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 .
Status of the Claims
Amendment filed on 10/16/2025 is acknowledged.
Claims 40 and 58 are amended. Claims 1-39, 41, 56, and 59 remain cancelled.
Claims 40, 42-55, and 57-58 are pending and being examined on merits herein.
Priority
This Application, 18421666, filed 01/24/2024 is a Continuation of 16499333, filed 09/30/2019, now U.S. Patent #11920162 and having one RCE-type filing therein 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 § 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.
Claim 57 is 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 57 recites the limitation “cancer tissue biopsy”. There is insufficient antecedent basis for this limitation in the claim because claim 40, which claim 57 depends upon, does not contain “cancer tissue biopsy”. In claim 40 the tissue is “cancer tissue core biopsy”.
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, 48-49, 51, 53, 55 and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Geer et al. (World J Gastroenterol, 03/21/2009, 15(11):1359-1366; in record of 06/16/2025) as evidenced by Merriam-Webster Dictionary (Biopsy, in record of 06/16/2025), in view of Clark et al. (AU2014277688, 01/22/2015, PTO-892).
Geer throughout the reference teaches Ex-vivo cancer tissue culture and evaluates Ex-vivo gene therapy vectors in human pancreatic (cancer) tissue slices (e.g., Abstract) obtained from patients undergoing a pancreaticoduodenectomy for pancreatic head tumors (Pg. 1361, Primary tissue slices).
Regarding instant claim 40, Geer discloses that the method of culturing human pancreatic cancer tissue slices from surgical specimen ex vivo for 1-6 days in an incubator using 95% oxygen (Methods, Pg. 1359), and specifies that the tissue slices are precision-cut using an automatic tissue slicer in order to achieve a more consistent size and shape (Right column, Pg. 1360). Geer indicates that the tissues are cultured in DMEM culture medium with continuous shaking back and forth as a type of agitation and rotation to the culture (Methods, Pg. 1361), which would result in intermittent submersion of the tissue slice in the culture medium. As evidenced by Merriam-Webster Dictionary, “biopsy” means “the removal and examination of tissue, cells, or fluids from the living body”, the pancreatic cancer tissue slices belong to tissue biopsy from human pancreas organ.
Regarding instant claim 42, Geer teaches using pancreatic cancer tissue, not liver tissue.
Regarding instant claim 44, Geer teaches that the tissue culture plates are placed in an Innova 4300 incubator that is humidified and gassed with 95% O2 and continuously shaken back and forth (90 times/min) at 37C as a type of rotation and agitation to the culture (Methods, Pg. 1361).
Regarding instant claim 46, Geer teaches the tissue slices are incubated in DMEM as culture medium with antibiotic drugs penicillin, streptomycin (Methods, Pg. 1361).
Regarding instant claim 48, Geer teaches the cancer tissue is pancreas tissue.
Regarding instant claims 49 and 51, Geer teaches the cancer tissue is kept in culture up to 6 days (Fig. 3, Pg. 1363; Results, Pg. 1359), overlapping with at least 4 days in instant claim 49, or at least 5 days in instant claim 51.
Regarding instant claims 53 and 55, Geer indicates that the tissue slices with a thickness of approximately 250 um are incubated in DMEM culture medium in an Innova 4300 incubator that is humidified and gassed with 95% O2 and continuously shaken back and forth (90 times/min) at 37C as a type of rotation and agitation to the culture (Methods, Pg. 1361).
Regarding instant claim 57, Geer teaches the pancreatic cancer biopsy tissue as discussed above, not liver cancer tissue biopsy.
Geer does not teach the pancreatic cancer tissue sample is cancer tissue core biopsy as recited in instant claim 40.
Clark throughout the reference directs to novel methods of processing cellular samples, in particular aggregated cells or solid tumors, e.g., live cancer cells, which can be used in clinical or research context (e.g., [0087]).
Clark teaches that example human cancers that can be tested with the methods include, but are not limited to, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, cervical cancer, lung cancer, small cell lung carcinoma, kidney cancer, liver cancer, brain cancer, skin cancer, and bladder cancer (e.g., [00094]). The cancer tissue sample can be obtained by any method as is known in the art, for example, by taking a biopsy from a patient by methods including, but not limited to incisional biopsies, core biopsies, punch biopsies and fine needle aspiration biopsies, as well as excisional biopsies (e.g., [0095]). Clark teaches core biopsy method in detail (e.g., [0097]).
It would have been prima facie obvious for a person with ordinary skill of art to swap the pancreaticoduodenectomy cancer tissue in Geer with cancer core biopsy tissue for Ex-vivo cancer cell culture method taught by Clark to arrive at current invention. While Geer indicates that precision-cut slicing of human pancreatic cancer tissue was never reported at the time (Pg. 1360, right column 3rd paragraph) at the time of 2009, Clark presents in 2015 various live cancer tissue sampling methods for ex-vivo cancer tissue culture including core biopsy, as Clark points out that an advantage of the methods is that the test reagent can be added at the point of care, and allows the testing of ex vivo biomarkers, optionally at the point of care, using live cells, further, the methods can be used with specific test reagents to manipulate samples ex vivo to facilitate the development of novel predictive biomarkers, monitor and determine cellular sensitivity to specific pharmaceutical agents, and other uses that one of skill in the art will appreciate (e.g., [00128]). The advantages to obtain cancer live tissue sample via core biopsy would have motivated scientists to swap pancreaticoduodenectomy cancer tissue post-surgery with cancer core biopsy, and would have provided reasonable expectation of success as Clark demonstrates the method being suitable for pancreatic cancer and other cancers. 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).
Claims 43, 50 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Geer et al. (World J Gastroenterol, 03/21/2009, 15(11):1359-1366; in record of 06/16/2025) as evidenced by Merriam-Webster Dictionary (Biopsy, in record of 06/16/2025), and Clark et al. (AU2014277688, 01/22/2015, PTO-892) as applied to claims 40, 42, 44, 46, 48-49, 51, 53, 55 and 57 above, further in view of Szalowska et al. (Toxicology in Vitro 27, 2013, 1513-1524; cited in IDS).
Combined teachings of Geer and Clark teaches ex-vivo cancer tissue culture methods of core biopsy cancer tissue, e.g., pancreatic cancer tissue, comprising precision-cut slices with approximately thickness 250 um in culture medium containing antibiotic drugs, with 90 rpm rotation agitation in culture incubator adjusted with 95% oxygen for up to 6 days, as discussed and applied above to instant claims 40, 42, 44, 46, 48, 49, 51, 53, 55 and 57 in greater detail and incorporated herein.
Geer further exhibits viability testing results of pancreatic cancer slices verse normal pancreatic slices post 3 days in culture (Fig. 2, Pg. 1362), For normal pancreas, 70% of the slices show moderate to good viability, while, for pancreatic cancer specimens, this is 57% (Fig. 1D, Pg. 1362, right column 1st paragraph). In the test of medium formulation on viability assay, Geer indicates that normal pancreas slices show good viability at day 6 (Fig. 3, Pg. 1363) in DMEM medium.
Geer and Clark combined teachings do not use atmosphere containing about 80% oxygen in the method as recited in instant claim 43. Geer and Clark do not explicitly teach at least 80% of the cells in the precision-cut tissue slice in ex vivo cell culture maintain viability after 4 or 5 days in culture as recited in instant claim 50 or 52.
Szalowska teaches that 80% oxygen is the most favorable condition in maintaining gene expression in precision cut liver slices for use as model to study hepatotoxicity.
It would have bene prima facie obvious for one with ordinary skills in the art to incorporate 80% oxygen for the ex vivo tissue culture in Szalowska with the method taught by Geer and Clark to arrive at current invention, because Szalowska indicates that 80% oxygen is the most favorable for maintaining gene expression for precision-cut liver tissue culture, one would be motivated to experiment and optimize oxygen conditions for culture viability. 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). Moreover, 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). 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).
Although the viability of cells in Geer’s tissue slice culture differ from those in instant claims, they are inherent properties of the cancer tissue culture method and do not add structural steps to the method. The ex vivo cancer tissue culture method in claim has already been taught by prior art as presented above, the properties are consequentially taught prior art. "A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments." Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), and "Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments." In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Claims 45, 47, 54 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Geer et al. (World J Gastroenterol, 03/21/2009, 15(11):1359-1366; in record of 06/16/2025) as evidenced by Merriam-Webster Dictionary (Biopsy, in record of 06/16/2025), and Clark et al. (AU2014277688, 01/22/2015, PTO-892), as applied to claims 40, 42, 44, 46, 48-49, 51, 53, 55 and 57 above, further in view of Parajuli et al. (In Vitro Cell. Dev. Biol. -Animal, 2009, 45:442-450, in record of 06/16/2025).
Combined teachings of Geer and Clark teaches ex-vivo cancer tissue culture methods of core biopsy cancer tissue, e.g., pancreatic cancer tissue, comprising precision-cut slices with approximately thickness 250 um in culture medium containing antibiotic drugs, with 90 rpm rotation agitation in culture incubator adjusted with 95% oxygen for up to 6 days, as discussed and applied above to instant claims 40, 42, 44, 46, 48, 49, 51, 53, 55 and 57 in greater detail and incorporated herein.
Geer and Clark combined teachings do not teach the tissue culture slice on tissue culture insert as recited in instant claims 45 and 58, the drug in culture medium as 5FU, oxaliplatin, irinotecan, cisplatin, 4-hydroperoxy cyclophosphamide, docetaxel, doxorubicin, navalbine, gemcitabine, gefitinib, tamoxifen, olaparib, cetuximab, trametinib, everolimus, or palbociclib as recited in instant claim 47, or culture medium is DMEM/F12 as recited in instant claim 54.
Parajuli teaches ex vivo culture of precision-cut slices (Lerche-Langrand and Toutain 2000) from MMTV-neu mice mammary tumors (Introduction, Pg. 443). Parajuli discloses that the precision-cut slices are loaded onto titanium grids (as a type of insert, corresponding to instant claims 45 and 58) in six-well plates with eight slices per well containing DMEM/F12 medium (corresponding to instant claim 54) supplemented with drugs including 2.5% Albumax (GIBCO, Langley, OK), 50 μg/ml gentamicin, and 1 % strepto-penicillin, and doxorubicin (1 μM; Sigma-Aldrich, St. Louis, MO) (corresponding to instant claim 47), and the slices are cultured in a rotating manner on an inclined plane in a humidified tissue culture incubator at 37°C.
It would have been prima facie obvious for one with ordinary skills in the art prior to filing date to incorporate Prajuli’s teaching on using the insert for tissue slices, the drug, and culture medium for the cancer tissue biopsy culture into the cancer tissue culture method of Geer and Clark to arrive at current invention. Because Parajuli specifies that incubation of slices on rotating grids is best suited for the experiments compared to slices without grids at different slice thickness in the range from 114 to 228 um (Pg. 447), and Parajuli demonstrates the culture medium in viability testing under different tissue slice conditions, one would have reasonable expectation of success to combine the teachings of Parajuli with Geer and Clark, especially Geer, Clark and Parajuli share same intended use of the methods. 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).
Response to Arguments
Applicant arguments/remarks filed on 10/16/2025 have been fully considered but moot, because the new ground of rejection with combined teachings of Geer and Clark teach cancer tissue slices obtained from core biopsy. Please refer to the entire office action presented above as a complete response to the arguments.
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.
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/DX.Z./Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616