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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Acknowledgment is made of applicants' claim for foreign priority to Japanese applications JP 2021-131168 filed on 08/11/2021.
It is noted, however, that applicant has not filed a certified copy of the JP 2021-131168 application as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/30/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 112
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The rejection is withdrawn following claim amendments to indicate specific cationic substances, heparin, and collagen as fragmented extracellular matrix component, polyelectrolyte and the extracellular matrix component as collagen.
Claim Rejections - 35 USC § 103
Claims 1-3, 5, 9, 11-17, and 19-20 were rejected under 35 U.S.C. 103 as being unpatentable over Son et al (Biotechnol J. 2016 Mar; hereinafter "Son;" See PTO-892) in view of JP2019033732A (Published March 7, 2019; hereinafter "Kitano;" See PTO-892).
Claims 4, 6-8 and 18 were rejected under 35 U.S.C. 103 as being unpatentable over Son et al (Biotechnol J. 2016 Mar; hereinafter "Son;" See PTO-892) in view of JP2019033732A (Published March 7, 2019; hereinafter "Kitano;" See PTO-892) further in view of Rajalekshmi et al (Int J Biol Macromol. 2020 Nov; hereinafter "Rajalekshmi;" See PTO-892).
The rejection is withdrawn following claim amendments.
Double Patenting
Claim 19 was provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 of copending Application No. 18/774,971 (reference application).
The rejection is withdrawn following claim amendments.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
37 C.F.R. § 1.105 Requirements for information
Under the provisions of 37 C.F.R § 1.105 (a)(1)(iii), Applicant is required to submit information reasonably necessary for the examination of this application. If the Applicant or an inventor presented, displayed, or disclosed subject matter related to the claimed invention at the American Association for Cancer Research in 2020, the Applicant is required to submit copies of any poster presentations, PowerPoint presentations, abstracts, handouts, speaker notes, or other presentation materials that were presented, displayed, or otherwise made available in connection with the AACR Annual Meeting 2020. This also includes copies of any supplementary materials, electronic files or other documents corresponding to or describing the presentation.
The requested information is reasonably necessary to determine the nature and extent of any public disclosure relating to the claimed invention for evaluation of patentability.
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.
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 1, 3-8, 12, 14-15, 19, and 21-25 is/are rejected under 35 U.S.C. 103 as being obvious over Abstract 322 (Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24; AACR; Cancer Res 2020; hereinafter “Abstract 322;” See PTO-892) in view of Yoo (WO2010030964A2; published Jun 10, 2010; hereinafter “Yoo;” See PTO-892), Yue et al (Biomaterials. 2018 Jul; hereinafter "Yue;" See PTO-892) and Raghunath et al (J. Biomed. Mater. Res.; hereinafter “Raghunath;” See PTO-892).
Regarding claim 1, 19, and 21: Abstract 322 was directed to “[l]ayered 3D stromal tissues with microvascular network were produced by culturing normal fibroblasts and endothelial cells coated with the extra-cellular matrix (ECM) and natural polysaccharide, namely collagen and heparin.” (See Abstract 322 Methods). As such Abstract 322 taught obtaining stromal cell containing composition use of collagen, heparin, and formation of 3D stromal tissues. Next, Abstract 322 also taught that “[t]he layered 3D stromal tissues and co-cultured tumor were morphologically evaluated by HE staining, immunohistochemistry and immunofluorescence (IF).” (See Abstract 322, Methods). As such Abstract 322 taught obtaining a target cell composition comprising the extracellular matrix, the polyelectrolyte and fragmented extracellular matrix component, wherein the target cells are cancer cells.
It is also submitted that layering reads on placing the target cell-containing mixture in contact with the first gel composition. It is submitted that Abstract 322 did not explicitly teach forming stromal cell-containing mixture and target cell mixture as gel compositions comprising fibrin. For example, Yoo taught, however, a method of producing three-dimensional multilayer hydrogel constructs by sequentially depositing hydrogel precursor layers and crosslinking each deposited layer to form a gel prior to deposition of subsequent layers. Yoo further taught that suitable hydrogel precursors include collagen and fibrinogen.
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the layered three-dimensional tumor model of Abstract 322 by employing the hydrogel fabrication method taught by Yoo, including forming the individual cell-containing layers as fibrin-containing gel compositions through crosslinking of hydrogel precursors. Abstract 322 expressly recognizes the need for an ex vivo three-dimensional model that more faithfully recapitulates the tumor microenvironment, while Yoo teaches a conventional method for fabricating multilayer three-dimensional hydrogel constructs by sequential gelation of individual hydrogel layers. A person of ordinary skill in the art would have reasonably expected that applying the known hydrogel fabrication technique of Yoo to the layered tumor model of Abstract 322 would produce the desired three-dimensional cellular tissue with predictable results because both references are directed to constructing multilayer three-dimensional tissue models using cell-containing hydrogel matrices.
It is also noted that none of the cited prior art taught target cell mixture is localized on a portion of the surface of the stromal cell-containing layer. It is noted that Abstract 322 noted that it is necessary to develop an “ex vivo model which recaptures the tumor microenvironment is required to perform drug evaluation mimicking the patient tumor tissue.” (See Abstract 322 Background). Yue “fabricated a stromal cell-laden microwell array system with tunable stiffness ranging from 200 Pa up to 3 kPa, which covers the stiffness range of normal and cancerous mammary tissues, to study the effect of ECM stiffness on stromal-cancer interaction. Our results showed that, tumor spheroids closely interacted with the pre-adipocyte stromal cells encapsulated within the microwell array, influencing their differentiation and maturation degree in a stiffness related manner.” (See Yue Abstract). Yue demonstrated that three-dimensional tumor models are designed with spatially organized tumor cells within an extracellular matrix/stromal environment to reproduce the tumor microenvironment. Accordingly, a person of ordinary skill in the art would have been motivated to localize the cancer cell-containing region within the stromal cell-containing layer when implementing the multilayer hydrogel construct of Abstract 322 and Yoo, because such spatial organization would improve physiological relevance by mimicking the localized nature of tumor growth and tumor-stroma interactions.
It is also noted that none of the cited prior art taught target Tris buffer as a component in the hydrogel compositions. Raghunath taught the use of Tris buffer in collagen-heparin systems during preparation and characterization of collagen-heparin compositions. (See Raghunath Abstract). Accordingly, the use of Tris-HCl as the buffering component for the collagen/heparin hydrogel compositions would have represented the use of a known buffering system suitable for collagen-heparin formulations. Substitution of Tris-HCl for another conventional biological buffer would have been an obvious design choice yielding the expected result of maintaining suitable physiological pH during hydrogel preparation, particularly where the present specification does not attribute any unexpected property or criticality to the selection of Tris-HCl.
Regarding the limitation that collagen and heparin are each present at concentrations of 0.025 mg/mL to 0.1 mg/mL, Takahashi teaches the use of collagen and heparin in forming the stromal tissue construct, while the cited art establishes collagen-heparin hydrogels as conventional tissue-engineering materials. The concentrations of collagen and heparin constitute result-effective variables affecting properties such as gel formation, mechanical characteristics, and cellular behavior. Selection of particular concentrations within an operable range would have been obtainable through routine optimization using ordinary skill in the art. In the absence of evidence demonstrating that the claimed concentration range is critical or produces unexpected results relative to other workable concentrations, selection of concentrations within the claimed range would have been obvious.
Regarding claims 3 and 5: Yoo taught that cross -linkable polymers or hydrogels which can be used in the present invention include but are not limited to one or a mixture of polymers selected from the group consisting of pectinic acid (See Yoo [0089]).
Regarding claims 4 and 6-8: Yoo taught that the hydrogel is fibrin which is made of fibrinogen, thrombin and heparin. (See Yoo [0092]).
Regarding claim 12: Yoo taught a heparin concentration of 4.76 μg/μL (See Yoo [0146]).
Regarding claim 14 and 15: Yoo taught trypsinizing murine neural stem cell (NSC) line C17.2 grown in T-75 flasks for approximately 5 to 7 days to > 80% confluency murine neural stem cell (NSC) line C17.2 for cell printing. Yoo indicated that “For use in printing, the cells were trypsinized for 3 minutes at 37°C by using Trypsin-EDTA (2.5 g/L Trypsin, 0.38 g/L EDTA) after rinsing with Dulbecco's phosphate buffer saline (DPBS; ScienCell Research Laboratories), and resuspended in the growth medium at a concentration of 1x1O6 cells/mL upon centrifuging at 1000 rpm for 3 minutes.” (See Yoo [0152]). The centrifugation step of Yoo reads on the external force.
Regarding claim 22: It is pointed out that Abstract 322 taught colorectal cancer cell lines.
Regarding claims 23-25: [0196] of Yoo taught that “The final concentrations of the printed fibrin gel were as follows; 31.4 mg/mL for fibrinogen, 66 U/mL for aprotinin, 66.6 NIH U/mL for thrombin, 2.38 μg/μL for heparin, 5.9 mg/mL for CaCl2, 50 ng/μL for VEGF.” It is recognized that the concentrations of the agents are different from the claimed concentrations. It is however, it is pointed that where the general conditions of a claim are disclosed in the prior art, it is obvious to arrive at an optimum or workable ranges by routine experimentation. It is pointed out that the use of fibrin in the hydrogel composition was taught by Yu by addition of Fibrinogen and Thrombin. Although the concentrations disclosed by Yu are different, it is pointed out that arriving at the claimed concentrations would have been within the purview of a person of ordinary skill in the art, absent unexpected results.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Abstract 322 (Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24; AACR; Cancer Res 2020; hereinafter “Abstract 322;” See PTO-892) in view of Yoo (WO2010030964A2; published Jun 10, 2010; hereinafter “Yoo;” See PTO-892) Yue et al (Biomaterials. 2018 Jul; hereinafter "Yue;" See PTO-892) and Raghunath et al (J. Biomed. Mater. Res.; hereinafter “Raghunath;” See PTO-892) further in view of Kaiser et al (ACS Biomater Sci Eng. 2019 Feb 11; hereinafter "Kaiser;" See PTO-892).
Regarding claim 10: The teachings of Abstract 322 in view of Yoo, Yue and Raghunath are set forth above. None of the cited references teach the concentration of the ECM components between the claimed concentration. However, it is generally known that the concentration of extracellular matrix components can be readily optimized to achieve a desirable cell viability or tissue. For example, Kaiser taught that “increased fibrin concentration and seeding density were each associated with increased compaction, while increased collagen concentration was associated with decreased compaction.” (See Kaiser, p. 892, col. 2, 4th para). As such Kaiser taught that scaffold composition including ECM/fibrin content, cell seeding densities are optimizable variables to achieve desired tissue formation. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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