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 .
Claim Status
Applicant’s election without traverse of claims 1 – 3, 6, 8 – 10, 14, 17, 28, 46 – 47, 49 – 51, 67 and 70 in the reply filed on 08/17/2026 is acknowledged.
Claims 15 – 16, 27, 62 – 64 and 69 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/17/2026.
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.
Claims 1, 3, 6, 9, 17 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Loh et al. (Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types, Cell, 166, 451-467, (2016); cited on IDS, hereinafter Loh) in view of Zhang et al. (Recapitulation of cartilage/bone formation using iPSCs via biomimetic 3D rotary culture approach for developmental engineering, Biomaterials, Volume 260, (2020); cited on IDS, hereinafter Zhang).
Regarding claims 1, 6 and 28, Loh teaches a method for generating chondrocytes from sclerotome cells that express COL2A1 (Fig. 4G). Loh further discloses the use of a FGF2 pathway activator (p. 465, Experimental Procedures, Mesoderm Differentiation “FGF2”) and a FGF inhibitor (Fig. 4H) in the process that meet the limitations of a and b of the instant application claim 1. The process from primitive streak to sclerotome takes about 6 days (Fig. 4 H). Loh does not teach the expression of ACAN or the use of an orbital culture. However, Zhang discloses a study that focuses on the recapitulation of cartilage/bone formation using iPSCs via biomimetic 3D rotary culture, in which the expression of ACAN and COL2A1 show the same tendency in their chondrocyte generation protocol (Fig. 2E). Furthermore, Zhang discloses the use of a 3-D orbital shaker (p. 2, Sect. 2.2) for a rotary suspension culture in which the cell pellets can receive fluid dynamic forces. The motivation to combine the cells of Loh and the orbital shaker of Zhang would be to improve the efficiency of a chondrocyte generation protocol.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the sclerotome cells (that take six days to differentiate from iPSCs) and the teachings of Loh about the FGF pathway (activation/inhibition) with the 3-D orbital shaker of Zhang. Doing so would enhance chondrocyte formation efficiency, cell yield, and homogeneity due to the orbital rotation and fluid dynamic forces according to Zhang (Fig. 2D).
Regarding claim 3, Loh discloses the use of human pluripotent stem cells (Fig. 1 A) and the expression of the sclerotome cells with the markers from instant claim 3 after step iv of claim 2), hedgehog (HH) activation and WNT inhibition including PAX1 and SOX9 (p. 457, 1st col, 3rd para.). Loh further discloses feeder-free differentiation (p. 465, Experimental Procedure, Mesoderm Differentiation).
Regarding claim 9, Zhang discloses (Fig. 2E) characteristics of the cell pellets during chondrogenic induction that includes ii) COL2A1 and Aggrecan (ACAN).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the chondrocyte generating protocol of Loh and Zhang in order to recover a population of cells with the 10:1 ratio from instant claim 9. Doing so would favor type II collagen production over aggrecan in chondrocytes, which can influence cartilage matrix composition. A collagen-dominant matrix may support better integration with host tissue and resist degradation in vivo.
Regarding claim 17, Zhang teaches a 14 day chondrogenic differentiation (p. 2, Section 2.2) and as mentioned above in the rejection of claim 6, Loh discloses a 6 day differentiation period for generating sclerotome cells.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Loh in view of Zhang as applied to claims 1, 3, 6, 9, 17 and 28 above, and further in view of Murakami et al. (Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Genes Dev. 2004 Feb 1;18(3):290-305; hereinafter Murakami).
Regarding claim 2, Loh teaches i) that activating TGFβ, WNT, and FGF and inhibiting PI3K signaling within 24 hours of PSC differentiation (p. 453, 2nd col., 1st para.). Loh discloses a schematic (Fig. 4 H) that focuses on somite patterning into dermomyotome or sclerotome and downstream differentiation, which encompasses ii and iv. Loh does not disclose MEK/ERK pathway inhibitor. However, Murakami discloses that MAPK pathway (Sox9) inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation (p. 291, 1st col., last para. – 2nd col, 2nd para.). It is well known that hypertrophic chondrocytes are necessary for endochondral ossification, because they initiate and regulate the mineralization of the cartilage. Murakami further discloses that the MAPK pathway is a negative regulator of bone growth and strongly suggests that the MAPK pathway plays an important role in the development of the dwarf phenotype in human achondroplasia and thanatophoric dysplasias (p. 291, 2nd col, 2nd para.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the chondrocyte generating protocol of Loh and Zhang with the knowledge from Murakami on the inhibition of the MEK/ERK pathway in order to generate hypertrophic chondrocytes.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Loh in view of Zhang as applied to claims 1, 3, 6, 9, 17 and 28 above, and further in view of Wu et al. (W.O. Patent Application Publication No. 2021/155265 A1; hereinafter Wu).
Regarding claim 8, Loh and Zhang teach all of the elements of the current invention as stated above except chondrocytes expressing COL9A1 or COL11A1. However, Wu discloses compositions and methods for stem cell chondrogenesis, in which COL9A1 and COL11A1 are upregulated in the process (para. [0022], FIG. 13A-13J; para. [00147]). Wu discloses chondrogenic markers that include ACAN, COL9A1, and COL2A1 (para. [00147]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the chondrocyte generating protocol of Loh and Zhang with the well-established chondrogenic markers of Wu. Doing so would follow/create a reproducible protocol for generating chondrocytes with well-known markers for chondrogenesis.
Claims 10, 14, 46, 47, 49 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Loh and Zhang as applied to claims 1, 3, 6, 9, 17 and 28 above, and further in view of Prockop et al. (United States Patent Application Publication No. 20040235165 A1; hereinafter Prockop), Truncale et al. (United States Patent No. 8834928 B1; hereinafter Truncale), and Hata et al. (E.S. Patent Application Publication No. 0282746)
Regarding claims 10 and 46, Loh and Zhang teach all of the elements of the current invention as stated above except using triiodothyronine in order to produce a population of hypertrophic chondrocytes. However, Prockop discloses an invention related to enhancing the differentiation of marrow stromal cells to hypertrophic chondrocytes, in which (para. [0074]) a set of cells (SAEC) used in the protocol are cultured with triiodothyronine. Triiodothyronine is the biologically active form of thyroid hormone. Zhang discloses Col10a1 as a marker of hypertrophic cartilaginous pellets (Fig 5 A).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the hypertrophic chondrocyte generating agent (Triiodothyronine) of Prockop in the chondrocyte generating protocol of Loh and Zhang. Doing so would utilize a known protocol and agent for the hypertrophic induction of COL10A1+ chondrocytes.
Regarding claims 14 and 46, Prockop discloses that chondrogenic medium comprises TGFβ-3 (para. [0064]).
Regarding claim 47, Prockop discloses (para. [0064]) a chondrogenic medium comprising dexamethasone, β-glycerolphosphate (para. [0013]), and ascorbate-2-phosphate (para. [0145]). Prockop does not disclose the use ascorbic acid 2-phosphate or sodium ascorbate. However, Hata discloses an invention related to artificially cultured tissue comprising cells and extracellular matrix produced by growing a connective tissue cell in an ascorbic acid phosphate-containing medium (Abstract). Hata particularly preferred ascorbic acid 2-phosphate (col. 4, line 50 – 55). Hata further discloses that ascorbic acid has been shown to be a cofactor of proline hydroxylase, which plays a key role in collagen synthesis (col. 2, line 46 – 56). Hata further discloses using sodium ascorbate for the activation of collagen synthesis (col. 9, line 25 – 30).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add the ascorbic acid 2-phosphate and sodium ascorbate of Hata in the chondrogenic medium of Prockop in order to enhance collagen synthesis.
Regarding claim 49, Loh discloses the use of CHIR99021 in Fig. 1 C and D ( key for C and D).
Regarding claim 70, Loh, Zhang, and Prockop teach all of the elements of the current invention as stated above except administering the composition to a subject with a chondral defect or an osteochondral defect. However, Truncale discloses that their implants can be used for the treatment of an osseous defect or fracture (col. 45, line 11 – 20).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the organoid created from the combined methods of Loh, Zhang, and Prockop in the implant treatment method of Truncale for osseous defects or fractures.
Claims 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Loh and Zhang as applied to claims 1, 3, 6, 9, 17 and 28 above, and unpatentable over Loh, Zhang, Prockop, Truncale, and Hata as applied to claims 10, 14, 46, 47, 49 and 70 above, respectively, and further in view of Ross et al. (United States Patent No. 9290738 B2; hereinafter Ross).
Loh and Zhang teach all of the elements of the current invention as stated above except a step of decellularizing said three-dimensional aggregation of chondrocytes. However, Ross discloses/provides motivation with methods of decellularizing bone (starting a col. 7, line 55 – col. 8, line 21), the concept/structure of a decellularized bone (col. 5, line 60 – 67), and the use as a scaffold for recellularization, e.g., ex vivo or in vivo. Ross further discloses pre-cellular perfusion growth medium for osteoblasts (col. 12, line 25 – 35).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the decellularization methods/teachings of Ross in the organoid of Loh and Zhang. Doing so would incorporate Ross’ protocol for decellularizing native bone to the bone organoid of Loh and Zhang in order to generate a decellularized scaffold that is suitable for recellularization. Also, doing so would incorporate Ross’ protocol for decellularizing native bone to the hypertrophic bone organoid of Loh, Zhang, Prockop, Truncale, and Hata.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Loh and Zhang as applied to claims 1, 3, 6, 9, 17 and 28 above, and further in view of Skardal et al. (U.S. Patent Application Publication No. 20200048601 A1; hereinafter Skardal) and Truncale.
Loh and Zhang teach all of the elements of the current invention except cells engineered to have a mutation associated with a bone or cartilage disease or disorder. However, Skardal discloses/provides that the motivation for introducing mutations into bone organoids (para. [0040]) is in order to identify compounds of interest for therapeutic purposes (para. [0046]). Truncale discloses, in an invention related to tissue-derived implants, that mutations in Wnt co-receptor, LRP5, lead to defective bone formation (col. 6, line 45 – 60).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the mutation of Truncale in the organoid of Loh and Zhang, in order to find potential therapeutic compounds (Skardal’ s motivation) for treatment of a bone or cartilage disease or disorder.
Conclusion
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/WALTER JACKSON III/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
