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 .
The amendment and response submitted on July 23,2025 has been entered.
Status of the Claims
Claims 1-19 are pending.
Claims 4, 6, 12 and 14 are amended.
Claims 1-16 and 19 are under current consideration.
Claims 17-18 are withdrawn.
The rejections of claim 6, 12, 13 and 14 under 112b are withdrawn in light of the amendments to the claims.
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.
Claim(s) 1-16 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Taniguchi (US2014/0289877-of record) in view of Rago (Biotechnology and Bioengineering, 2009-of record).
Regarding claims 1, 15 and 16, Taniguchi teaches a method of preparing a tissue or an organ by culturing an organ cell with a vascular endothelial cell and a mesenchymal cell and generating an organ bud (abstract). Taniguchi describes the formation of cell masses, spheroids and organ buds [0012] [0048] [0145]. Preparation of liver buds (LBs) is done on Matrigel® in a culture dish and so is done on a plane capable of cell adhesion [0063] [0117] [0129]. Taniguchi further teaches the three-dimensional organization of LBs in Transwell medium (culture medium is fed from both the obverse and reverse sides) [0053] [0154].
Regarding claim 3, the cell mass comprises vascular cells and mesenchymal cells [0107]. Regarding claims 4, 5, 9 and 10, Taniguchi discloses a preferable cell count ratio of organ cell:vascular endothelial cell:undifferentiated mesenchymal cell of 10:10-5:2-1 [0112]. However, Taniguchi discloses that culture ratios of the three cell types in coculture are not particularly limited as long as the ratio enables the formation of organ buds and that the three different cell components may be cultured at an optimal mixture ratio [0112] [0013]. Therefore, the cell ratios taught by Taniguchi fall within the claimed ratios and would have been optimized by a person of ordinary skill in the art to enable the effective formation of organ buds.
Regarding claim 6, the resulting three-dimensional tissue structure (fused cell mass) forms vascular networks [0154] [0038]. Regarding claim 7, the cell mass is an organ bud (a liver bud) [0154] and regarding claim 8, the organ bud has been formed from an organ cell [0016-0021]. With respect to claim 11, liver buds were cultured in two-dimensional conditions [0154] and culture dishes have surfaces that are non-cell adhesive such as the sides. With respect to claim 12, the organ bud is a liver bud and forms vascular networks [0154]. Regarding claim 13, vessel-like luminal structures are formed [0133]. With respect to claim 14, the liver bud forms bile ducts when transplanted [0216]. Regarding claim 19, Taniguchi discloses spheroid formation [0048].
Claims 6, 12, 13 and 14 contain a wherein clause that recites the intended result of the method rather than requiring an additional step be performed. MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, since these claims only recite the results of the steps, then art reading on claim 1 will also read on these results since performing the same steps will inherently lead to the same results in the absence of evidence to the contrary including unexpected results.
While Taniguchi teaches plating liver cells, vascular cells and mesenchymal cells and observing self-organization into macroscopically visible three-dimensional cell clusters after seeding and culturing as a culture medium is fed from both the obverse and reverse sides, Taniguchi does not teach seeding cell masses and culturing said cell masses under the claimed conditions.
However, Rago teaches a method for the easy production of 3D microtissues by microtissue fusion (pg. 1232, left col., par. 2). Spheroid-shaped microtissues (cell masses) were self-assembled and cultured for 1, 4 or 7 days, then harvested and subsequently seeded onto new micromolds where the microtissues contact one another and undergo fusion (pg. 1232, left col., par. 2; Fig. 4). The preformed microtissues are seeded into a micromolded agarose gel with trough recesses at a high enough density that they fill the trough, contact each other and undergo tissue fusion (the ratio of the area occupied by the cell masses to the seeded plane is 100%) (regarding claim 2) (pg. 1233, right col., par. 4-5). Furthermore, cell sorting that occurs after two heterotypic microtissues are fused of spheroids pre-cultured for 24 hours were similar to monodispersed cells but differed significantly when microtissues were pre-cultured for 4 and 7 days (pg. 1239, right col.). These heterotypic spheroids (having different types of cells) that have been assembled for 24 hours from monodispersed cells and have undergone self-sorting, which Rago calls “building units”, can be fused to form larger and complex structures (pg. 1240, left col, par. 1; Fig. 6), which were similar to those assembled from monodispersed cells in terms of shape, size and stability (pg. 1236, left col., par. 2). In addition, Rago teaches that structures made from fused microtissues (3D building units) can create novel structures, and also teaches that the shape of microtissues self-assembled from monodispersed cells is not limited to a spherical geometry, since complex lumen containing shapes such as toroids and honeycombs can be self-assembled from monodispersed cells or from preformed microtissues (pg. 1240, right col., par. 2).
Lastly, Rago concludes that use of pre-formed microtissues that undergo fusion may be advantageous relative to individual cells since microtissues may be better able to preserve their viability during handling procedures, microtissues already have a high cell density approximating that of native tissue, and microtissues create an immediate three-dimensional structure upon assembly, thus reducing the time necessary to create a structure (pg. 1240, left col., par. 4).
Accordingly, it would have been obvious to one of ordinary skill in the art at the effective filing date of the claimed invention to combine the method taught by Taniguchi of generating organ buds by co-culturing three types of cells on a plane capable of cell adhesion (Matrigel®) with Rago’s teachings regarding the ability of pre-formed spheroids to fuse and form larger and complex structures to arrive at the invention as claimed. A person of ordinary skill in the art would have been motivated to combine Taniguchi’s method with Rago’s since Rago teaches that structures made from fused pre-formed microtissues are large and complex, and that using preformed microtissues that undergo fusion is advantageous compared to individual cells for reasons regarding survival during handling, high cell density and reducing the time it takes to create a three-dimensional structure. Therefore, a person of skill in the art would have done it with the purpose of obtaining large and complex structures, such as vascularized organs in an effective way, with structures that better resist handling and in less time than when using monodispersed cells. Furthermore, a skilled artisan would have had a reasonable expectation o success since Rago taught that the structures obtained from fused pre-formed spheroids were similar to those obtained from individual cells, and Taniguchi was able to form liver buds with individual cells in a plane capable of cell adhesion.
In conclusion, the combination of Taniguchi and Rago renders an improved method of obtaining large and complex cellular structures that resemble organs by fusing pre-formed spheroids which are better suited for handling and can form such complex structures in less time than when using individual cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 7/23/25 have been fully considered but they are not persuasive.
Applicant argues that the examiner and her supervisor, during an interview held on July 9, 2025, agreed that Taniguchi and Rago are silent about “culturing cell masses as a culture medium is fed from both the obverse and reverse dies of the cell mass-seeded plane” as claimed.
In response, the rejection of record at the top of page 3 above states Taniguchi teaches liver buds which are cultured in Transwell medium, where the medium is fed from both obverse and reverse sides. See paragraphs [0053] and [0154] of Taniguchi. Applicant has not provided any evidence that Transwell culturing does not provide culture medium fed from both obverse and reverse sides of the seeded plane. Further the interview summary does not state that the examiner and her supervisor agreed that Taniguchi does not teach an obverse and reverse medium feed. It does state that the examiner would reconsider to ensure all aspects of the claim are covered by the applied references. Taniguchi teaches Transwell medium culturing, which has not been argued by Applicant.
Applicant also argues that Taniguchi does not teach or suggest a method of fusing cell mass in a culture medium from above and below the seeding surface and Rago fails to cure this deficiency.
In response, it is pointed out that Rago teaches fusion of cultured cell masses. See beginning at the bottom of page 4 above. Applicant has not provided any arguments stating why the fusion of cultured cell masses as taught by Rago does not meet the claim limitations.
Accordingly, the rejection is maintained for the reasons of record.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 Peter Paras whose telephone number is (571) 272-4517. The examiner can normally be reached Monday-Friday, 8:30 AM-5:30 PM ET. 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, Daniel Sullivan, can be reached on 571-272-0900. 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.
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632