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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/10/2026 has been entered.
Claims 1, 5, 6, 7, 9-14 and 17 are pending in this application and were examined on their merits.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 02/10/2026 is insufficient to overcome the rejection of claims 1, 6, 7, 9-12 and 14 based upon Takahashi et al. (04/5-08/2016) in view of Kanai et al. (2014), as evidenced by Maehara et al. (11/01/2017), all cited in the IDS as set forth in the last Office action because:
The Declarant argues that Takahashi reported poor treatment outcomes and no positive results for type II collagen even after implantation in animal experiments (Declaration, Pg. 2, #8).
This is not found to be persuasive for the following reasons, the reference was not cited for its treatment outcomes and the reference remains relevant for its’ teachings even of non-preferred embodiments. The Examiner notes that similar to Takahashi, the current claims require that type II collagen be negative for immunostaining after culturing is stopped (e.g. implantation occurs), thus the reference meets the claimed limitation.
The Declarant argues that the cultured cell sheet of Takahashi and Maehara are different (noting that the cell sheet of Takahashi is not positive for type II collagen) and Maehara only performed pre-implantation analysis. Declarant concludes that, in his opinion, the cell sheets of Takahashi and Maehara are not the same (Declaration, Pg. 2, #9 and Pg. 3, #s 11-12 and Pg. 3, #16).
This is not found to be persuasive for the following reasons, as discussed below, the cell sheet transplants of Takahashi were negative for immunostaining for safranin O and type II collagen after transplantation. Maehara evidences that culturing the same cells, on the same substrate, for the same period of time will result in a cell sheet which is capable of immunostaining (e.g. when culturing is stopped) for: safranin O (negative), type Il collagen (negative), type I collagen (positive), fibronectin (positive) and aggrecan (positive). The Examiner notes that both Takahashi and Maehara exemplify cell sheets which are negative for staining against type II collagen, and therefore Declarant has not provided evidence that the cell sheets would not be expected to have the same properties and characteristics.
The Declarant argues that Takahashi does not teach or describe the state of the cell sheet before transplantation, particularly with regard to Safranin O and aggrecan and therefore the ordinary artisan would not have been motivated to focus on these characteristics prior to transplantation (Declaration, Pg. 3, # 14).
This is not found to be persuasive for the following reasons, the claims only require that the cell sheet be “capable” of being positive for immunostaining against aggrecan and that culturing is stopped before the cell sheet is “capable” of being positive for safranin O immunostaining.
Takahashi already teaches the cell sheet transplants of Takahashi were negative for immunostaining for safranin O and type II collagen after transplantation and Maehara evidences that culturing the same cells, on the same substrate, for the same period of time will result in a cell sheet which is capable of negative immunostaining (e.g. when culturing is stopped or prior to implantation ) for: safranin O and positive immunostaining for aggrecan. Thus, the ordinary artisan would have expected both cell sheets to have the same properties and characteristics.
The Declarant argues that the cell sheets of Takahashi (before transplantation) have not been confirmed to be positive for type II collagen after transplantation and thus would not be suitable for transplantation (Declaration, Pg. 3, #15).
This is not found to be persuasive for the following reasons, the claims do not require that the cell sheets be conformed to be positive for type II collagen after transplantation, merely that “the cell sheet is ‘evaluated’ for immunostaining against type II collagen and is ‘suitable’ for cartilage repair when the cell sheet…” is negative for staining against type II collagen. As discussed below, Takahashi already teaches the cell sheet transplants of Takahashi were negative for immunostaining for safranin O and type II collagen after transplantation and Maehara evidences that culturing the same cells, on the same substrate, for the same period of time will result in a cell sheet which is capable of immunostaining (e.g. when culturing is stopped) for type Il collagen (negative). Thus, the ordinary artisan would have expected both cell sheets to have the same properties and characteristics.
The Declarant argues that Takahashi does not teach or suggest that the cell sheets that are evaluated as negative for type II collagen become type II positive after transplantation (Declaration, Pg. 3, #16).
In response to Declarant's argument that the reference fails to show certain features of the invention, it is noted that the features upon which Declarant relies (i.e., that the cell sheets that are evaluated as negative for type II collagen become type II positive after transplantation) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The Declarant argues that the ordinary artisan would not find the specific claimed staining conditions for obtaining a cell sheet suitable for transplantation to be obvious over Takahashi. Declarant notes that at the time of the invention, it was considered important for a cell sheet to be positive for type II collagen and the inventors discovered that after evaluating a cell sheet as negative for type II collagen, it would become positive after transplantation (Declaration, Pg. 4, #17-19).
The Examiner maintains that the ordinary artisan would find the claimed invention obvious for reasons of record set forth below.
The Examiner notes that features upon which Declarant relies (i.e., that the cell sheets that are evaluated as negative for type II collagen become type II positive after transplantation) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim Rejections - 35 USC § 103
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.
Claims 1, 6, 7, 9, 10, 11, 12, 14 and 17 are rejected under 35 U.S.C. § 103 as being unpatentable over Takahashi et al. (04/5-08/2016) in view of Kanai et al. (2014), as evidenced by Maehara et al. (11/01/2017), all cited in the IDS.
Takahashi et al. teaches a method comprising: culturing (therefore continuing
culturing) chondrocyte cells from polydactyly (PDT) cartilage (e.g., not synovium) tissue
on the surface of a temperature-responsive culture inserts (a membrane as evidenced
by instant Claim 7) for two weeks to form cell sheets, before transplantation (thereby
stopping culturing) into rabbits,
wherein after four weeks the transplants were immunostained for type I collagen, safranin O and type II collagen,
wherein the transplants were negative for immunostaining for safranin O and
type II collagen (Lines 10-23), and reading on Claims 1, 7, 9, 12 and 14.
The teachings of Takahashi et al. were discussed above.
Takahashi et al. does not specifically teach or is silent with regard to the claimed
limitation of:
the cell sheet shows positive in immunostaining with an antibody against type I
collagen (thereby being capable of being positive for staining using an antibody against
type I collagen when culturing is stopped);
wherein culturing is continued until the cell sheet becomes capable of being positive for immunostaining using an antibody against aggrecan, as required by Claim 1;
or wherein the cell sheet is capable of being positive for immunostaining against fibronectin when culturing is stopped, as required by Claim 17.
Post-filing, evidentiary reference Maehara et al. (11/01/2017) evidences the
culturing cartilage derived chondrocytes of young polydactyly subjects (PDC) onto
temperature responsive culture inserts and culturing for two weeks (Pg. 2, Column 2,
Lines 21-51) followed by immunostaining for safranin O (negative), type Il collagen
(negative), type I collagen (positive), fibronectin (positive) and aggrecan (positive) (Pg. 4, Column 2, Lines 25-30).
In this instance, post-filing evidentiary reference Maehara et al. (11/01/2017) is cited as evidence of the inherent characteristics and properties of a cultured cell
sheet comprising cartilage derived chondrocytes of young polydactyly (PDC) subjects
after two weeks of culturing. See the MPEP at 2124 for a discussion of post-filing
evidentiary references. Therefore, as the PDC sheets of Takahashi et al. were obtained
from the same origin, cultured under the same conditions, and immunostained against
the same markers as Maehara et al. and the instant invention, they should also
inherently have the same characteristics and properties with regard to immunostaining
of the cell sheet (specifically against type I collagen, type II collagen, fibronectin, safranin O and aggrecan). See the MPEP at 2112.01, I. & II.
Thus, Takahashi et al. whom teaches culturing chondrocyte cells from
polydactyly (PDT) cartilage tissue on the surface of a temperature-responsive culture
inserts for two weeks to form cell sheets, before transplantation (thereby stopping
culturing) into rabbits wherein after four weeks the transplants were immunostained for
type I collagen, safranin O and type II collagen, and wherein the cell sheet transplants were negative for immunostaining for safranin O and type Il collagen would also, in view of the evidence of Maehara et al.; 1) be expected to show positive immunostaining for type I collagen, fibronectin and aggrecan.
Takahashi et al. did not specifically teach wherein the membrane is a pore
membrane, and in the culturing, the cells are in contact with a culture medium on an
upper side of the pore membrane and in contact with a culture medium on a lower side
of the pore membrane through pores in the pore membrane, as required by Claims 6
and 10;
or wherein the temperature-responsive polymer being immobilized on the
membrane surface is poly(N-isopropylacrylamide), as required by Claim 11.
Kanai et al. teaches a cell sheet production method wherein temperature-
responsive cell culture inserts having a pore membrane with cells thereon are in contact
with a culture medium on an upper side of the membrane and in contact with a culture
medium on a lower side of the pore membrane through pores in the pore membrane
(Pg. 3, Fig. 2),
and wherein the temperature-responsive polymer poly(N- isopropylacrylamide) is
immobilized on the surface of the pore membrane (Pg. 2, Fig. 1A and Pg. 3, Fig. 2).
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the claimed invention to modify the cell sheet production method of
Takahashi et al. whom cultures cells on temperature-responsive culture inserts to use
temperature-responsive cell culture inserts wherein the temperature-responsive polymer
poly(N-isopropylacrylamide) is immobilized on the surface of the pore membrane and
culturing so that the cells on the pore membrane are in contact with a culture medium
on an upper side of the membrane and in contact with a culture medium on a lower side
of the pore membrane through pores in the pore membrane as taught by Kanai et al.
because Takahashi et al. does not specify whether their membrane is porous, what the
temperature-responsive polymer is and how it is configured on the insert or the culturing
conditions and Kanai et al. teaches a suitable cell culture insert and culture conditions
for producing a cell sheet. Those of ordinary skill in the art would have been motivated
to make this modification in order to produce a cell sheet on a temperature-responsive
polymer coated porous cell culture insert. There would have been a reasonable
expectation of success in making this modification because both Takahashi and Kanai
are directed to the same field of endeavor, that is, producing cells sheets using
temperature-responsive polymer coated culture apparatus.
Claims 1, 5, 6, 7, 9, 10, 11, 12, 14 and 17 are rejected under 35 U.S.C. § 103 as being unpatentable over Takahashi et al. (04/5-08/2016) in view of Kanai et al. (2014), as evidenced by Maehara et al. (11/01/2017), as applied to Claims 1, 6, 7, 9, 10, 11, 12, 14 and 17 above, and further in view of Nakayama et al. (2014), all cited in the IDS.
The teachings of Takahashi et al. and Kanai et al. were discussed above.
Neither Takahashi et al. or Kanai et al. teach a method wherein the amount of
temperature-responsive polymer immobilized on the surface of the membrane is 0.3 to
5.0 µg/cm², as required by Claim 5.
Nakayama et al. teaches a method of culturing cells to produce cell sheets on
temperature-responsive polymer coated cell culture substrates (Pg. 1, Abstract and Fig.
1) wherein the amount of immobilized polymer was from 1.18-1.60 µg/cm² (which lies
inside the claimed range) and is therefore rendered prima facie obvious. See the MPEP
at 2144.05, I. Those of ordinary skill in the art would have been motivated to make this
modification to the temperature-responsive polymer coated culture inserts of Takahashi
et al. because Takahashi does not teach what amount of temperature responsive
polymer is immobilized on the culture inserts and Nakayama teaches a specific amount
of temperature-responsive polymer which can be immobilized onto cell culture
substrates for use in producing cell sheets. There would have been a reasonable expectation of success in making this modification because at least both Takahashi and Nakayama are directed to the same field of endeavor, that is, producing cells sheets using temperature-responsive polymer coated culture apparatus.
Claims 1, 6, 7, 9, 10, 11, 12, 13, 14 and 17 are rejected under 35 U.S.C. § 103 as being unpatentable over Takahashi et al. (04/5-08/2016) in view of Kanai et al. (2014), as evidenced by Maehara et al. (11/01/2017), as applied to Claims 1, 6, 7, 9, 10, 11, 12, 14 and 17 above, and further in view of Sakai (EP1857126A1), all cited in the IDS.
The teachings of Takahashi et al. and Kanai et al. were discussed above.
Neither Takahashi et al. or Kanai et al. teach a method wherein the polydactyly
chondrocytes are seeded into the membrane in an amount of 1x104 cells/cm², as
required by Claim 13.
Sakai teaches a method of plating articular chondrocyte cells into a temperature-
responsive polymer in an amount of 0.7 x 10⁴ cells/cm² (Column 15, Paragraphs 0052]-
[0053] and wherein the cells are seeded at a density of at least 0.1 cells/cm² (Column
20, Claims 19 and 22).
While the Takahashi reference does not specifically teach the limitation of Claim
13, one of ordinary skill in the art would recognize that the cell seeding density is a
result-effective, optimizable variable. Sakai teaches an articular chondrocyte seeding
density of 0.7x10⁴ cells/cm2 and at least 0.1x10⁴ cells/cm².
These are endpoints in a useful concentration range which encompasses the claimed amount of 1x10⁴ cells/cm². This is motivation for someone of ordinary skill in the art to practice or test cell seeding values widely to find those that are functional or optimal to produce the desired cell sheet which then would be inclusive or cover the instantly claimed value. Absent any teaching of criticality by the Applicant concerning the cell seeding density, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain the desired cell sheet. There would have been a reasonable expectation of success in making these modifications because at least the Takahashi and Sakai references are reasonably drawn to the same field of endeavor, that is, plating articular chondrocytes onto temperature-sensitive polymer coated substrates to produce cell sheets.
Response to Arguments
Applicant's arguments filed 02/10/2026 have been fully considered but they are not persuasive.
The Applicant argues that Claim 1 defines that after culturing is stopped, the cell sheet is negative for type II collagen immunostaining but the inventor’s that the cell sheet is suitable for transplantation when the sheet is negative for type II collagen but becomes positive for after transplantation (Remarks, Pg. 5, Lines 22-29 and Pg. 6, Lines 1-6).
This is not found to be persuasive for the following reasons, in response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the sheet which is negative for type II collagen becomes positive for after transplantation) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Since no transplantation is required to occur, the cell sheet transplants of Takahashi which were negative for immunostaining type II collagen after transplantation (e.g. culturing stops) meet the claimed limitation.
The Applicant argues that it was discovered that after evaluating a cell sheet as negative for type II collagen staining, the sheet becomes positive for type II collagen after transplantation. Thus, the ordinary artisan would not understand that the claimed cell sheet suitable for transplantation could be obtained as the reference only describes cell sheets which are not suitable for transplantation (Remarks, Pg. 6, Lines 7-17).
This is not found to be persuasive for the following reasons, the Applicant’s “discovery” is not relevant as the claims do not require that the sheet becomes positive for type II collagen after transplantation. The reference was not cited for its treatment outcomes and the reference remains relevant for its’ teachings even of non-preferred embodiments. The Examiner notes that similar to Takahashi, the current claims require that type II collagen be negative for immunostaining after culturing is stopped (e.g. implantation occurs), thus the reference meets the claimed limitation.
The Applicant argues that the cell sheets of Takahashi and Maehara are bot the same and would not be expected to have the same immunostaining characteristics (Remarks, Pg. 7, Lines 5-9).
This is not found to be persuasive for the following reasons, as discussed above, the cell sheet transplants of Takahashi were negative for immunostaining for safranin O and type II collagen after transplantation. Maehara evidences that culturing the same cells, on the same substrate, for the same period of time will result in a cell sheet which is capable of immunostaining (e.g. when culturing is stopped) for: safranin O (negative), type Il collagen (negative), type I collagen (positive), fibronectin (positive) and aggrecan (positive). The Examiner notes that both Takahashi and Maehara exemplify cell sheets which are negative for staining against type II collagen, and therefore Applicant has not provided evidence that the cell sheets would not be expected to have the same properties and characteristics.
The Applicant argues
The Declarant argues that Takahashi does not teach or describe the state of the cell sheet before transplantation, particularly with regard to Safranin O and aggrecan and therefore the ordinary artisan would not have been motivated to focus on these characteristics prior to transplantation (Declaration, Pg. 3, # 14).
This is not found to be persuasive for the following reasons, the claims only require that the cell sheet be “capable” of being positive for immunostaining against aggrecan and that culturing is stopped before the cell sheet is “capable” of being positive for safranin O immunostaining.
Takahashi already teaches the cell sheet transplants of Takahashi were negative for immunostaining for safranin O and type II collagen after transplantation and Maehara evidences that culturing the same cells, on the same substrate, for the same period of time will result in a cell sheet which is capable of negative immunostaining (e.g. when culturing is stopped or prior to implantation ) for: safranin O and positive immunostaining for aggrecan. Thus, the ordinary artisan would have expected both cell sheets to have the same properties and characteristics.
The Declarant argues that the cell sheets of Takahashi (before transplantation) have not been confirmed to be positive for type II collagen after transplantation and thus would not be suitable for transplantation (Declaration, Pg. 3, #15).
This is not found to be persuasive for the following reasons, the claims do not require that the cell sheets be conformed to be positive for type II collagen after transplantation, merely that “the cell sheet is ‘evaluated’ for immunostaining against type II collagen and is ‘suitable’ for cartilage repair when the cell sheet…” is negative for staining against type II collagen. As discussed below, Takahashi already teaches the cell sheet transplants of Takahashi were negative for immunostaining for safranin O and type II collagen after transplantation and Maehara evidences that culturing the same cells, on the same substrate, for the same period of time will result in a cell sheet which is capable of immunostaining (e.g. when culturing is stopped) for type Il collagen (negative). Thus, the ordinary artisan would have expected both cell sheets to have the same properties and characteristics.
The Applicant argues that Takahashi does not teach or suggest that the cell sheets that are evaluated as negative for type II collagen become type II positive after transplantation and that the ordinary artisan would not find the specific claimed staining conditions for obtaining a cell sheet suitable for transplantation to be obvious over Takahashi. Applicant notes that at the time of the invention, it was considered important for a cell sheet to be positive for type II collagen and the inventors discovered that after evaluating a cell sheet as negative for type II collagen, it would become positive after transplantation (Remarks, Pg. 7, Lines 11-29 and Pg. 8, Lines 1-10).
In response to Applicant's argument that the reference fails to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., that the cell sheets that are evaluated as negative for type II collagen become type II positive after transplantation) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner maintains that the ordinary artisan would find the claimed invention obvious for reasons of record set forth above.
The Applicant argues that the Declaration provides rebuttal evidence against the obviousness rejection (Remarks, Pg. 8, Lines 12-27).
This is not found to be persuasive for the reasoning provided in the Response to Amendment above.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/Examiner, Art Unit 1653 04/07/2026
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