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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/05/2026 has been entered.
Response to Amendment
Applicant's amendment and argument filed 03/05/2026, in response to the final rejection, are acknowledged and have been fully considered. Any previous rejection or objection not mentioned herein is withdrawn.
Claims 1, 11, 23-24, 29, 35-36, 41-45, 47, 58-62, 64-70 are pending of which claims 11, 42-45, 47, 58-62 and 70 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 05/16/2025.
Claims 1, 23-24, 27, 29, 35-36, 41 and 64-69 are being examined on the merits.
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.
This rejection is maintained with slight modifications to take into account the amendments filed on 11/17/2025.
Claims 1, 23-24, 27, 29, 35-36, 41 and 64-69 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite a cell sheet formed from cultured cells derived from cartilage tissue, comprising chondrocytes and cells expressing transcription factors that promote differentiation into chondrocytes. The first step of the eligibility analysis evaluates whether the claim falls within a statutory category (see MPEP 2106.03). Since the claim is directed to a composition comprising chondrocytes and cells expressing transcription factors that promote differentiation into chondrocytes the claim is a composition of matter. Step 2A prong one of the analyses evaluates whether the claim is a judicial exception (see MPEP 2106.04). Because the claim states the nature-based products which are chondrocytes and cells the markedly different characteristics is performed by comparing the nature-based product limitation to its natural counterpart.
When so broadly claimed, the claims recite cells which are chondrocytes and for instance mesenchymal stem cells which can be a cell that expresses transcription factors to promote differentiation into chondrocytes. The applicant is merely claiming those natural judicial exceptions and nothing more. These cell types are indeed found together in nature within the human body. The closest naturally occurring counterparts of these cells (cell types) are indeed those cells found in the human body, which are the same cells being claimed. Cells are dynamic in nature and can be induced from hormones, minerals, drugs, other cells, etc. to express transcription factors. Cells can form a sheet per se in 2 dimensions because cells will typically begin forming in a monolayer when cultured. The properties of the nature-based product as claimed are not markedly different than the properties of these naturally occurring counterparts found in nature as these activities would inherently be found within the cells they come from. The components which would give the activities claimed in the instant invention would inherently do the same in nature as there has been nothing done in the instant invention that would make them act in any different way. The applicant also claims a culture support that is removable from the cell sheet. This limitation when claimed so broadly does not overcome the rejection as a culture support which is also removable can simply be any natural compound to support the growth of the cells and this would ultimately get the same analysis as above.
Step 2A prong two evaluates whether the claim as a whole integrates the recited judicial exception into a practical application (see MPEP 2106.04(d)). This evaluation is performed by (a) identifying whether there are any additional recited elements in the claim beyond the judicial exception and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application.
This judicial exception is not integrated into a practical application because the only additional elements or limitations being claimed are directed to the cells having increased expression of specific genes relative to cells from non-polydactyl cartilage from adults, or wherein there are two chondrocyte cell sheets, or wherein there is a polymer-coated culture support that can be removed from the cell sheet. The applicant also claims a culture support that is removable from the cell sheet. This limitation when claimed so broadly does not overcome the rejection as a culture support which is also removable can simply be any natural compound to support the growth of the cells and this would ultimately get the same analysis as above.
Doing so would be implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b).
The claims do not integrate the judicial exceptions into a practical application because in this context, such integration for a claimed product would be a physical form of the specific practical application instead of a more general composition that is not so limited.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these components and their activity are already found naturally occurring in nature and the addition of an intended use does not impart any added benefit to the compounds or integrate the composition into a practical application.
Step 2 B evaluates whether the claim as a whole, amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (see MPEP § 2106.05(b)). The addition of a temperature responsive polymer-coated culture support that is removable from the cell sheet is also considered here and does not amount to significantly more than the recited judicial exceptions being claimed because when so broadly claimed can be yet another judicial exception. Claiming so broadly a temperature-responsive culture support that is removable from the cell sheet does not remove them from their natural counterparts and does not necessarily add any additional element that amounts to significantly more than claiming those natural judicial exceptions together in a composition. Many polymers exist in naturally which are “responsive” to temperatures. All polymers degrade at temperatures that are extreme heat and merely claiming that they are “coated” or can be removed does not suggest that these natural polymers are anything more than those found in nature as natural polymers can indeed be found on top of and removable from other natural judicial exceptions. For example, proteoglycans are polymers found existing alongside chondrocytes and can be removed through specific process and will respond to extreme high temperatures.
Response to Arguments
Applicant's arguments filed 03/05/2026 have been fully considered but they are not persuasive. The applicant believes the new limitation overcomes the rejection but does not articulate why it overcomes the rejection. Merely claiming a temperature responsive polymer coated culture support that is removable from the cell sheet, when claimed so broadly does not overcome the rejection because the support could be proteoglycans as just discussed, which are also judicial exceptions.
The applicant is advised to not be so broad in their claims and to possibly narrow the scope to more specific embodiments to help overcome the 101 rejection. For example, the new limitation can be narrower and the temperature responsive polymer being so broadly claimed could be amended to poly(N-isopropyl acrylamide) which is not a natural polymer and a polymer that is utilized in the application. The applicant has support at page 5 in their specifications for this limitation. This is merely a suggestion however the advice can be more broadly taken to other formulations.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 23, 41, 64-66, 68-69 are rejected under 35 U.S.C. 103 as being unpatentable over Sato and Sakai (from IDS, US20080226692A1), with support from Michele Goret-Nicaise (Identification of Collagen Type I and Type II in Chondroid Tissue, Calcif. Tissue Int., 1984, 36:682-689) and Tian-Fang Li et. al. (TGF-β SIGNALING IN CHONDROCYTES, Front Biosci. 2005 Jan 1; 10:681-688). This rejection is new based on the amendments filed on 03/05/2026.
Regarding claims 1 and 23, Sato discloses a cultured cell sheet that expresses phenotypes of the chondroids tissue (see abstract) and which comprises of chondrocytes and chondroprogenitor cells and combinations of cell types such as mesenchymal stem cells (see claims 1-2), and where the culture medium may be a chondrocyte differentiation-inducing medium which includes factors for differentiating cultured cells into the chondrocytes (see 0053). It can be appreciated that the chondrocytes in media with cells such as mesenchymal stem cells would express transcriptions factors that promote differentiation into chondrocytes as mesenchymal stem cells are known for such activity. Salto also discloses that the cells should grow to become confluent (see 0054, 0068, 0073).
Sato also discloses of temperature responsive polymers such as poly(N-isopropyl acrylamide) (see at least claim 21).
Sato discloses “a method of superimposing the highly adhesive cultured cell sheet in close contact with the abovementioned carrier by the steps of attaching the first cell sheet in close contact with the carrier to the cell culture support, and afterwards, removing the carrier off the first cell sheet by the addition of a culture medium, and layering the second cell sheet by attaching the second cell sheet in close contact with a carrier, and repeating the steps” (see 0041). Here, with the broadest interpretation, the carrier can act as the instantly claimed culture support that is removable.
Sato teaches “the cultured cell sheet according to claim 1, wherein the cultured cell sheet is layered by superimposing a cell sheet which is any one type or combination of two or more types of cells selected from the group consisting of: chondrocytes, chondroprogenitor cells” (see claim 7).
Regarding the cultured cells further comprising cytokines and genes related to extracellular matrix that promote differentiation into chondrocytes, Sato already teaches cells that would ultimately have genes/cytokines related to ECM because Sato teaches both chondroprogenitor cells and mesenchymal stem cells (see above and see 0033).
Regarding wherein at least 1% of the cultured cells express transcription factors that promote differentiation into chondrocytes, Sato teaches the abovementioned cells may be differentiated, for example, by a chondrogenic induction medium (see 0029).
Sato does not specifically teach wherein the cells are obtained from a subject; however this limitation would have been obvious given the relied upon art and to those skilled in the art because these cells would be compatible for treatment in humans and humans are known to have these cell types. For instance, these cells can be obtained from human subjects, cultured and created into a chondrocyte sheet as claimed. It would have been obvious to persons having skill in the art before the effective filing date to use cells from a subject in creating the chondrocyte cell sheet and to use a polymer-coated culture support that is removable from the cell sheet because Sato teaches this method directly from a patented publication.
Sato does not specifically teach that the cells express TGF-β1 and TGF-β2.
Goret-Nicaise is relied upon to show that chondroid tissue indeed expresses both collagen type I and type II.
Goret-Nicase describes that cartilage can be distinguished from bone by the cartilage-specific type II collagen marker and that through immunofluorescence with antibodies they were able to detect both collagen type I and type II in chondroid tissue (see abstract, materials and methods, and results). Therefore the invention taught by Sato would inherently express collagen I and II as instantly claimed, because Sato describes that the cultured sheet expresses the phenotype of chondroid tissue.
Li’s general disclosure is a report on TGF-β signaling in chondrocytes (see abstract) and is relied upon to show that chondrocytes indeed express TGF-β1 and TGF-β2.
Li teaches specifically that “TGF-β is produced by chondrocytes as a latent, high molecular weight molecule in association with latent TGF-β binding protein (LTBP)”. “In the epiphyseal growth plate, TGF-β1 and TGF-β3 are expressed in the resting, proliferating, and hypertrophic zones in 6 to 24-week-old rats. TGF-β2 is expressed at similar areas at 6-weeks of age, but decreased during growth”. “TGF-β2 exits in all zones of endochondral ossification, with the highest expression seen in hypertrophic and mineralizing zones”. “TGF-β1 is only found in the proliferative and upper hypertrophic zones” (see 7. Expression of TGF-β and related molecules in chondrocytes).
Regarding claims 68-69, these limitations are intended uses for the composition and do not structurally change the composition in any meaningful way. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In this case the intended use merely suggests a way in which to use the composition.
Therefore it would have been obvious to persons having ordinary skill in the art before the effective filing date to create a cultured composition for cartilage tissue repair comprising a culture sheet formed from cultured cells from cartilage tissue, comprising chondrocytes and cells expressing transcription factors that promote differentiation into chondrocytes and the cells expressing both collagen I, collagen II, TGF-β1, and TGF-β2 and with a temperature responsive polymer-coated removable culture support, because that is what Sato teaches and implies. Sato teaches each limitation except that the chondroid tissue express both collagen I and II, TGF-β1, TGF-β2, however Sato teaches that the cultured sheet has a phenotype of chondroid tissue and as Goret-Nicaise teaches, chondroid tissue indeed expresses both collagen I and II as can be confirmed with immunofluorescence. Li teaches chondrocytes express TGF-β1 and TGF-β2 especially during proliferating, and hypertrophic zones. Persons skilled in the art would recognize that chondrocytes express each of these proteins and during culturing processes these growth factors and proteins are beneficial to the cells for cartilage repair. It would have also been obvious to obtain chondrocytes from zones of endochondral ossification for culturing to make certain that those chondrocytes would indeed express TGF-β1 and TGF-β2 for the benefit of the growing cartilage tissues.
Therefore these limitations would have been prima facie obvious to persons having ordinary skill in the art.
Claims 24-25, 27, 29, 35, 36, 67 rejected under 35 U.S.C. 103 as being unpatentable over Sato and Sakai (from IDS, US20080226692A1). Michele Goret-Nicaise and Tian-Fang Li, as applied to claims 1, 23, 41, 64-66, 68-69 above, and further in view of Emma Cavaalli et. al. (Characterization of polydactyly chondrocytes and their use in cartilage engineering, Scientific Reports, 12, March 2019, 9:4275). This rejection is new based on the amendments filed on 03/05/2026.
Sato teaches a chondrocyte cell sheet comprising of one or more layers of confluent cells comprising chondrocytes and chondroprogenitor cells however is silent on the cells being from that of a human subject, being polydactyly chondrocytes or from a human aged 1.5 to 6 years old.
Cavaalli teaches that “polydactyly chondrocytes are currently being investigated as an alternative, allogeneic cell source for chondrocyte sheet transplantation23. Cell sheet technology has shown promising results already with adult chondrocytes in preclinical studies and in clinical studies with osteoarthritis patients24. However, the use of autologous chondrocytes requires a two-step surgical procedure and is associated with high donor-to-donor variability. Additionally, human polydactyly chondrocytes that are retrovirally transduced to express TGF-β1 are currently commercially available in South Korea as INVOSSA (TissueGene-C) and are undergoing phase III clinical trials in the USA” (see page 2, 2nd para.).
Cavaalli teaches “human infant chondrocytes (5 male donors and 4 female donors, aged 13 ± 6 months) were isolated from the epiphyseal cartilage in joints removed during corrective surgery for polydactyly” (see last lines of page 2).
Cavaalli teaches “Infant polydactyly chondrocytes showed a stable and high proliferation capacity during 2D expansion on tissue culture plastic up to passage 5 (Fig. 3b). On the contrary, adult articular chondrocytes displayed a significantly lower (p < 0.01) growth rate (population doubling per day) (Fig. 3b,c) and a more elongated morphology (Fig. 3d) during expansion. The results are in line with what was previously reported in the literature36. Additionally, the fast and steady proliferation rate supports the potential of polydactyly chondrocytes as an allogeneic cell source for cartilage repair techniques” (see bottom of page 6 and top of page 7).
Cavaalli teaches “It is known that polydactyly chondrocytes require a constant supply of chondrogenic factors to maintain a chondrogenic phenotype after being passaged in monolayer culture” (see page 13, before Conclusions).
Cavaalli teaches “human polydactyly chondrocytes that are retrovirally transduced to express TGF-β1 are currently commercially available in South Korea as INVOSSA (TissueGene-C) and are undergoing phase III clinical trials in the USA. After being proven safe in a range of pre-clinical animal mode” (see page 2, 2nd para.).
“In conclusion, we could demonstrate that due to their high proliferative rate, immunosuppressive properties and high responsiveness to chondrogenic induction, polydactyly infant chondrocytes represent a promising cell source for allogeneic cell-based therapies for cartilage repair. In addition, infant polydactyly chondrocytes can proliferate and produce cartilage-like matrix in 3D biomimetic hydrogels in the presence of TGF-β. The versatility of our hyaluronic acid-based hydrogel allows the release of the chondrogenic factor TGF-β and the reinforcement with collagen sponges, opening the opportunities to use polydactyly chondrocytes for focal cartilage defect treatment and not only for osteoarthritis” (see page 13, Conclusions).
Therefore it would have been obvious before the effective filing date to persons having ordinary skill in the art to use polydactyly chondrocytes from human subjects between the ages of 1.5-6 years of age for creating chondrocyte cell sheets because Caavalli teaches that these cells are stable and have high proliferation capacity during 2D expansion on tissue culture plastic up to passage 5 and outperform adult chondrocytes. It would have also been obvious to select the INVOSSA (TissueGene-C) cells which are commercially available in South Korea and are known to express TGF-β1 which is needed in order to maintain chondrogenic phenotypes after being passaged in monoculture.
Response to Arguments
Applicant's arguments filed 03/05/2026 have been fully considered but they are not persuasive. The applicant argues that Sato does not teach that the cells express collagen I, or TGF-β1, and TGF-β2. Sato teaches the cell sheet to have a chondroid phenotype and Michele Goret-Nicaise and Tian-Fang Li are relied upon to teach that chondrocytes indeed express these components especially during proliferation. These are inherent to the cell type, even if at different passages during expansion. These are properties of the cells known to those having ordinary skill in the art and to give further evidence please see the article from G.J. Zlabinger et. al. (Change in collagen synthesis of human chondrocyte culture, Rheumatol Int (1986) 6:63-68) which is supplied in the file wrapper. Zlabinger teaches “Conversion of type II to type I synthesis by chondrocytes was investigated by immunofluorescence. Staining with anti-type II collagen antibodies could be detected during primary cultures and in the first subpassage, whereas staining with anti-type I collagen antibodies occurred beginning from the end of primary cultures and was present up to the eighth subpassage” (see abstract). Furthermore, Zabinger teaches “During the first days in primary culture, the chondrocytes showed staining with anti-type II collagen antibodies only (Fig. 3 C). No staining appeared with anti-type I collagen antibodies. At the end of the observation of the primary culture, when cells in culture became confluent, a few cells already showed staining with anti-type I collagen antibodies. During the first subpassage a mixed pattern of staining was observed. Some cells still showed staining with anti-typeII collagen antibodies, some however with anti-type I collagen antibodies (Fig. 3 D, E). From the second to the eighth subpassage, staining occurred only with anti-type I collagen antibodies (Fig. 3F, G)” (see page 65, above discussion). Persons having ordinary skill in the art know that chondroyctes will express collagen type I and II depending on culture techniques and timing conditions.
Additionally, Li teaches that chondrocytes express TGF-β1, and TGF-β2 during proliferation and these growth factors support cartilage growth during proliferation. Including cells such as chondrocytes in the composition described above is prima facie obvious.
In regards to the applicant arguing against a separate patent application by Sato (US2018/0243476); The applicant recites in their specifications at page 2, “The cell sheets were positive for immunostaining using an antibody against type II collagen and negative against type I collagen” referring to the Sato document relied upon here US2008/0226692. However nowhere in this document teaches this directly or indirectly. In the Sato document US2018/0243476, this is noted in paragraph 0011. Therefore it was assumed that the applicant is arguing this document and not the relied upon US2008/0226692. The statement in the application is not supported by any evidence. Sato teaches generally that the cell sheet has a chondroid phenotype and as pointed out these cells express both collagen I and collagen II.
Conclusion
Currently no claims are allowed.
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JACOB A BOECKELMAN Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
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