of Translational Medicine, 2018), further in view of Hollingshead (WO 1994025074 A1), further in view of Mizuno et al. (WO 2022174077 A1).
The teachings of Wen et al., Pu et al., and Hollingshead are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 6: Following the discussion of claims 1-5, 7-10, 13-16, and 18-20, Wen et al., modified by Pu et al. and Hollingshead, render obvious the implantation of tumor and immune cells in a PVDF capsule that has been activated with 70% ethanol but do not teach the use of dehydrated alcohol.
Mizuno et al. teach cell transplantation for promoting intervertebral disc regeneration (See Abstract). In one model, cells were placed in membrane pouches made from 500 kDa PVDF tubing that had been immersed for 30 min in 200 proof ethyl alcohol (which reads on “rinsing the tube in dehydrated alcohol”) (See page 9, line 28-32).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Wen et al., modified by Pu et al. and Hollingshead, to substitute 200 proof ethanol, as taught by Mizuno et al., for 70% ethanol for activating the PVDF membrane. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results.
Claims 1-4, 7-14, 16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (US 20190154663 A1) in view of Pu et al. (Journal of Translational Medicine, 2018), further in view of Balch et al. (Archives of Surgery, 1990).
The teachings of Wen et al. and Pu et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 11-12: Following the discussion of claims 1-4, 7-10, 13-14, 16, and 18-19, Wen et al., modified by Pu et al., render obvious the implantation of tumor and immune cells in a PVDF capsule but do not expressly teach the specific composition of cells.
Balch et al. teach immune cell compositions of multiple types of human cancers (See Abstract and table 1-2). Cell viability in the tumors exceeded 80% (See page 200, col. 2, full ¶3). The percentage of tumor-infiltrating lymphocytes among total tumor cells ranged between 30-65%, with the majority of the lymphocytes being CD3+ in most tumors (which reads on “a ratio of tumor cells to CD3+ T immune cells in a range from 1.5:1 to 15:1, or 1.5:1 to 9:1”) (See page 201, col. 2, full ¶3 and table 1-2). The percentage of CD8+ T cells in the lymphocytes ranged between 18-57% (which reads on “the percentage of CD8+ T cells to total live cells is from 0.5% to 15%”) (See table 2).
It would have been obvious to one of ordinary skill in the art to modify the method of Wen et al., modified by Pu et al., to comprise the ratios of tumor cells to T cells taught by Balch et al. One would be motivated to make this modification because Balch et al. teach these ratios as representative of various actual human tumors (See Abstract), which that suggests similar ratios in experimental conditions may allow recapitulation of tumor microenvironments. There would be a reasonable expectation of success in making this modification because the cells could be readily prepared prior to implantation.
Claims 1-4, 7-10, 13-14, and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (US 20190154663 A1) in view of Pu et al. (Journal of Translational Medicine, 2018), further in view of Regev et al. (US 20210171938 A1) and Schmid et al. (Journal of Immunological Methods, 2000).
The teachings of Wen et al. and Pu et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 17: Following the discussion of claims 1-4, 7-10, 13-14, 16, and 18-19, Wen et al., modified by Pu et al., render obvious the implantation of tumor and immune cells in a PVDF capsule and analysis of the cells but do not expressly teach staining for 7-AAD, CD45, CD3, CD8, CD270, CD33, CD38, CD20, PD-L1, PD-1, CD68, and CD25.
Regev et al. teach the use of oligonucleotide-tagged antibodies for “barcoding” cells and that immune cells can be analyzed for expression of common surface proteins including CD45, CD3, CD8a and CD8b (which read on “CD8”), HVEM (which reads on “CD270”), CD33, CD38, CD20, PD-L1, PD-1, CD68, and CD25 (See Abstract and ¶0076-0077).
Schmid et al. teach the use of 7-AAD staining for analyzing immune cell populations via flow cytometry (See Abstract).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Wen et al., modified by Pu et al. to comprise staining of the immune cells with 7-AAD and antibodies to CD45, CD3, CD8, CD270, CD33, CD38, CD20, PD-L1, PD-1, CD68, and CD25. One would have been motivated to make this modification for characterizing the immune cell population present in tumor tissue because Schmid et al. teach 7-AAD as effective for staining DNA (See Abstract) and because Regev et al. teach the surface proteins as common markers of immune cells (See ¶0076-0077). There would be a reasonable expectation of success in doing so because the immune cells in the method of Wen et al., modified by Pu et al., could be readily assessed by flow cytometry in such a manner.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633