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 .
Response to Amendment
Applicant's amendment and argument filed 08/26/2026, in response to the non-final rejection, are acknowledged and have been fully considered. Any previous rejection or objection not mentioned herein is withdrawn.
Claims 1, 11, 23-25, 29, 35-36, 41-45, 47, 58-62, 64-71are pending of which claims 11, 42-45, 47, 58-62 and 70 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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, 64-69 and 71 are being examined on the merits.
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), Hyun Joo Yoon et. al. (Type II collagen and glycosaminoglycan expression induction in primary human chondrocyte by TGF-β1, BMC Musculoskeletal Disorders, 2015, 16: 141) 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 and arguments filed on 08/26/2026.
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 temperature responsive polymers such as poly(N-isopropyl acrylamide) (see at least claim 21) and these polymers comprise synthetic homopolymers obtainable by polymerization of one or more monomers of N-isopropyl acrylamide.
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.
Yoon’s general disclosure is about collagen type II and glycosaminoglycan expression induction in primary human chondrocytes by TGF-β1 (see abstract).
Yoon teaches that “In addition to the matrix, bioactive factors added to chondrocytes or mesenchymal stem cells have been used to maintain the integrity of chondrocytes [14, 15]. A com bination of basic fibroblast growth factor (bFGF) and type I/II collagen matrix showed increased GAG expression compared with the addition of each component singly [16]. GAG synthesis was also stimulated by TGF-β1, which is a known induction factor for the differentiation of stem cells to cartilage [17, 18]”
We have reported that the re-differentiated status of chondrocytes and induced cartilage regeneration could be maintained by providing a continuous supply of TGF-β1[19–21]. Additionally, we have found that pro viding chondrocytes with TGF-β1 producing cells helps cartilage regeneration [22]. Our pre-clinical studies showed the production of hyaline cartilage using a mixture (TG-C) of human chondrocytes (hChonJ) and irradiated TGF-β1 producing chondrocytes (hChonJb#7) [23]. To elucidate the mechanism of cartilage regeneration, the effects of TGF-β1produced from irradiated hChonJb#7 in TG-C on the de-differentiated chondrocytes were investigated. Additionally, to evaluate the adherence of TG-C when injected directly without a scaffold, an assessment of TG-C binding to the damaged cartilage surface was performed. This study suggests the mechanism of new cartilage formation by TG-C, in which chondrocytes bound to the damaged cartilage accumulate ECM including type II collagen and GAG through continuous induction of TGF-β1 produced from co-injected hChonJb#7cells. This, therefore, provides a favorable environment for chondrocyte re-differentiation eventually resulting in cartilage regeneration. (see page 2, para. 2-3).
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 to patentably distinguish the claimed invention from the prior art. If the prior art structure can perform 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. Yoon teaches that type II collagen and GAG production were induced in hChonJ cells by TGF-β1. It would have been obvious to include the cells taught by Yoon, which express TGF-β1 to provide a favorable environment for chondrocyte re-differentiation eventually resulting in cartilage regeneration.
Li teaches chondrocytes express TGF-β1 and TGF-β2 especially during proliferating, and hypertrophic zones. People who have ordinary skill 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 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Sato and Sakai (from IDS, US20080226692A1), Hyun Joo Yoon 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 08/26/2026.
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 patients. 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 literature. 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 to maintain chondrogenic phenotypes after being passaged in monoculture. It would have also been obvious to increase the expression of TGF-β1 for the same purpose. Regarding the limitations pertaining to the cell sheet expressing more of this gene or any other claimed relative to a cell sheet prepared from cells isolated from non-polydactyl cartilage from an adult, the Office does not have the facilities for examining and comparing applicants’ composition with the composition of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Response to Arguments
Applicant's arguments filed 08/26/2026 have been fully considered but they are not persuasive. The applicant argues that the chondroid tissue disclosed in Sato would not necessarily express collagen type II as previously argued. The Office no longer relies on this argument and brings in new art from Yoon to teach that it would have been obvious to include cells which express TGF-β1 to provide a favorable environment for chondrocyte re-differentiation eventually resulting in cartilage regeneration. Yoon teaches that TGF-β1 expression can induce collagen type II expression in human chondrocytes and that the mixture (TG-C) of allogeneic human chondrocytes (hChonJ) and irradiated genetically modified human chondrocytes expressing TGF-β1 (hChonJb#7) attach to the damaged cartilage area to produce type II collagen-GAG matrices by providing a continuous supply of active TGF-β1 (see abstract: conclusions). Thus, including these in the invention taught by Sato would have been prima facie obvious for creating a cultured composition for cartilage repair.
Conclusion
Currently no claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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JACOB A BOECKELMANExaminer, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
