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 .
Claim Status
As of the Final Office Action mailed 10/21/2025, claims 1-2, 4-14, and 20-21 were pending and claims 2(A1), 2(A3), and 4-14 were withdrawn for being drawn to nonelected invention.
In Applicant's Response filed on 12/22/2025 (After Final) and 2/23/2026, claims 1, 2, 4-6, 8-10, and 12-14 were amended.
Response to Re-Traversal of Restriction Requirement
On March 20, 2025, Applicant elected Group I (claims 1, 2(A2), 2(A4), and 18-21) with traverse on the grounds that the groups share the same special technical feature.
In the Non-Final Office action mailed April 22, 2025, the examiner stated that this argument was not persuasive as the different mediums were distinct from each other, and thus did not share a special technical feature. Claims 2(A1), 2(A3), and 4-14 were withdrawn from consideration.
In response to the Final Office action mailed October 21, 2025, Applicant amended withdrawn claims 2(A1), 2(A3), 4-5, 8-10, and 12-14 to include limitations recited in independent claim 1 and argues in Remarks that Groups I-IV share a technical feature of the specific formulation of the medium and reagents recited in the claims. Applicant argues that even if the components of the claimed compositions can be found in the prior art, that it would not be possible for one of ordinary skill in the art to directly derive the culture medium without undue experimentation. Applicant argues that even if the recited components have a known utility, the Office has not demonstrated the cumulative effects of the components in combination would be understood by one of ordinary sill in the art based on the disclosures of the cited references. Applicant argues that the number of components incorporated into the medium, as well as the number of known and available components that were not incorporated, are inconsistent with a position that there is a finite number of identified medium compositions having reasonably predictable properties and that one of ordinary skill would not have been able to arrive at the recited compositions through any “routine” practice.
In response to Applicant’s arguments, the examiner notes that the claims lacked unity of invention for not having the same technical feature at the time the Restriction requirement was made. Even if, arguendo, the amendments to the withdrawn claims do incorporate the limitations of at least claim 1 (Group I) to form the same technical feature, the prior art of Huch Ortega et al (WO 2012014076, 29 July 2011; Published 2 Feb 2012), Vlachogiannis et al (Science. 2018 Feb 23;359(6378):920-926), Wang et al (WO2017206837A1, 27 May 2017; Published 7 Dec 2017), Bartfeld et al (J Vis Exp. 2015 Nov 12;(105):53359), and Steele et al (Cell Mol Gastroenterol Hepatol. 20 Sept 2018;7(1):161-184) make obvious the technical features that are shared between the Groups. Thus, a feature found in the prior art cannot be considered a special technical feature. The expression “special technical feature” refers to those features that define a contribution which each of the claimed invention, considered as a whole, makes over the prior art. Therefore, a lack of unity still exists between the restricted groups.
It is noted that in the event of rejoinder, the requirement for restriction between the product claims and rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103, and 112. Unless and until all claims to the elected product are found allowable, an otherwise proper restriction requirement between product claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product claim will not be rejoined. See MPEP 821.04.
However, the requirement is still deemed proper and is therefore made FINAL.
As such, claims 1-2, 4-14, and 20-21 are pending and claims 1, 2(A2), 2(A4), and 20-21 have been examined herein.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
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.
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.
Claim(s) 1 and 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huch Ortega et al (WO 2012014076, 29 July 2011; Published 2 Feb 2012; of record) in view of Vlachogiannis et al (Science. 2018 Feb 23; 359(6378):920-926; of record), Wang et al (WO2017206837A1, 27 May 2017; Published 7 Dec 2017; of record), Bartfeld et al (J Vis Exp. 2015 Nov 12; (105):53359; of record), and Steele et al (Cell Mol Gastroenterol Hepatol. 20 Sept 2018; 7(1):161-184; of record).
Huch Ortega teaches a cell culture medium comprising a basal medium for animal or human cells containing EGF, FGF10, HGF, gastrin, nicotinamide, B27, N2, N-acetylcysteine, a BMP inhibitor, and a Wnt agonist, such as Wnt3a (see claims 45 and 46 of Huch Ortega). The reference teaches that the that the BMP inhibitor can be noggin and can be present at concentration of at least 10 ng/mL with a preferred concentration of approximately 100 ng/mL (“BMP inhibitors” para 4 and 6). The basal medium also comprises amino acids, Advanced DMEM F12, Hepes, and penicillin/streptomycin (“Culture media”, para 1 and 6). The EGF is added at a concentration of 5 to 500 ng/mL with a preferred concentration of at least 50 ng/mL and not higher than 100 ng/mL (“Mitogenic growth factors” para 2). For FGF10 and HGF, the same concentration can be used; preferred concentrations for FGF10 are 20, 50, 100, 500 ng/ml, not higher than 500ng ml and preferred concentrations for HGF are 1, 10, 20, 50 ng/ml, not higher than 50ng/ml (“Mitogenic growth factors” para 3). The gastrin and nicotinamide can be present in amounts of 10 nM and 10 mM, respectively (“Preferred Expansion Media” para 2). N2 supplement may be used at a lx final concentration or at other final concentrations and is a convenient way to incorporate transferrin, insulin, progesterone, putrescine and sodium selenite into a culture medium (Expansion medium, para 5). B27 supplement may also be used at a lx final concentration or at other final concentrations as a convenient way to incorporate biotin, cholesterol, linoleic acid, linolenic acid, progesterone, putrescine, retinol, retinyl acetate, sodium selenite, tri-iodothyronine (T3), DL-alpha tocopherol (vitamin E), albumin, insulin and transferrin into a culture medium (“Preferred Expansion Media” para 3). The reference also teaches that the Wnt3a can be present in concentrations of 100 ng/mL to 1000 ng/mL (Wnt Agonist, para 10). The medium can also contain a TGF-beta inhibitor such as A83-01, present at concentrations of between 400-600 nM (i.e., 0.4-0.6 uM) (Expansion medium para 4). The medium can also include a ROCK inhibitor such as Y27632 (Expansion medium, para 3). This reads on “A primary cell culture medium . . . wherein the medium consists of antibiotic-antimycotic, HEPES, . . . , human recombinant protein EGF, . . ., human recombinant protein HGF, human recombinant protein FGF-10, human recombinant protein Wnt-3a, human recombinant protein Noggin, . . . , A83-01, . . . , N-acetyl-L-cysteine, Nicotinamide, N-2 Supplement, . . . , B27, . . . , Gastrin 1, Y-27632 and Advanced DMEM/F12 culture medium; wherein . . . a final concentration of the human recombinant protein EGF is 10-100 ng/mL; . . . ; the final concentration of the human recombinant protein HGF is 5-25 ng/mL; a final concentration of the human recombinant protein FGF-10 is 5-25 ng/mL; a final concentration of the human recombinant protein Wnt-3a is 200-300 ng/mL; a final concentration of the human recombinant protein Noggin is 100-200 ng/mL; . . . ; a final concentration of the A83-01 is 0.25-1.25 pM; . . . ; a final concentration of the Nicotinamide is 5-10 mM; a final concentration of the N-2 Supplement is 1% (volume percentage); . . . ; a final concentration of the B27 is 1.5-2.5%; . . . ; a final concentration of the Gastrin 1 is 8-12 nM; a final concentration of the Y-27632 is 5-20 uM; and the rest a remainder of the primary cell culture medium is the Advanced DMEM/F12 medium” as in instant claim 1 in-part.
Huch Ortega differs from the instant invention in that it does not teach that the medium can be used to culture gastric cancer cells, the concentration of penicillin as 100-200 U/mL, concentration of streptomycin as 100-200 ug/mL, concentration of N-acetylcysteine as 0.5-2mM, concentration of Hepes as 8-12 mM, or the concentration of Y27632 as 5-20 uM. It also does not teach the presence of Glutamax at concentration of 0.8-1.2%, NEAAs at concentration of 80-120 uM each, bFGF at a concentration of 10-50 ng/mL, amphotericin B at a concentration of 100-200 ug/mL, SB202190 at a concentration of 5-10 uM, Primocin at a concentration of 1%, cortisol at concentration of 20-50 ng/mL, or ITS-X at concentration of 0.8-1.2%.
Vlachogiannis teaches patient derived organoids from metastatic gastrointestinal cancers (title). PDOs were derived from ultrasound, computer-tomography (CT)-guided or endoscopic biopsies of metastatic CRC, metastatic GOC, and metastatic cholangiocarcinoma patients (fig. S1) (“the gastric cancer is metastatic lesion of the primary gastric cancer . . . the cholangiocarcinoma is a metastatic lesion of the primary cholangiocarcinoma” as in claim 1 in-part; “the primary cells of gastric cancer are primary cells in solid tumor of gastric cancer; and the primary cells of cholangiocarcinoma are primary cells in solid tumor of cholangiocarcinoma” as in instant claim 20; “the primary cells of gastric cancer are isolated from surgical samples of patients with gastric cancer; and the primary cells of cholangiocarcinoma are isolated from a surgical sample, a puncture sample or a bile sample” as in instant claim 21). The reference teaches GI PDOs were cultured in Advanced DMEM/F12, supplemented with 1x B27 additive, 1x N2 additive, 0.01% BSA, 2 mM L-Glutamine, 100 units/ml penicillin-streptomycin, and containing the following additives: EGF, Noggin, R-spondin, gastrin, FGF10, bFGF at 10 ng/mL, prostaglandin E2, Y-27632 at 10 uM, nicotinamide, A83-01, SB202190 at 5 uM, and HGF (which was specifically used for cholangiocarcinoma organoids) (see p. 5 of Supplementary Materials; “human recombinant protein bFGF . . . a final concentration of the bFGF is 10-50 ng/mL . . . Y-27632 . . . a final concentration of the Y-27632 is 5-20 uM . . .SB202190 . . . a final concentration of the SB202190 is 5-10 uM” as in instant claim 1 in-part). The reference also teaches that the phenotypic and genotypic profiling of PDOs showed a high-degree of similarity to the original patient tumor (Fig. 1A, Fig. 1B, fig. S2A and fig. S2B). Molecular profiling of tumor organoids was matched to drug screening results, suggesting PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses (abstract).
Wang teaches a reprogramming medium for digestive tract epithelial cells containing Advanced DMEM/F12 containing 2 mM glutamine (Glutamax), cyan-streptomycin (100 U/mL penicillin and 0.1 mg/mL streptomycin), 2 μM SB43154 or 0.5 μM A83-01, 0.5 mM VPA, 0.5 μM PD0325901, 0.04 μM RG108, 0.5 μM Bix01294, 2 μM Bay K8644, 5 μM PS48, 3.5 mM FBP (see claim 9 and 10 of Wang) (“a final concentration of penicillin . . . is 100-200 U/mL; a final concentration of streptomycin . . . is 100-200 ug/mL”; “Glutamax” as in instant claim 1 in-part). The medium can also contain ITS-X to supplement insulin-transferrin-selenium-ethanolamine complex solution (Main medium, para 1) (“ITS-X” as in instant claim 1 in-part). Hydrocortisone, as well as non-essential ammino acids, can also be used in medium (Main reagents, para 1) (“non-essential amino acids . . . cortisol” as in instant claim 1 in-part). The medium has the advantage of improving proliferation especially for rapidly renewing gastrointestinal tissue cells.
Bartfeld teaches culture of human stomach organoids from human tissue obtained from gastric resections or biopsies (title; “Establishment of gastric organoid culture”). The reference teaches that the basal medium for culture contains Advanced DMEM/F12 supplemented with HEPES; an appropriate glutamine source such as Glutamax and appropriate antibiotics such as 1x Primocin (“Establishment of gastric organoid culture” para 2; “Primocin” as in instant claim 1 in-part). The protocol described here has been developed for optimal long-term culture and allows unlimited maintenance of the organoids (Discussion, para 7).
Finally, Steele teaches an organoid-based model of human gastric cancer (title). The organoids derived from gastric cancer tissue were cultured in medium containing DMEM/F12, HEPES (10 mmol/L) (“a final concentration of Hepes is 8-12 mM” as in instant claim 1 in-part), 1X L-glutamine, 1X Pen/Strep, 1X N2, 1X B27, N-acetylcysteine, nicotinamide, epidermal growth factor, noggin, R-spondin conditioned media, Wnt conditioned media, FGF10, gastrin, Y-27632, and 1X amphotericin B (“Materials and Methods” para 1) (“amphotericin B . . . a final concentration of Hepes is 8-12 mM” as in instant claim 1 in-part). The reference teaches that the patient-derived gastric cancer organoids phenotypically resemble native tumor tissue and the cultures also rapidly developed tumors in an in vivo xenograft mouse model (Abstract, results). The reference concludes that the cultures are useful to predict individual therapy response and patient outcomes.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a cell culture medium as taught by Huch Ortega, where medium also contains bFGF and SB202190 as taught by Vlachogiannis, to arrive at the instantly claimed invention. As Vlachogiannis shows a medium containing at least Advanced DMEM/F12, B27 additive, N2, L-Glutamine, penicillin-streptomycin, EGF, Noggin, gastrin, FGF10, Y-27632, nicotinamide, A83-01, and HGF can also contain bFGF and SB202190 and can be used to culture patient derived gastric cancer and cholangiocarcinoma cells, one of ordinary skill would have been motivated to modify the medium as taught by Huch Ortega to include SB202190 and bFGF with a reasonable expectation of advantageously being able to use the medium to culture metastatic gastric and cholangiocarcinoma cells that maintain a high-degree of similarity of the phenotypic and genotypic profiling of the original patient tumor as taught by the prior art.
It also would have been obvious prior to the effective filing date of the instantly claimed invention to create a cell culture medium as taught by Huch Ortega, where the medium contains Glutamax, hydrocortisone, non-essential amino acids, and ITS-X as taught by Wang, to arrive at the instantly claimed invention. As Wang shows that a medium for digestive tract cells containing at least Advanced DMEM/F12, cyan-streptomycin (100 U/mL penicillin and 0.1 mg/mL streptomycin), SB43154 and 0.5 μM A83-01 can also contain Glutamax, hydrocortisone, non-essential amino acids, and ITS-X, one of ordinary skill would have been motivated to modify the medium of Huch Ortega to include these ingredients with a reasonable expectation of advantageously improving proliferation of rapidly renewing gastrointestinal tissue cell as taught by the prior art.
It would have been obvious prior to the effective filing date of the instantly claimed invention to create a cell culture medium as taught by Huch Ortega, where the medium contains Primocin as taught by Bartfeld, to arrive at the instantly claimed invention. As Bartfeld shows a medium for culturing gastric cells can contain Primocin as an antibiotic, one of ordinary skill would have been motivated to modify the medium of Huch Ortega to include Primocin with a reasonable expectation of advantageously creating an optimal long-term culture and allowing unlimited maintenance of gastric organoids as taught by the prior art.
Finally, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a cell culture medium as taught by Huch Ortega, where the medium contains amphotericin B as taught by Steele, to arrive at the instantly claimed invention. As Steele shows that a medium for gastric organoids can contain amphotericin B, one of ordinary skill would have been motivated to modify the medium of Huch Ortega to include amphotericin B with a reasonable expectation of advantageously having patient-derived gastric cancer organoids and cultures that phenotypically resemble native tumor tissue as taught by the prior art.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1 and 20-21 have been considered but are not persuasive.
On p. 17-21, Applicant argues that the core technical problem being addressed by the claims is culture medium capable of culturing primary solid tumor cells derived from gastric cancer, gallbladder cancer, and cholangiocarcinoma and that none of the references cited and applied addresses this core problem. Applicant argues that “Huch-Ortega is directed to a general culture medium for human or animal cell organoids, does not address cancer-type-specific primary solid tumor cells, and does not mention applicability to gastric/gallbladder/ cholangiocarcinoma cancer; Vlachogiannis is directed to metastatic gastrointestinal cancer organoids, not primary solid tumor cells, and does not cover gallbladder cancer or cholangiocarcinoma; Wang is directed to normal digestive tract cells, which is the opposite of the requirements for culturing primary cancer cells (e.g., anti-apoptosis, maintenance of tumor microenvironment, avoidance of differentiation); Bartfield is directed to gastric organoids derived from gastric resections/biopsies, does not involve cancerous tissue, and contains no disclosure related to gallbladder cancer or cholangiocarcinoma; and Steele is directed to a gastric cancer organoid model, does not involve gallbladder cancer or cholangiocarcinoma, and concerns organoids, which does not direct to primary solid tumor cells” and that none of the above cited references addresses the core technical problem solved by Applicant and that they are not references in the same field of endeavor. Applicant contends that because the references are not analogous art, one of ordinary skill in the art would have no motivation to combine them or any reasonable expectation that such a combination would address the core technical problem.
Applicant further argues that the applied references do not teach or suggest that a single formulation can be simultaneously applicable to primary solid tumors from three distinct cancer types and that one of ordinary skill would have no reasonable basis for anticipating that a single formulation could be effective for all three types of primary tumor cells. Applicant also argues that the composition in claim 1 is not a “general purpose medium,” and states that the composition is functionally tied to the technical effect of culturing primary solid tumor cells of gastric, gallbladder, and cholangiocarcinoma cancers. Applicant argues that the claim expressly limits the medium to the use of solid tumor cultures from these specific cancer cell types and argues that none of the references applied teach or suggest this specific use. Applicant argues that the Office does not address the portions of the applied references that teach away from the claimed composition such as teachings that certain components were considered unsuitable for primary cells or particular cancer types.
In response to applicant's argument that the references applied are nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, as previously stated, a reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). Note that "same field of endeavor" and "reasonably pertinent" are two separate tests for establishing analogous art; it is not necessary for a reference to fulfill both tests in order to qualify as analogous art. See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212. The examiner must determine whether a reference is analogous art to the claimed invention when analyzing the obviousness of the subject matter under examination. When more than one prior art reference is used as the basis of an obviousness rejection, it is not required that the references be analogous art to each other. See Sanofi-Aventis Deutschland GMbH v. Mylan Pharms. Inc., 66 F.4th 1373, 1380, 2023 USPQ2d 552 (Fed. Cir. 2023) and Corephotonics, Ltd. v. Apple Inc., 84 F.4th 990, 1007, 2023 USPQ2d 1202 (Fed. Cir. 2023). When determining whether the "relevant field of endeavor" test is met, the examiner considered "explanations of the invention’s subject matter in the patent application, including the embodiments, function, and structure of the claimed invention." Airbus S.A.S. v. Firepass Corp., 941 F.3d 1374, 1380, 2019 USPQ2d 430083 (Fed. Cir. 2019) (quoting Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212). When determining whether a prior art reference meets the "same field of endeavor" test for the analogous art, the primary focus is on what the reference discloses. Airbus, 41 F.3d at 1380. The examiner considered the disclosure of each reference "in view of the ‘the reality of the circumstances.’" Airbus, 41 F.3d at 1380 (quoting Bigio, 381 F.3d at 1326, 72 USPQ2d at 1212). These circumstances were weighed "from the vantage point of the common sense likely to be exerted by one of ordinary skill in the art in assessing the scope of the endeavor." Airbus, 41 F.3d at 1380. See also Donner Technology, LLC v. Pro Stage Gear, LLC, 979 F.3d 1353, 2020 USPQ2d 11335 (Fed. Cir. 2020); Sanofi-Aventis, 66 F.4th at 1378; and Netflix, Inc. v. DivX, LLC, 80 F.4th 1352, 1358-59, 2023 USPQ2d 1057 (Fed. Cir. 2023) ("The field of endeavor is ‘not limited to the specific point of novelty, the narrowest possible conception of the field, or the particular focus within a given field.’") (quoting Unwired Planet, LLC v. Google Inc., 841 F.3d 995, 1001, 120 USPQ2d 1593, 1597 (Fed. Cir. 2016)). The examiner also notes that Vlachogiannis teaches the use of biopsies of various metastatic CRC, GOC, and cholangiocarcinoma patients in culture as organoids (i.e., containing these cells) with instantly claimed medium components (Advanced DMEM, EGF, gastrin, FGF10, bFGF, nicotinamide, A83-01, etc.)
In response to applicant's argument, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. As noted in previous Office actions, the instant claims are drawn to a cell culture medium consisting of particular components. The recitation of “for culturing gastric cancer cells, gallbladder cancer cells, or cholangiocarcinoma cells” and that kind of gastric, gallbladder, and or cholangiocarcinoma are how the medium could be used but it is not necessary for the claimed invention.
Applicant further argues that the instant application is the first to present systematic verification of scientific validity and superiority of the claimed medium and reagents and points to Examples 12-15 and Table 28 of the instant specification to support this contention. Applicant, in sum, contends that the experimental data of the specification and the medium and reagents as claimed “yields a synergistic effect that could not have been reasonably predicted from the teachings of the cited prior art references.”
In response, the examiner notes that Applicant has not point to any specific teachings, citations, etc. to support this contention. The examiner notes that applicant only makes general statements of “synergistic effects” but provides no arguments related to specific effects/unexpected results nor provides empirical evidence on the record in the form of an affidavit or declaration to support the contention. 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.
Claim(s) 2(A2) is/are rejected under 35 U.S.C. 103 as being unpatentable over Huch Ortega et al in view of Vlachogiannis et al, Wang et al, Bartfeld et al, and Steele et al as applied to claims 1 and 20-21 above, and further in view of Orlando et al (US20150238656A1, 30 Jan 2015; published 27 Aug 2015; of record).
The teachings of Huch Ortega, Vlachogiannis, Wang, Bartfeld, and Steele in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claim 2(A2) depend. The combination of the references render obvious “consisting of a culture medium . . . the final concentration of penicillin in the P/S is 100-200 U/mL; the final concentration of streptomycin in the P/S is 100-200 ug/mL, . . . wherein the culture medium is composed of antibiotic-antimycotic, HEPES, GlutaMax, non-essential amino acids, human recombinant protein EGF, human recombinant protein bFGF, human recombinant protein HGF, human recombinant protein FGF- 10, human recombinant protein Wnt-3a, human recombinant protein Noggin, SB202190, A83- 01, Primocin, N-acetyl-L-cysteine, Nicotinamide, N-2 Supplement, cortisol, B27,ITS-X, Gastrin 1, Y-27632 and Advanced DMEM/F12 culture medium” as in instant claim 2(A2) in-part.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach a cell isolation buffer contains, heparin sodium, and PBS or that the final concentration of the heparin sodium is 10 IU/mL.
Orlando teaches decellularization of diseased tissues and organs (abstract; para 5). The reference teaches that tissue or organs of interest can be decellularized by washing the tissue in neutral buffer, where the neutral buffer is phosphate buffered saline and where the neutral buffer contains 10 U/mL of heparin (see para 11-12 of Orlando) (“cell isolation buffer composed of heparin sodium and PBS; . . . the final concentration of the heparin sodium is 10 IU/mL; and the rest is PBS” as in instant claim 2(A2) in-part). This shows PBS containing at least heparin can be used to isolate cells from diseased tissues and organs.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a cell culture medium for gastric cancer cells as taught by Huch Ortega, Vlachogiannis, Wang, Bartfeld, and Steele in combination, where the medium in accompanied by a cell isolation solution as taught by Orlando, to arrive at the instantly claimed invention. As Orlando shows at least neural buffer PBS and heparin can be used to decellularize diseased tissues, one of ordinary skill would have been motivated to combine the cell culture medium of Huch Ortega, Vlachogiannis, Wang, Bartfeld, and Steele in combination with the cell isolation medium of Orlando according to known methods to yield the predictable result of advantageously being able to separate cells from diseased tissue before culturing the cells with a reasonable expectation of as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments with respect to previously cited Orlando reference or attempted to distinguish the teachings of Orlando and the specific subject matter rendered obvious by the reference. Thus, the rejection is maintained.
Claim(s) 2(A4) is/are rejected under 35 U.S.C. 103 as being unpatentable over Huch Ortega et al in view of Vlachogiannis et al, Wang et al, Bartfeld et al, Steele et al, and Orlando et al as applied to claim 2(A2) above, and further in view of Thirumala et al (Stem Cells Dev. 2010 Apr;19(4):513-22; of record).
The teachings of Huch Ortega, Vlachogiannis, Wang, Bartfeld, Steele, and Orlando in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 2(A2) of which claim 2(A4) depend. The combination of the references render obvious “consisting of 2(A2), . . . wherein the culture medium is composed of antibiotic-antimycotic, HEPES, GlutaMax, non-essential amino acids, human recombinant protein EGF, human recombinant protein bFGF, human recombinant protein HGF, human recombinant protein FGF- 10, human recombinant protein Wnt-3a, human recombinant protein Noggin, SB202190, A83- 01, Primocin, N-acetyl-L-cysteine, Nicotinamide, N-2 Supplement, cortisol, B27,ITS-X, Gastrin 1, Y-27632 and Advanced DMEM/F12 culture medium” as in instant claim 2(A4) in-part.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach a cell digestion solution, digestion termination solution, or cell cryopreserving solution (instant claim 2(A4) in-part).
Thirumala teaches the evaluation of methylcellulose and DMSO as cryoprotectants (title). The reference teaches that the investigation of the post-freeze/thaw viability and apoptotic behavior of Passage 1 (P1) adult stem cells (ASCs) in 11 different media: (i) the traditional media containing Dulbecco’s modified Eagle’s medium (DMEM) with 80% fetal calf serum (FCS) and 10% dimethyl sulfoxide (DMSO), (ii) DMEM with 80% human serum (HS) and 10% DMSO, (iii) DMEM with 1% methyl cellulose (MC) and 10% of either HS or FCS or DMSO, and (iv) DMEM with 0%, 2%, 4%, 6%, 8%, or 10% DMSO (abstract) (“the cell cryopreserving solution is composed of Advanced DMEM/F12 medium, DMSO and 1% methylcellulose solution; wherein the volume ratio of the Advanced DMEM/F12 medium, the DMSO and the 1% methylcellulose solution is 20:2: (0.8-1.2); the 1% methylcellulose solution is an aqueous solution of methylcellulose with a concentration of 1 g/100 ml” as in instant claim 2(A4) in-part). The reference teaches that the percentage of necrotic cells with 10% DMSO and 1% MC was significantly lower (4.1% ± 3.1%) from the other 3 treatments investigated with 1% MC (∼35%–40%) (Results para 4). It also teaches that the addition of 10% DMSO significantly improves the cell viability, that is, the post-thaw cell viability with 1% MC in DMEM (∼47%) is significantly lower than that obtained with DMEM containing 1% MC and 10% DMSO (∼80%) (same para). The data obtained with 10% DMSO and 1% MC in DMEM is comparable to control data obtained with 80% FCS (or 80% HS) with 10% DMSO in DMEM, suggesting that the serum (FCS or HS) in the freezing media can be replaced by 1% MC (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a cell culture medium and isolation solution for gastric cancer cells as taught by Huch Ortega, Vlachogiannis, Wang, Bartfeld, Steele, and Orlando in combination, where the medium is accompanied by a cryopreservation solution containing DMSO, methylcellulose, and DMEM as taught by Thirumala, to arrive at the instantly claimed invention. As Thirumala shows adult cells can be frozen with cryopreservation solution containing DMEM, methylcellulose, and DMSO, one of ordinary skill would have been motivated to modify the kit of reagents as taught by Huch Ortega, Vlachogiannis, Wang, Bartfeld, Steele, and Orlando in combination to include a cell cryopreservation solution as taught by Thirumala with a reasonable expectation of advantageously having a cryopreservation solution that has improved cell viability and lower cell necrosis as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments with respect to previously cited Thirumala reference or attempted to distinguish the teachings of Thirumala and the specific subject matter rendered obvious by the reference. Thus, the rejection is maintained.
Conclusion
No claim is allowed.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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