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 .
This action is responsive to papers filed 03/12/2026.
No claims have been amended, newly added or newly canceled.
Claims 1-7, 9, 11-14, 16-17, 19-24 are currently pending.
Claims 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/23/2025.
Claims 17, 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/23/2025.
Claims 1-7, 9, 11-14, 16, and 22 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claim(s) 1-5, 7, 11-14, 16, and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Peeters et al (US 2010/0261270-previously cited) in view of Lee et al (Journal of Industrial and Engineering Chemistry, available online May 13, 2020) and Keisuke et al (JP 2015224332-using a machine translation).
Regarding claims 1 and 5, Peeters disclose methods for the production of cell sheets comprising at least two different cell types comprising steps of providing a cell sheet which is disposed on a substrate comprising shape transition properties and/or alterable surface characteristics; exposing the cell sheet to a releasing agent, washing the cell sheet after exposure to the releasing agent, and repopulating the gaps remaining after the cells which have been affect by the releasing agent have been removed (abstract, pages 1, para 16-20). The release of the patterned cell sheet which grows in culture on a substantially flat surface (a plurality of cells plated and grown on a petri dish) is provided by a stimulus such as raising and/or lowering the pH of the medium (page 5 para 97, 100) to obtain a substantially planar untethered cell sheet. Growing (culturing) the cells on a flat surface such that they are >90% confluence (at least 80% confluence) is disclosed (page 5 para 90) and inherently provides intercellular linkages to form a cell sheet form by self-assembly in culture.
Peeters is silent with regard to the pH levels used to release the patterned cell sheet from the substrate surface.
Keisuke disclose methods of using stimulus response type material for culturing cells. Keisuke disclose that when cells are cultured in a medium maintained at pH 6.8-7.6 that the cells grew without being detached, but when the pH fell to below 6.8 that the cells detached from the culture surface (page 5 last paragraph of the machine translation).
Lee disclose methods for detaching cell sheets without using enzymes using a pH-responsive substrate that dissolved in a medium with a pH of 6.0 (page 380, column 2).
One of ordinary skill in the art would have been motivated to lower the pH of the culture medium in the method of Peeters to less than 6.8, such as 6.0, because Keisuke teach and suggest that this is a suitable pH in order to release a cell sheet from a substrate. One of ordinary skill in the art would have had a reasonable expectation of success because Lee teach and suggest that human adipose-derived stem cell sheets exposed to this lower pH treatment showed similar cellular behavior and therapeutic efficacy for wound closing compared to the same cells detached with the more traditional trypsin (page 381, column 1). One of ordinary skill in the art would have been motivated to then replace the lower pH culture medium with a higher pH medium (such as 7.6 pH) for washing steps (steps d and e) and/or maintenance steps (steps d and e) of the untethered cell sheet because Keisuke disclose that a pH of 7.6 is a suitable pH for the maintenance of cells and cell sheets. One of ordinary skill in the art would have had a reasonable expectation of success because Peeters teach and suggest steps for washing the cell sheet as well (page 1 para 16).
Regarding claims 2-3, Peeters disclose wherein the plated cells are cultured using standard methods known in the art (page 5 para 90). It is standard practice in the art of cell culture to obtain animal cells from a tissue for plating in a culture vessel by first dissociating a plurality of cells from the tissue source to a single cell suspension using enzymes such as trypsin.
Regarding claim 4, Peeters discloses the use of differentiated cells for their cell sheets and Lee discloses that adipose derived stem cells (partially differentiated cells) are also suitable and beneficial for use in the formation of a cell sheet.
Regarding claim 7, Peeters disclose stacking two or more cell sheets (pages 4-5, para 72, para 81-87).
Regarding claim 11, Peeters suggest wherein at least one region of cell non-adhesive material on the substantially flat surface prevents the plurality of cells from attaching to the at least one region (page 2 para 22-26).
Regarding claim 12, Peeters teach and suggest applying electrical stimuli to the plurality of cells after plating (pages 2-3 para 38).
Regarding claim 13, Peeters disclose wherein the plurality of cells comprise multiple cell types (page 1 para 16).
Regarding claim 14, Peeters disclose wherein the cells comprise animal cells (mouse cells) (page 5 para 90).
Regarding claims 16 and 22, Peeters does not specifically disclose the use of stem cells for their cell sheets, but they do indicate that the cell sheets are for the treatment of a human (page 5 para 87) and Lee disclose that cell sheets comprised of human adipose-derived stem cells (animal cells) are beneficial for use in therapeutic methods (page 381, column 1). Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use human adipose-derived stem cells in the method of Peeters because Lee suggest that they form cell sheets that have therapeutic benefits and Peeters teaches using their cell sheets for the treatment of humans.
Therefore, the combined teachings of Peeters et al, Keisuke et al and Lee et al render obvious Applicant’s invention as claimed.
Claim(s) 6 remains rejected under 35 U.S.C. 103 as being unpatentable over Peeters et al (US 2010/0261270-previously cited) in view of Lee et al (Journal of Industrial and Engineering Chemistry, available online May 13, 2020) and Keisuke et al (JP 2015224332-using a machine translation) as applied to claims 1-5, 7, 11-14, 16, and 22 above, and further in view of Zhou, Shi (CN 108559700).
Regarding claim 6, the combined teachings of Peeters et al, Keisuke et al and Lee et al render obvious Applicant’s invention as described above, but do not specifically disclose transferring the cell sheet to a different culture medium in order to change the pH of the culture.
Zhou disclose a cell sheet transferring device and processing system (Title and abstract). Zhou teach and suggest where their cell sheet transferring device can be used culture, wash and transport cell sheets without damaging the cell sheet (page 2 of the machine translation).
One of ordinary skill in the art would have been motivated to use the cell sheet transferring device of Zhou in the cell sheet production method of Peeters with a reasonable expectation of success because Zhou teach and suggest that this transferring device allows for the culture, wash and transport of cell sheets without damaging the cell sheet.
Therefore, the combined teachings of Peeters et al, Keisuke et al, Lee et al and Zhou render obvious Applicant’s invention as claimed.
Claim(s) 9 remains rejected under 35 U.S.C. 103 as being unpatentable over Peeters et al (US 2010/0261270-previously cited) in view of Lee et al (Journal of Industrial and Engineering Chemistry, available online May 13, 2020) and Keisuke et al (JP 2015224332-using a machine translation) as applied to claims 1-5, 7, 11-14, 16, and 22 above, and further in view of Cooper et al (US 2009/0275129).
Regarding claim 9, the combined teachings of Peeters et al, Keisuke et al and Lee et al render obvious Applicant’s invention as described above, but do not specifically disclose rolling or folding the cell sheet.
Cooper disclose methods for producing tissue engineered blood vessels to treat patients with vascular disease (abstract). Cooper disclose wherein cell sheets can be rolled into a tube form to form a construct that can be used as a tissue engineered blood vessel (page 12 para 101, 103, pages17-18, para 148).
One of ordinary skill in the art would have been motivated to roll the cell sheets method of Peeters with a reasonable expectation of success because Cooper teach and suggest that rolled cell sheets can be used to treat patients with vascular disease and Peeters also discloses using their cell sheets to treat patients as well.
Therefore, the combined teachings of Peeters et al, Keisuke et al, Lee et al and Cooper et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 03/12/2026 have been fully considered but they are not persuasive.
Applicant argues that the references cited in the 103 rejection do not disclose or lead one of ordinary skill in the art to the presently claimed steps. Applicant first argues that Peeters does not disclose the pH used to release the cell sheets and then argues that Lee and Keisuke do not teach the claimed invention as well.
This is not found persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In the current case, Peeters teaches all the limitations of claim 1 except for the specific pH values that were to be used for detaching and maintaining the cell sheet. These pH values are well known in the art and taught and suggested by Lee and Keisuke as described above.
Applicant argues that Lee only teaches detachment of individual cells and not a cell sheet and further leaches that when the polymer concentration is low that exposure to low pH does not lead to significant detachment from the substrate.
This is not found persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In the current case the obviousness rejection is based on the modification of the Peeters method as described above. Lee is cited in the obviousness rejection to demonstrate that cell sheets can be exposed to a pH of 6.0 during detachment and still provide a cell sheet for further use. This 6.0 pH value of Lee coincides with the teaching of Keisuke which indicates that a suitable pH for detaching a cell sheet needs to be less than 6.8 and the teaching of Peeters which indicates that their cell sheets can be detached by lowering the pH as described above.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant argues that Keisuke only states that when cultured in medium maintained at pH 6.6 to 7.6 that cells grew without being detached and that when pH fell below 6.8 due to bacterial contamination that the cells were detached from the culture surface. Applicant argues that Keisuke like Lee uses stimuli responsive polymers for inducing delamination.
This is not found persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the current case the teachings of Lee and Keisuke are relied upon to demonstrate specific pH values of the culture environment are known for affecting cell attachment to a substrate and detaching and maintaining cell sheets as described above.
Applicant argues that there is no teaching or suggestion in Lee or Keisuke of a stepwise treatment of acid, basic and neutral culture medium to release a cell sheet from a surface. Applicant argues that only these specific steps resulted in the detachment of cells from the surface of standard tissue culture plates that do not need a stimulus responsive polymer as taught in Lee and Keisuke and maintenance of the cells in a substantially planar cell sheet. Applicant points to their specification at pages 24-25 and Figure 2C to demonstrate their invention.
This is not found persuasive. Peeters is the primary reference in the obviousness rejection and it is Peeters that teaches modifying the pH of the cell culture in order to detach the cell sheet from the substrate as described above. While Peeters is silent with regard to exact pH values to be used to carry out this cell sheet detachment and maintenance process, the teachings of Lee and Keisuke are relied upon to demonstrate that the specific pH values that affect cell attachment and maintenance are well known in the prior art as described above. In addition, with regard to the references to the specification and Figure 2C, these limitations are not necessarily required by the claims.
According to M.P.E.P. § 2111, the pending claims must be given their broadest reasonable interpretation consistent with the specification. Broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In In re Prater (citations omitted), the court ruled that ‘reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from reading limitations of the specification into a claim,' to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim. The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ravkin et al., “Multiplexed Cell Analysis System”, US 2003/0059764, (specifically page 18 paragraph 241, which states that cells may be detached from a substrate by any suitable method including a pH change).
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 LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631
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