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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/11/2026 has been entered.
Status of the Claims
Amendment filed on 05/11/2026 is acknowledged.
Claims 1-39, 41, 56, and 59 remain cancelled. Claims 49-50 are now cancelled.
Claims 40 and 57-58 are amended.
Claims 40, 42-48, 51-55, and 57-58 are pending and being examined on the merits herein.
Priority
This Application, 18421666, filed 01/24/2024 is a Continuation of 16499333, filed 09/30/2019, now U.S. Patent #11920162 with a terminal disclaimer filed on 04/25/2025 in record; 16499333 is a National Stage entry of PCT/IL18/50390, with an International Filing Date: 04/03/2018; PCT/IL18/50390 claims priority from Provisional Application 62481738, filed 04/05/2017.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 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 40, 42-44, 46, 48, 53-55, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Carranza-Torres et al. (BioMed Research International, 2015, Article ID 618021, 13 pages, in record of 11/07/2024; Hereafter “Carranza”) in view of Szalowska et al. (Toxicology in Vitro 27, 2013, 1513-1524; cited in IDS of 04/23/2024; uploaded, PTO-892).
Carranza throughout the reference directs to culture breast tumor explants obtained from precision-cut breast tumor slices to evaluate natural or synthetic compounds with antitumor properties within the complex microenvironment of the tumor (e.g., Abstract).
For Claims 40, 42, 44, 46, 48, 53-55, and 57, Carranza teaches the method of culturing breast cancer tissue: obtaining cylindrical tissue cores in 10 mm diameter (Pg. 3, 2.3 Preparation of slices and explants from breast tumor) from infiltrating ductal adenocarcinoma specimens (known as common breast cancer type, corresponding to not liver tissue in instant claim 42, breast tissue as in instant claim 48, and not a liver cancer tissue biopsy as in instant claim 57) collected from patients during surgery (Pg. 3, 2.2 tumor samples), processing the tissue by Krumdieck tissue slicer and biopsy punch to achieve 4 mm in diameter and 250-300 um slices (overlapping with slice thickness range 200-300 um thick in instant claim 53), culturing the precision-cut tumor explants/slices in six-well microplates containing DMEM/F12 culture medium (corresponding to instant claim 54) supplemented with fetal bovine serum, bovine insulin, insulin-transferrin-selenium and glucose, gentamicin (corresponding to instant claim 46), incubating plates for 1 hr at 37 C, 5% CO2/95% air with agitation at 25 rpm (Pg. 3, 2.3) (corresponding to agitation in rotation in instant claim 44, or 50-100 rpm in instant claim 55), during which agitation the tissue slices in culture would result in intermittent submersion of the tissue slices in culture as known by person with ordinary skills in the field. Carranza exhibits that tumor tissue explants (e.g., precision cut cancer tissue core biopsy slices) cultured ex vivo remain viable and actively proliferating for up to 96 h (= 4 days) (Pg. 5, Fig. 2; 3.2.2) (corresponding to at least 80% maintain viability after 4 days in culture as recited in claim 40).
Carranza teaches the incubator air contains 5% CO2/95% air, but does not teach the atmosphere contains less than 95% oxygen as recited in instant claim 40, or 80% oxygen in instant claim 43.
Szalowska throughout the reference directs to optimization of culturing precision cut liver slices, e.g., dynamic culture conditions compared to static ones to improve viability, addition of serum, insulin, and dexamethasone in culture medium beneficial for long term culture, oxygen concentration during culture incubation (most often at 95% oxygen) (Pg. 1513, bottom-Pg. 1514, 1st paragraph).
Szalowska discovers that medium composition does not affect precision cut liver slices’ viability while 80% oxygen yields the best biochemical characteristics for sliced tissue cultures; and that 80% oxygen is the most favorable condition in maintaining gene expression in precision cut liver slices for use as model to study hepatotoxicity (e.g., Abstract), after cultural plates containing the liver precision cut slices incubated with continuous shaking (70 rpm, corresponding to 50-100 rpm in instant claim 55) at 20%, 40%, 60%, and 80% of oxygen; 5% CO2 and the remaining gas volume filled up to 95% with N2 (Pg.1514, right Col., 2nd paragraph). The most favorable 80% oxygen level corresponds to at least 70% and less than 95% oxygen in instant claim 40; or about 80% oxygen in instant claim 43.
It would have been prima facie obvious for a person with ordinary skill of art to adjust oxygen level taught by Szalowska to arrive at current invention. Szalowska discloses that 80% oxygen level is the most favorable condition with respect to maintenance of expression of genes involved in drug and energy metabolism in culturing precision cut liver slices. The advantage of favorable oxygen level for precision cut tissue culture would have motivated scientists to lower the oxygen level from 95% to 80%, and would have provided reasonable expectation of success. This renders obviousness as “use of known technique to improve similar devices (methods, or products) in the same way” or as “applying a known technique to a known device (method, or product) ready for improvement to yield predictable results”. See MPEP §2143. (I)(C) and (I)(D). An improvement in the art would have been obvious if “it is likely the product not of innovation but of ordinary skill and common sense.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). For this instance, the oxygen level is the same or falls within the claimed levels, slice thickness, agitation frequency, and slice thickness overlap with those in prior art. Furthermore, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than “routine experimentation,” because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition (MPEP §2144.05 (II)). See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claims 40, 42-48, 51-55, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Carranza-Torres et al. (BioMed Research International, 2015, Article ID 618021, 13 pages, in record of 11/07/2024; Hereafter “Carranza”) in view of Szalowska et al. (Toxicology in Vitro 27, 2013, 1513-1524; cited in IDS of 04/23/2024; uploaded, PTO-892) as applied to claims 40-44, 46, 48, 53-55, and 57 above, further in view of Woodruff et al. (US20150252328, 09/10/2015).
Combined teaching of Carranza and Szalowska teaches a method for culturing cancer tissue e.g., breast cancer tissue (not a liver cancer tissue), comprising culturing a precision-cut cancer tissue slice in culture medium, e.g., DMEM/F12, under 5% CO2 with the most favorable 80% oxygen atmosphere condition; and agitating the culture results in intermittent submersion of the tissue slice in culture medium, wherein the tissue slice is a slice of biopsy generated from cancer cylindrical tissue cores, resulting in cancer tissue core biopsy, wherein the cells in the precision-cut tissue slice maintain viability after 96 hr (4 days) in culture, as discussed and applied to claims 40-44, 46, 48, 53-55, and 57 above in detail, and incorporated herein.
Combined teaching of Carranza and Szalowska does not teach the tissue culture slice is on tissue culture insert as recited in instant claims 45 and 58, specific drug as recited in instant claim 47, the tissue culture slice is cultured for at least 5 days as recited in instant claim 51, 80% cells maintain viability after 5 days in culture as recited in instant claim 52.
Woodruff throughout the reference directs to 3D (three-dimensional) ex-vivo cell and tissue culture system for female reproductive tract (e.g., Abstract).
Woodruff indicates that the systems comprise cultures, e.g., 3D culture, comprising disease cells/tissues derived from uterine fibroid tissue, cancer tissue (e.g., ovarian, uterine, cervical, breast, liver, etc.) [0010]. Woodruff exemplifies that uterine tissue or endocervical tissue cells of 3D cultures are established in Transwell culture inserts(e.g., [0158]; [0195]), or fallopian epithelium tissue pieces grown on Transwell inserts (e.g., Claim 20) (corresponding to instant claims 45 and 58). Woodruff teaches that cisplatin (CDDP) and cyclophosphamide (CTX) (corresponding to specific drugs in instant claim 47), which are known to be toxic to the ovary and to follicles specifically [0130], are the drugs used in the female reproductive follicle culture (Example 2, [0121]) to assess difference in survival of follicles (Fig. 8; [0130]), wherein follicles with or without drug are cultured at 37C in a humidified atmosphere of 5% CO2 in air for up to 6 days (e.g., [0123]; [0130]) (corresponding to instant claim 51), resulting in about 95.40% follicle cell viability at 6 days of the control without drug compared to only 32.43% and 11.49% survival in the 1 uM and 5 uM CTX treated cultures (Fig. 8A; [0130]); ovarian follicles 3D cell culture remain viable for at least one simulated menstrual cycle (e.g., Claim 16), corresponding to at least 80% cells maintain viability after 5 days in culture as recited in instant claim 52.
It would have been prima facie obvious for a person with ordinary skill of art to incorporate the culture inserts and specific drugs taught by Woodruff into the culturing cancer tissue culturing method taught by Carranza and Szalowska to arrive at current invention, especially because Szalowska suggests that dynamic culture conditions compared to static ones to improve viability, while Woodruff specifically teaches 3D cultures on Transwell membrane inserts maintaining tissue architecture and viability for as long as 28 days (e.g., [0034], Fig. 13), it would have motivated artisans in the field to implement this element into the culturing method for reasonable expectation of success. This renders obviousness as combining prior art elements according to known methods to yield predictable results, see In Supreme Court KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007); or, it renders obviousness as “use of known technique to improve similar devices (methods, or products) in the same way” or as “applying a known technique to a known device (method, or product) ready for improvement to yield predictable results”. See MPEP §2143. (I)(C) and (I)(D). Moreover, It is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (MPEP §2144.07). See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). For this instance, the oxygen level falls within the claimed levels, viability of cells, and culturing days overlap with those in prior art. Furthermore, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than “routine experimentation,” because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition (MPEP §2144.05 (II)). See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Response to Arguments
Applicant’s arguments filed on 05/11/2026 with respect to all previously rejected claims have been considered but are moot because the new ground of rejection does not rely on the references Geer and Clark applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Please refer to the entire office action as presented above as a complete response to the arguments.
Declaration
The declaration from Dr. Ravid Straussman filed on 05/11/2026 has been considered but is moot. In light of the declaration and claim amendment, the office action has found new ground of rejection as presented above in detail:
Combined prior art Carranza and Szalowska teaches a method for culturing cancer tissue e.g., breast cancer tissue (not a liver cancer tissue), comprising culturing a precision-cut cancer tissue slice in culture medium, e.g., DMEM/F12, under 5% CO2 with the most favorable 80% oxygen atmosphere condition; and agitating the culture results in intermittent submersion of the tissue slice in culture medium, wherein the tissue slice is a slice of biopsy generated from cancer cylindrical tissue cores, resulting in cancer tissue core biopsy, wherein the cells in the precision-cut tissue slice maintain viability after 96 hr (4 days) in culture.
Conclusion
Claims are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DONGXIU ZHANG SPIERING whose telephone number is (703)756-4796. The examiner can normally be reached 7:30am-5:00pm (Except for Fridays).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SUE X. LIU can be reached at (571)272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DX.Z./ Examiner, Art Unit 1616
/MONICA A SHIN/ Primary Examiner, Art Unit 1616
Prosecution Insights