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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/5/2025 has been entered.
Claims status
Claims 7-9 is/are cancelled. Claims 1, 2, 10, 14-23, 25 and 26 is/are currently pending and is/are under examination.
Claim Rejections - 35 USC § 112(b) - Withdrawn
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.
Rejection of Claims 7-9 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 is moot due to claim cancellation.
Claim Rejections - 35 USC § 112(d) – Withdrawn
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Rejection of Claims 7-9 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is moot due to claim cancellation.
Claim Interpretation – Updated to incorporate claim amendments
Claims 1, 20 and 25 are product claims that each recite a process step(s) therefore these claims are interpreted as product-by-process claims. According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
Claim 1 is directed to the following product: a cell microsheet of area 20mm2 or less comprising chondrocytes, chondroblasts or cartilage-like cells. Claim 20 is similar to claim 1 however requires the cell microsheet to comprise mammalian-derived cells and have an area within the recited range of 0.02-20mm2. Claim 25 recites an additional process step.
The process step recited in claims 1 and 20 is “the microsheet is formed by culturing cells on a surface of a cell cultureware, a stimulus-responsive polymer being immobilized on the surface of the cell cultureware, the surface having divisions of 20 mm2 or less formed by grid walls, and detaching the cells from the cell cultureware, and the cells in the culture of cells are derived from articular cartilage tissue of an animal with polydactyly, wherein said culturing cells consists of two-dimensional cultivation without three-dimensional cultivation.” The process step recited in claim 25 is “wherein said stimulus-responsive polymer is a temperature-responsive polymer and wherein cells are separated from the temperature responsive polymer without use of proteolytic enzyme by allowing the microsheets to stand at room temperature for 30 minutes or more”.
The structure implied by the process step(s) is that the generated microsheet is a two-dimensional structure i.e. a sheet and would have an area less than 20mm2 and the cells that form the microsheet are derived from a specific source i.e. articular cartilage tissue of an animal with polydactyly. The structural limitation pertaining to the size of the cell microsheet is already positively recited to limit the structure of the product i.e. the cell microsheet is required to be less than 20mm2 (for claim 1) or 0.02-20mm2 (for claims 20, 25). Therefore, in the absence of evidence to the contrary, the recited process steps provide the following structure to the product of claim 1: a cell microsheet of area 20mm2 or less comprising chondrocytes, chondroblasts or cartilage-like cells derived from articular cartilage tissue of an animal with polydactyly. Similarly, the structure to the product of claim 20 is: a cell microsheet of area 0.02-20mm2 comprising mammalian chondrocytes, chondroblasts or cartilage-like cells derived from articular cartilage tissue of an animal with polydactyly.
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.
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.
Rejection of Claim(s) 1, 2, 7, 8, 14-20, 22, 23, 25 under 35 U.S.C. 103 as being unpatentable over Mori (Journal of Hard Tissue Biology, 2014; ref of record) in view of Cavalli et al (Sci Reports, 2019; ref of record) is withdrawn in favor of the new grounds of rejection below.
Rejection of Claim(s) 7-9 under 35 U.S.C. 103 as being unpatentable over Mori (Journal of Hard Tissue Biology, 2014) in view of Cavalli et al (Sci Reports, 2019; ref of record) as applied to claims 1, 7, 8 above, and further in view of Lee et al (Stem Cell Research & Therapy (2017) 8:244; ref of record) is moot due to claim cancellation.
Rejection of Claim(s) 10, 21 and 26 under 35 U.S.C. 103 as being unpatentable over Mori (Journal of Hard Tissue Biology, 2014) in view of Cavalli et al (Sci Reports, 2019; ref of record) as applied to claims 1, 20 and 25 above, and further in view of Wang et al (Cardiovascular Research, 2008; ref of record) and Akahane et al (J Tissue Eng Regen Med 2010; 4: 404–411; ref of record) is withdrawn because previous U.S.C. 103 rejection of claims 1, 20 and 25 that the instant rejection depended from is now withdrawn.
Claim(s) 1, 2, 14-20, 22, 23, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mori (Journal of Hard Tissue Biology, 2014; ref of record) in view of Sato (US 2018/0243476 A1, Aug. 30, 2018).
Regarding claims 1, 2, 14-19, 20, 22, 23, Mori teaches a cell microsheet of size about 3mm x 3mm i.e. 9mm2 (which is less than 20mm2 as required for claim 1, less than 15mm2 as required for claim 14 less than 10mm2 as required for claim 15, between 0.02mm2 and 20mm2 as required by claim 16 and 20, between 0.02mm2 and 15mm2 as required by claim 22 and between 0.02mm2 and 10mm2 as required by claim 23) (Abstract, Materials and Methods: Chondrocyte culture, Figure 2). Mori’s cell microsheet comprises human chondrocytes derived from human cartilage tissue (=mammal, primate, human as required by claims 17-19) (Abstract, Materials and Methods: Chondrocyte culture, Figure 2).
Mori also teaches the process of generating their cell microsheets that comprises two-dimensional culturing the chondrocytes on NIPPAM-coated dishes with 3 × 3 mm2 grids ( φ6 cm, RepCell, CellSeed, Tokyo, Japan) and then cooling the dishes to 20 °C to detach the cell microsheets (page 102, right column, para 2; RepCell cultureware was used same as instant specification [080] and NIPPAM is the stimulus responsive polymer).
Mori explicitly states that “Many chondrocyte sheets were prepared to form homogenous cartilage elements. The chondrocytes cultured under the monolayer condition were made to be detached from culture dishes with low temperature treatment (A, C and E) or enzyme treatment (B, D and F). After detachment of cells, the cell sheets were transferred into the low-attachment dishes” (Figure 2 legend). Thus, for cell microsheet preparation Mori teaches two-dimensional cultivation without teaching any three-dimensional cultivation.
Furthermore, since the cell microsheet of Mori is the same size as the instantly claimed cell sheet, Mori’s cell microsheet is inherently capable of passing through an injection needle, including an 18G injection needle as required by claims 2 and 20 (see MPEP 2112.01(II)).
Regarding claim 25, in view of the product-by-process claim interpretation presented above, Mori’s process of making the cell microsheets is the same as disclosed in the instant specification and comprises separating cells from the temperature-responsive culture dish without enzymes by allowing the sheets to stand at 20°C (Materials and Methods: Chondrocyte culture).
Although, Mori teaches the cell microsheet comprising chondrocytes derived from human cartilage from the ear (Materials and Methods: Chondrocyte culture), Mori does not teach deriving chondrocytes from articular cartilage of an animal with polydactyly. However methods to deriving chondrocytes from articular cartilage of an animal with polydactyly were known.
Sato teaches deriving chondrocytes from articular cartilage of a human with polydactyly (=mammal, primate, human as required by claims 17-20; [0110]). Sato also teaches the use of their chondrocytes in a method for preparing cell sheet wherein the cell sheet is prepared by culturing the chondrocytes on a temperature-responsive culture dish, same as Mori. Sato also teach the use of their cell sheets for cartilage repair in vivo ([0157], Table 2).
The combination of prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007): See MPEP 2143 for Exemplary rationales that may support a conclusion of obviousness.
In the present situation, rationale B) “Simple substitution of one known element for another to obtain predictable results” is applicable. MPEP 2143 guides that for rationale B “Office personnel must articulate the following: (1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components; (2) a finding that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness”.
In the instant case:
(1) The prior art of Mori teaches the base product which differs from the claimed product by the substitution of the following components: substituting Mori’s auricular cartilage derived chondrocytes in the preparation of the cell microsheet with the chondrocytes that are derived from articular cartilage of an animal with polydactyly in the claimed cell microsheet.
(2) The substituted components were known in the art as taught by Sato ([110]).
(3) An ordinary artisan would have substituted Mori’s auricular cartilage derived chondrocytes with Sato’s chondrocytes derived from articular cartilage of an animal with polydactyly because, same as Mori that cultured chondrocytes on temperature-responsive culture dish, Sato also teaches culturing their chondrocytes on temperature-responsive culture dish. Thus, an ordinary artisan would have predicted that Sato’s chondrocytes that are derived from articular cartilage of an animal with polydactyly could be used to generate cell microsheets when substituted in Mori’s method.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art to substitute Mori’s auricular cartilage derived chondrocytes with Sato’s chondrocytes derived from articular cartilage of an animal with polydactyly to yield a predictable a cell microsheet wherein the cells are chondrocytes derived from articular cartilage of an animal with polydactyly.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 10, 21 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mori (Journal of Hard Tissue Biology, 2014; ref of record) in view of Sato (US 2018/0243476 A1, Aug. 30, 2018) as applied to claims 1, 20 and 25 above, and further in view of Wang et al (Cardiovascular Research, 2008; ref of record) and Akahane et al (J Tissue Eng Regen Med 2010; 4: 404–411; ref of record).
Mori and Sato’s teachings as detailed in the U.S.C. 103 rejection of claims 1, 20 and 25 are relied upon for the instant rejection.
Mori and Sato teach the cell microsheet of claim 1, 20 and 25 comprising human chondrocytes from articular cartilage tissue of a human with polydactyly and of the size 9mm2. Mori also teaches using a micropipette for transferring cell microsheets (page 102, right column para 3). Mori does not teach using syringe to transfer their cell microsheets.
Mori and Sato do not teach a syringe containing their cell microsheet.
Wang teaches syringe containing cell microsheet (Figure 1, Preparation of the cell-sheet culture system). Wang use their syringe containing cell microsheet to transfer the cell microsheet into the myocardium of a subject (Animal study). Similarly, Akahane teaches syringe containing cell microsheet to transfer the cell microsheet into the bone (Figure 6, Materials and Methods: Cell culture, Injection of the cell sheet and cell suspension, Cell sheet injection into dead bone).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to fill a syringe with Mori and Sato’s cell microsheet for the purpose of transferring the cell microsheet, such as for transferring into a subject as taught by Wang and Akahane. An ordinary artisan would be motivated to fill a syringe with Mori and Sato’s cell microsheet because it would allow for transfer of cell microsheet from the culture dish to other sites, such as an injection site. To this end, both Mori and Sato use surgical approach for cell sheet transplantation to the subject (Figure 5 in Mori and [157] in Sato), while Wang and Akahane teach a less invasive approach of injecting cell sheets using syringes. Akahane teaches that injection of cell sheet “may have advantages in avoiding damage to the vasculature because injection is a less invasive technique” (page 410, right column, para 1). An ordinary artisan would reasonably expect to fill a syringe with Mori and Sato’s cell microsheet because of the small size of the cell microsheet which is similar to Wang and Akahane’s microsheets that were easily contained in syringes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant’s arguments with respect to U.S.C. 103 rejection of claim(s) 1, 2, 14-20, 22, 23, 25 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Arguments pertinent to instant U.S.C. 103 rejections are addressed below.
Regarding Mori, Applicant argue that “Mori describes the preparation of pellets, ,which are spherical or block-shaped structures that are three-dimensional.” and “The Mori process involves the formation of sheets of auricular chondrocytes in temperature-responsive culture dishes, but those intermediate product sheets are then always further processed to form pellets before transplanting “ (page 6, paras 2-3). Applicant allege that based on Mori’s description “Pellet formation is based on the premise that chondrocytes are prone to dedifferentiation in 2D and cannot sufficiently produce cartilage matrix unless in a 3D environment” and thus “a person skilled in the art would predict that "transplanting without pelleting" would actually impair the transplant effect” (page 6, paras 4-5). Similarly, Applicant allege that “According to the conventional wisdom in the art, aborting the Mori method and transplanting without pellet formation would likely result in a loss of effectiveness. Thus, one skilled in the art would have no motivation to eliminate the pellet formation portion of the Mori method” (page 7, para 4).
In response, as acknowledged by the Applicant, Mori indeed prepares the cell microsheet albeit as a “intermediate product sheets”. Mori describes the use of the cell microsheet for preparing pellets. However, regardless of how Mori ends up using their cell microsheet, Mori teaches cell microsheets made of cultured chondrocytes of the same as size as recited in the claims. An ordinary artisan would substitute other cultured cells, such as chondrocytes derived from articular cartilage from an animal with polydactyl as taught by Sato in the instant rejection, in Mori’s method and the end result would be the claimed product. Such an artisan may intend to use this product for any purpose, including making a pellet or further culturing or direct injection. To this end, see teachings in instant rejection from Sato that use cell sheets (i.e. not pellet or 3D) for cartilage repair treatment. Thus, Applicants allegation regarding need for 3D environment or pellet formation are unfounded. In fact, direct injection of chondrocytes, not even cell sheets, for treatment was also known. See [003] in Sato stating “For example, Non-Patent Document 1 discloses that healthy chondrocytes were cultured and the cultured chondrocytes were injected into the area of a full-thickness cartilage defect (Abstract)”. herein Sato is referring to Brittberg et al (NEJM, Vol. 331, No. 14, 1994) that injects single cell suspension of chondrocytes in the knee (Figure 1).
It is essential to recognize that using the cell microsheet for pellet formation, as in Mori, does not teach away from making a product, although an intermediate product, that is the same as claimed cell microsheet. Thus, there is no need to “abort the Mori method” or “eliminate the pellet formation” to produce the cell microsheet since the cell microsheet is produced regardless of if an artisan aborts or not.
Applicant’s arguments with respect to U.S.C. 103 rejection of claim(s) 10, 21, 26 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Arguments pertinent to instant U.S.C. 103 rejections are addressed below.
Regarding the secondary references of Wang, Applicant argue that “Wang's method involves fragmenting MSC-derived cell sheets and injecting them into the myocardium, rather than using chondrocytes or intra-articular injection. MSCs do not require 3D culture; rather, they tend to grow in 2D and maintain their function even after fragmentation” and “are specific to MSC-based cells and cannot be directly applied to chondrocytes (as in the present invention) “ (page 7, para 8; page 8, para 2).
In response, Applicant provide no evidence that because Wang teaches MSC cells it cannot be directly applied to chondrocytes. Wang teaches cell microsheets of MSCs and filing syringes with their microsheets. It appears that Applicant is alleging that MSCs and chondrocytes are different because MSCs do not require 3D culture; rather, they tend to grow in 2D and maintain their function even after fragmentation. There is no evidence that chondrocytes require 3D culture and cannot maintain their function after fragmentation. Both Mori and Sato culture chondrocytes in 2D culture and it appear chondrocytes maintain some valuable function even after being completely dissociated (see Brittberg). Thus, Wang’s teachings regarding filing syringes with cell microsheets are applicable to instant claims regarding chondrocytes.
Regarding the secondary references of Akahane, Applicant argue that “Akahane is cited by the Examiner for teachings about injection methods, but the reference does not cure the above discussed deficiencies in the other cited references.” (page 8, para 3).
In response, arguments present above were not persuasive. Thus, this argument regarding Akahane is not persuasive.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632