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 .
Claims 1, 5-7, 9-14, 17 and 18 are pending in this application and were examined on their merits.
The rejection of Claims 1, 6, 7, 9, 10, 11, 12, 14 and 17 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 (11/01/2017), all cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 08/17/2026.
The rejection of Claims 1, 5, 6, 7, 9, 10, 11, 12, 14 and 17 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), and further in view of Nakayama et al. (2014), all cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 08/17/2026.
The rejection of Claims 1, 6, 7, 9, 10, 11, 12, 13, 14 and 17 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 (11/01/2017), and further in view of Sakai (EP1857126A1), all cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 08/17/2026.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 9 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 9 recites, “the culturing”, however the claim depends from Claim 1 which recites, “culturing cells” as well as “culturing is continued” and “culturing is stopped”. It is unclear of the culturing time of Claim 9 is intended to limit one or all the Claim 1 recited culturing steps, such that the ordinary artisan would appreciate the metes and bounds of the claim. For purposes of examination the Examiner has interpreted the claim as requiring culturing cells for at least ten days to form a cell sheet.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 5-7, 9-14 and 17 are rejected under 35 U.S.C. § 101 because the claimed invention is directed to Judicial Exception(s) without significantly more. The claim(s) recite(s) Abstract Ideas and/or Mental processes. These judicial exceptions are not integrated into a practical application because they amount to a general linkage of the use of the JEs to a particular technological environment/field of use, that is, classifying white blood cells. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following analysis:
Step 1) The claims are drawn to a process
Step 2A, P1) The claims(1 and 18) recite the Judicial Exception of Abstract Ideas:
“evaluating the cell sheet of cultured cells” and “determining that said sheet of cultured cells shows immunostaining…”. These are data-gathering steps to obtain information about the natural immunostaining properties of the cultured cell sheet which are then interpreted by the practitioner with regard to the suitability of the cell sheet for grafting into an animal for cartilage repair.
Step 2A, P2) These judicial exceptions are not integrated into a practical
application because they amount to a general linkage of the use of the JEs to a
particular technological environment/field of use, that is, staining a cell sheet and making a determination as to its’ suitability for use as a graft based on immunostaining characteristics.
Step 2B) The claims do not recite additional elements that amount to significantly
more than the JEs. Claim 1 recites "culturing cells derived from a cartilage tissue on a surface of a membrane to produce a cell sheet, wherein a temperature-responsive polymer is immobilized on said surface”, “immunostaining said cell sheet using an antibody against type I collagen, an antibody against type II collagen, an antibody against aggrecan and Safranin O staining”. These are well known, routine and conventional activity, see for example, Takahashi et al. (04/5-08/2016), cited in the IDS, whom teaches a method comprising culturing (therefore continuing 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, and wherein the transplants were negative for immunostaining for safranin O and type II collagen (Lines 10-23). Claim 5 merely defines the amount of temperature-responsive polymer immobilized on the membrane surface,
Claims 6 and 10 merely further define a physical characteristic of the membrane and the orientation thereof with respect to the cells and culture media, Claim 7 further defines the type of membrane, Claim 9 merely defines the time of culturing, Claim 11 limits the temperature-responsive polymer, Claim 12 defines the cultured cells, Claim 13 defines the seeding density of the cells and Claims 14 and 17 merely define a characteristic of the cells.
Claim 18 contains a step of a practical application of the Judicial Exception of transplanting the cell sheet into an animal for cartilage repair. This is a specific application to a limited animal population in need of cartilage repair.
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, 7, 9, 12, 14, 17 and 18 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, in view of McPherson et al. (US 6,150,163) and Wang et al. (2001).
Takahashi et al. teaches a method for evaluating chondrocyte cell sheet for articular cartilage repair 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,
and 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, 14 and 18.
The teachings of Takahashi et al. were discussed above.
Takahashi et al. does not specifically teach the claimed limitations of:
the cell sheet shows positive in immunostaining with an antibody against type I collagen;
wherein culturing is continued until the cell sheet becomes positive for immunostaining using an antibody against aggrecan, as required by Claims 1 and 18;
or wherein the cell sheet is capable of being positive for immunostaining against fibronectin when culturing is stopped, as required by Claim 17.
McPherson et al. teaches a method wherein cells derived from cartilage tissue (chondrocytes) are cultured in a monolayer and further cultured before determining the differentiation state of the cell by gene expression analysis of type II and type I collagen and the cartilage specific proteoglycan aggrecan, safranin O staining was used to detect matrix deposition as well an antibody staining against type II collagen wherein the monolayer expressed type I collagen and trace type II collagen and aggrecan expression (Column 10, Lines 61-67 and Column 11, Lines 1-14).
Wang et al. teaches that immunostaining may be used to detect type I collagen, type II collagen and aggrecan in chondrocytes in vitro (Pg. 75, Table I).
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 method of preparing a cell-sheet for transplantation, transplanting the cell sheet into an animal for cartilage repair and then evaluating the transplanted cell sheet for immunostaining against type I collagen, and type II collagen and staining with Safranin O as taught by Takahashi et al. with the analysis of the cell sheet for type I collagen, immunohistological detection of type II collagen, aggrecan and safranin O taught by McPherson et al. and the use of antibodies against type I collagen and aggrecan as taught by Wang et al., prior to implantation because this would provide information as to the differentiation state of the chondrocytes in the cell sheet, whether the cells are producing cartilage specific proteoglycan and are depositing matrix.
Those of ordinary skill in the art would have found obvious the use immunohistochemistry of Wang in place of the gene analysis of McPherson because while both can be used to detect the presence of the compounds, immunochemistry provides detection of the actual protein in or produced by the cell. Those of ordinary skill in the art would have further found obvious the use of immunochemical staining prior to implantation as the staining can only be performed either before or after implantation. Those of ordinary skill in the art would have been motivated to make this modification in order to assess the characteristics of the chondrocytes in the cell sheet such as the differentiation state, whether the cells are producing cartilage specific proteoglycan and whether the cells are depositing matrix. There would have been a reasonable expectation of success in making this modification because all of the references are reasonably drawn to the same field of endeavor, that is, characterizing cultured chondrocytes.
With regard to 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 fibronectin). 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, would also, in view of the evidence of Maehara et al.; be expected to show positive immunostaining for fibronectin.
Claims 1, 6, 7, 9, 10, 11, 12, 14, 17 and 18 are rejected under 35 U.S.C. § 103 as being unpatentable over Takahashi et al. (04/5-08/2016), as evidenced by Maehara et al. (11/01/2017), both cited in the IDS, in view of McPherson et al. (US 6,150,163) and Wang et al. (2001), as applied to Claims 1, 7, 9, 12, 14, 17 and 18 above, and further in view of Kanai et al. (2014), cited in the IDS.
The teachings of Takahashi et al., McPherson et al. and Wang et al. were discussed above.
None of the above references taught 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., McPherson et al. and Wang 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 at least 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, 7, 9, 12, 14, 17 and 18 are rejected under 35 U.S.C. § 103 as
being unpatentable over Takahashi et al. (04/5-08/2016), as evidenced by Maehara et al. (11/01/2017), both cited in the IDS, in view of McPherson et al. (US 6,150,163) and Wang et al. (2001), as applied to Claims 1, 7, 9, 12, 14, 17 and 18 above, and further in view of Nakayama et al. (2014), cited in the IDS.
The teachings of Takahashi et al., McPherson et al. and Wang et al. were discussed above.
None of the above references taught 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, 7, 9, 12, 13, 14, 17 and 18 are rejected under 35 U.S.C. § 103 as
being unpatentable over Takahashi et al. (04/5-08/2016), as evidenced by Maehara et al. (11/01/2017), both cited in the IDS, in view of McPherson et al. (US 6,150,163) and Wang et al. (2001), as applied to Claims 1, 7, 9, 12, 14, 17 and 18 above, and further in view of Sakai (EP1857126A1), cited in the IDS.
The teachings of Takahashi et al., McPherson et al. and Wang et al. were discussed above.
None of the above references taught 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 1x103 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, see Remarks, filed 08/17/2026, with respect to the rejection(s) of claim(s) 1, 5-7, 9-14 and 17 under 35 U.S.C. § have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the newly applied interpretation and references as set forth 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 10/02/2026
