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 .
Compliance with 37 C.F.R. § 1.121
The amendments to the claims filed on 03/27/2026 is considered non-compliant , because the status “Previously Presented” for the claims 24-26 is incorrect. The claims 24-26 are withdrawn, and their status should be indicated as “withdrawn”. In the interest of compact prosecution, the amendments have been entered. Applicant is hereby notified that any future amendments that do not comply with 37 C.F.R. § 1.121 may not be entered.
Remarks
The amendments and remarks filed on 03/27/2026 have been entered and considered. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior office action. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn. Claims 1-29 are pending; Claims 28-29 are new; Claims 1-12 and 24-26 are withdrawn; and Claims 13-23 and 27-29 are under examination.
The restriction requirement set forth in the prior office action mailed on 12/29/2025 is still maintained since the elected claims under examination are not allowable.
Priority
This application, U.S. Application number 17/777786, is a national stage entry of International Application Number PCT/JP2020/042824 filed on 11/17/2020, which claims priority under 35 U.S.C. 119 (a)-(d) to JAPAN 2019-208933 filed on 11/19/2019.
English translation is not provided for the foreign priority application JAPAN 2019-208933. According to MPEP 706.02(b)(1)(C), the filing date of the priority document is not perfected unless applicant has filed a certified priority document in the application and an English language translation when the document is not in English (see 37 CFR 1.55(g)). Accordingly, the instant claims are afforded the filing date of the PCT application (11/17/2020), no that of foreign application.
Withdrawal of Rejections
The rejection of Claim 27 under 35 U.S.C. 103 over Atala et al. in view of Matsusaki et al. (as applied to Claims 13-18 and 21-23) further in view of Benjamin et al. is withdrawn due to Applicant’s persuasive arguments based on criticality of the mixing order defined in the claim 27 in the 03/27/2026 response (page 9/last para – page 10/para 2), which are supported by the factual evidence provided in Declaration under 37 CFR 1.132 by Inventor Yasuyuki Hiraoka, filed on 03/27/2026. Specifically, Inventor Hiraoka demonstrates in the Declaration (pages 4-5) that it is critical to mix a heparin solution, a collagen solution, a cell mixture, a thrombin solution, and a fibrinogen solution in the specific order defined in the claim 27 for achieving promotion of intercellular adhesion and formation of liver plate-like structures; and when the cells and components are added in a different order (i.e. the heparin, collagen, and cells are mixed with fibrinogen solution and then with thrombin solution), the cells are present in a undesirable granular shape due to inhibition of cell migration and organization, caused by immediate formation of fibrin.
The rejection of Claim 27 under 35 U.S.C. 103 over Shiro et al. in view of Atala et al. (as applied to claims 13-18 and 21-23) further in view of Benjamin et al. is withdrawn due to Applicant’s persuasive arguments based on criticality of the mixing order recited in the claim 27 in the 03/27/2026 response (page 9/last para – page 10/para 2), which are supported by the Declaration under 37 CFR 1.132 by Inventor Hiraoka, as indicated above.
Claim Objections
Claim 28 is objected to because of the following informality “at least 3.0 x 104 cells or more”. The recited term appears redundant. It is suggested to change the phrase to either “at least 3.0 x 104 cells” or “3.0 x 104 cells or more”. Appropriate correction is required.
Claim 29 is objected to because of the recitation of “the obtained structure is a liver sinusoidal network”. Given that the recited liver sinusoidal network is a part of the obtained structure, the phrase should be changed to “the obtained structure has a liver sinusoidal network” or to “the obtained structure comprises a liver sinusoidal network”. Appropriate correction is required.
Claim Rejections - 35 USC § 112, First Paragraph
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 28 is 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 claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Newly submitted Claim 28 is directed to the method of claim 27 for producing a cell structure, with the additional limitation: “wherein the cell mixture comprises at least 3.0 x10^4 cells or more”. Support for the claimed range of at least 3.0 x 104 cells or more is not found in the specification of the originally filed instant application. Applicant in the 03/27/2026 response points to the paragraph [0154] for a written description of the additional limitation, but such support is not found. It is noted that the paragraph [0154] only provides support for 3.0 x 104 cells, not for more than 3.0 x 104 cells. Therefore, claim 28 is directed to new matter.
Claim Rejections - 35 USC § 112(b), or 112, Second Paragraph
Claims 13-23 are 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 pre-AIA the applicant regards as the invention. This rejection is maintained.
Claim 13 is indefinite due to the recitation of “… performed under conditions in which aggregation of the extracellular matrix components … is restricted”. It is noted that the term “restricted” is not defined in the specification of the instant application. According to the Google Dictionary (see the printout for the meaning of “restricted”, of record), the term “restricted” appears to be a relative term and has a meaning similar to the term ‘small”. Without a benchmark, it is unclear at what specific level the aggregation of the extracellular matrix components can be considered as being restricted.
The remaining claims are rejected for depending from an indefinite claim.
Claim Rejections - 35 USC § 102
Claims 13-14, 17-18, and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Atala et al. (WO2017/070007, 2017, cited in IDS). This rejection is maintained.
Atala et al. teach a method for producing an artificial liver cell construct, comprising: forming a cell mixture of hepatocytes, sinusoidal vascular endothelial cells, Kupffer cells, hepatic stellate cells, and cholangiocytes, and sinusoidal endothelial cells; contacting the cell mixture with extracellular matrix components/proteins; and culturing the cell mixture while being in contact with the extracellular matrix components/proteins to form the liver cell construct (page 12/line 16 – page 13/line 5; page 2//lines 9-24; page 6/lines 25-28); wherein the extracellular matrix components are fibrous and comprise collagen (page 12/line 32 – page 13/line 2). It is noted that the sinusoidal vascular endothelial cells, Kupffer cells, and hepatic stellate cells cultured in the method of Atala et al. are hepatic non-parenchymal cells. Thus, the culturing step of Atala et al. is performed under conditions suitable for culturing hepatic non-parenchymal cells. Regarding the limitation “aggregation of the extracellular matrix components … is restricted” in Claim 13, it appears that the contacting step of Atala et al. is performed under the condition with aggregation of collagen being restricted, because the collagen in this step is controlled at specific concentration level, and it is mixed well with the cells without any indication of aggregation (see the Example of Atala et al.). Furthermore, the restricted aggregation is directed to the outcome of the claimed contacting step. Given Atala et al. teach a method comprising the same active steps, it is presumed that methods having substantially the same steps are capable of generating substantially the same outcome. Thus, the teachings of Atala et al. meet the claimed limitation.
Regarding the claim 14, the collagen is a fibrous protein, thus meeting the claimed limitation.
Regarding the claim 17, the limitation about accumulating cells and EMC components is directed to the outcome of the claimed contacting step. Given Atala et al. teach a method comprising the same active steps, it is presumed that methods having substantially the same steps are capable of generating substantially the same outcome. Thus, the teachings of Atala et al. meet the claimed limitation.
Regarding the claim 23, the recited term “angiogenesis promoting factors” is not defined in the specification of the instant application. Atala et al. teach the culture medium comprises human epidermal growth factor (page 12, line 8). Given human epidermal growth factor contributes to angiogenesis, it can be considered as an angiogenesis promoting factor, thus meeting the claimed limitation.
Therefore, in view of the teachings of Atala et al., the method of Claims 13-14, 17-18, and 21-23 is anticipated by the method of Atala et al.
Claims 13-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shiro et al. (JP2019033732, published on 2019-03-07, cited in IDS, machine-translated English version of record). This rejection is maintained.
Shiro et al. teach a method for producing a 3D liver cell construct in which hepatocytes are at an amount of 40% or more of a total cells, comprising steps: mixing/contacting cells comprising hepatocytes and vascular endothelial cells with polyelectrolyte/heparin and extracellular matrix components/collagen to form a mixture (mixed cell suspension); seeding/culturing the mixed cell suspension in an aqueous medium in a culture container; and obtaining the 3D liver cell construct, wherein the hepatocytes and vascular endothelial cells are human cells; and wherein the 3D liver cell construct is used for screening/evaluating a compound by culturing it with the 3D liver cell construct (Example 1; Claims 1-11, 15, and 19-20; paras 0020-21, 0027-28, 0030, 0061).
Regarding the limitation about conditions suitable for culturing hepatic non-parenchymal cells in claim 13, the condition of Shiro et al. is suitable for culturing vascular endothelial cells, thus meeting the requirement of the limitation. Regarding the limitation “aggregation of the extracellular matrix components … is restricted” in Claim 13, it appears that the contacting step of Shiro et al. is performed under the condition with aggregation of collagen being restricted, because the collagen in this step of Shiro et al. is mixed with the cells without any indication of aggregation. Furthermore, the restricted aggregation is directed to the outcome of the claimed contacting step, and. Given Shiro et al. teach a method comprising the same active steps, it is presumed that methods having substantially the same steps are capable of generating substantially the same outcome. Thus, the teachings of Shiro et al. meet the claimed limitation.
Regarding the claim 14, the collagen is a fibrous protein, thus meeting the claimed limitation.
Regarding the claim 17, the limitation about accumulating cells and EMC components is directed to the outcome of the claimed contacting step. Given Shiro et al. teach a method comprising the same active steps, it is presumed that methods having substantially the same steps are capable of generating substantially the same outcome. Thus, the teachings of Shiro et al. meet the claimed limitation.
Therefore, in view of the teachings of Shiro et al., the method of Claims 13-18 is anticipated by the method of Shiro et al.
Claim Rejections - 35 USC § 103
Claims 13-14 and 17-23 are rejected under 35 U.S.C. 103 as being unpatentable over Atala et al. (WO2017/070007, 2017, cited in IDS) in view of Michiya et al. (WO/2018/143286, published on 8/9/2018, cited in IDS, machine-translated English version of record). This rejection is maintained.
The teachings of Atala et al. are described above.
Regarding the claims 19 and 20, Atala et al. do not teach the extracellular matrix components/collagen comprise fragmented extracellular matrix components/collagen, and they do not teach the fragmented extracellular matrix components/collagen are defibrated extracellular matrix (ECM) components (i.e. defibrated collagen).
It would have been obvious to contact the cell mixture with defibrated ECM components/collagen in the method of Atala et al. for forming the cell structure, because it is well known in the art that compared to conventional ECM components, it is easy for defibrated ECM components such as defibrated collagen to come into contact with cells in an aqueous medium by being dispersed in an aqueous medium, which promotes formation of a more stable three-dimensional tissue structure. In support, Michiya et al. teach a method of forming a 3D tissue by using fragmented collagen, comprising (i) contacting cells with fragmented collagen in an aqueous medium; and (ii) culturing the cells in contact with the fragmented collagen for production of 3D tissue (paras 0029 and 0042, Example 2-13). Michiya et al. further teach a method of fragmenting collagen extracellular matrix by using a homogenizer such as an ultrasonic homogenizer, a stirring homogenizer, and a high-pressure homogenizer, wherein the fragmented collagen extracellular matrix has a length of 100 nm – 200 mm (paras 0040-0041). Michiya et al. further teach compared to conventional extracellular matrix, the fragmented extracellular matrix of their invention becomes easy to come into contact with cells in an aqueous medium by being dispersed in an aqueous medium, and promotes formation of a three-dimensional tissue (para 0040). Michiya et al. further teaches that their method that uses the fragmented collagen results in 3D tissue which is less susceptible to shrinkage/contraction because it allows for incorporation of higher collagen amount in the tissue (para 0011, para 3, Example 2-4). It is Noted that the fragmented extracellular matrix/collagen generated by method of Michiya et al. reads on the claimed “defibrated extracellular matrix components” in the claim 20, as evidenced by the disclosure in para 0036 of the specification of instant application. This provides motivation in and of itself, along with a reasonable expectation of success, because the fragmented collagen/extracellular matrix has advantages of easily contacting the cells and promoting generation of stable 3D cell structure (which provides the motivation), and it has been demonstrated in the art that fragmented collagen is readily applicable for generating 3D cell structure, as supported by Michiya et al. (providing reasonable expectation of success).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 13-18 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Atala et al. (WO2017/070007, 2017, cited in IDS) in view of Matsusaki (WO2017/146124US, 2017, cited in IDS, machine-translated English version of record). This rejection is maintained.
The teachings of Atala et al. are described above.
Regarding the claims 15 and 16, Atala et al. do not teach the contacting step is performed in the presence of polyelectrolyte, wherein the polyelectrolyte is heparin. However, it would have been obvious to perform the contact step by mixing the cells, extracellular matrix components/collagen, and polyelectrolyte/heparin in the method of Atala et al. for forming a 3D cell structure, because it is well known in the art that a combination of heparin and collagen facilitates the formation of 3D cell structure comprising a vascular network. In support, Matsusaki discloses a method for producing a three-dimensional cell structure comprising steps: contacting/mixing cells with an extracellular matrix component and a polymeric electrolyte (i.e. polyelectrolyte), and culturing the cells to obtain a three-dimensional cell tissue, wherein the extracellular matrix component and polyelectrolyte are respectively collagen and heparin; wherein the three-dimensional cell tissue comprises a vascular network; wherein the cells can comprise vascular endothelial cells (vein endothelial cells) and hepatocytes (Claims 1, 15, and 21; paras. 0031, 0059, 0061); and wherein the polyelectrolyte/heparin and extracellular matrix component/collagen are at a level from 0 to 1.0 mg/ml (paras 0026, 0028), or specifically 0.1 mg/mL collagen and 0.1 mg/mL heparin (paras. 0059 and 0061). This provides motivation in and of itself, along with a reasonable expectation of success, because a combination of heparin (polyelectrolyte) and collagen has the advantage of facilitating the formation of 3D cell structure comprising a vascular network (which provides motivation), and it is readily applicable to the method of Atala et al. for generating 3D cell structure, as supported by Matsusaki (providing reasonable expectation of success).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 13-20 are rejected under 35 U.S.C. 103 as being unpatentable over Shiro et al. (JP2019033732, published on 2019-03-07, cited in IDS, machine-translated English version of record) in view of Michiya et al. (WO/2018/143286, published on 8/9/2018, cited in IDS, machine-translated English version of record). This rejection is maintained.
The teachings of Shiro et al. and Michiya et al. are described above.
Regarding the claims 19 and 20, Shiro et al. do not teach the extracellular matrix components/collagen comprise fragmented extracellular matrix components/collagen, and they do not teach the fragmented extracellular matrix components/collagen are defibrated extracellular matrix (ECM) components (i.e. defibrated collagen).
It would have been obvious to contact the cell mixture with defibrated ECM components/collagen in the method of Shiro et al. for forming the 3D cell structure, because it is well known in the art that compared to conventional ECM components, it is easy for defibrated ECM components such as defibrated collagen to come into contact with cells in an aqueous medium by being dispersed in an aqueous medium, which promotes formation of a three-dimensional tissue structure less susceptible to shrinkage/contraction, as supported by Michiya et al. (described above). This provides motivation in and of itself, along with a reasonable expectation of success, because the defibrated collagen components have advantages of easily contacting the cells and promoting generation of a stable 3D cell structure (which provides the motivation), and it has been demonstrated in the art that fragmented collagen is readily applicable for generating 3D cell structure, as supported by Michiya et al. (providing a reasonable expectation of success).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 13-18 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Shiro et al. (JP2019033732, published on 2019-03-07, cited in IDS, machine-translated English version of record) in view of Atala et al. (WO2017/070007, 2017, cited in IDS). This rejection is maintained.
The teachings of Shiro et al. and Atala et al. are described above.
Regarding the claims 21-22, Shiro et al. do not teach the vascular endothelial cells are sinusoidal endothelial cells, the cell suspension mixture comprises hepatic stellate cells. However, Shiro et al. teach other types of cells may be included in the mixed cell suspension for forming the 3D cell structure.
It would have been obvious to include sinusoidal endothelial cells as the vascular endothelial cells and further include hepatic stellate cells in the mixed cell suspension in the method of Shiro et al. for forming the 3D cell structure, because Shiro et al. expressively teach including other types of cells in the mixed cell suspension for forming the 3D cell structure. Furthermore, it is well known in the art that the 3D cell structure can be effectively formed when sinusoidal endothelial cells are used as the vascular endothelial cells and hepatic stellate cells are included in the cell mixture, as supported by Atala et al. This provides motivation in and of itself, along with a reasonable expectation of success.
Regarding the claim 23, it would have been obvious to further include an angiogenesis promoting factor in the culturing step because Shiro et al. teach forming a vascular network structure in the 3D cell structure (para 0027), and it is well known in the art to include an angiogenesis promoting factor the medium in the culturing step, as supported by Atala et al.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Allowable Subject Matter
The subject matter of Claims 27-29 are free of art.
Claim 27 is allowed.
Response to Arguments
As a first matter, Applicant only traverses the rejections of Claim 27 under 35 USC 103 in the 03/27/2026 response (pages 9-11), but did not traverse or address the rejections of Claims 13-23 under 35 USC 102(a)(1) or 103 and the claims 13-23 have not been amended either to overcome the rejections. Applicant is reminded of 37 C.F.R. 1.111, requiring a complete reply to every ground of objection and rejection in the prior Office action.
Applicant's arguments about the rejection of Claims 13-23 under 35 USC 112(b) in the 03/27/2026 response (pages 11-12) have been fully considered but they are not persuasive. It is noted that since the disclosure of the specification cannot read on claims, the disclosure of the paragraphs 0077-0078 is not considered as the definition for the term “restricted”. In addition, Applicant’s arguments about components such as polyelectrolytes and fragmented extracellular matrix are based on the features not recited in the claims. Examiner reminds Applicant that the base claim 13 does not recite any limitation to require the cells to contact polyelectrolytes or fragmented extracellular matrix for restricting the aggregation. Furthermore, even assuming that the limitation “aggregation … is restricted” recited in claim 13 stands for the meaning of “result in more uniform cell structure” as Applicant argued, the claim 13 is still indefinite. This is because the “more” is a relative term, and in the absence of any benchmark or comparison phrase it is unclear which specific cell structure can be considered as a more uniform cell structure. Therefore, this rejection is maintained.
Applicant’s arguments about the 103 rejections of Claim 27 over Atala in view of Matsusaki and Benjamin, or over Shiro in view of Atala and Benjamin, in the 03/27/2026 response (pages 9-11) are based on Declaration under 37 CFR 1.132 by Inventor Hiraoka filed on the same day. As indicated above, the 103 rejections of the claim 27 are withdrawn because of Applicant’s persuasive arguments in the response (page 9/last para – page 10/para 2) and in the Declaration (pages 4-5) about criticality of the mixing order specifically defined in the claim 27. It is noted that Applicant’s remaining arguments in pages 10-11 of the response have been fully considered but they are moot given the rejections have been withdrawn for the reasons indicated above.
As indicated above, Applicant did not address the rejections of Claims 13-23 under 35 USC 102(a)(1) or 103 in the previous office action. Specifically, these rejections are: (i) the rejection of Claims 13-14, 17-18, and 21-23 under 35 U.S.C. 102(a)(1) as being anticipated by Atala et al.; (ii) the rejection of Claims 13-18 under 35 U.S.C. 102(a)(1) as being anticipated by Shiro et al.; (iii) the rejection of Claims 13-14 and 17-23 under 35 U.S.C. 103 over Atala et al. in view of Michiya et al.; (iv) the rejection of Claims 13-18 and 21-23 under 35 U.S.C. 103 over Atala et al. in view of Matsusaki; (v) the rejection of Claims 13-20 under 35 U.S.C. 103 over Shiro et al. in view of Michiya et al.; and (vi) the rejection of Claims 13-18 and 21-23 under 35 U.S.C. 103 over Shiro et al. in view of Atala et al. Examiner notes that the claims 13-23 have not been amended to overcome these rejections, and they do not comprise any novel features of Claim 27 about the critical order for mixing fibrinogen, thrombin, and other components for producing a cell structure. Therefore, these rejections have been maintained in this office action.
Conclusion
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 extension fee 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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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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