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 .
Election/Restrictions
1. Applicant’s election without traverse of the invention of Group I (drawn to an isolated chondroprogenitor cell) and BMPR1B/ITGA4 as the expressed biomarkers in the reply filed on 07/27/2026 is acknowledged.
Upon further considerations, the restriction requirements between the inventions of Groups I-III is withdrawn.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 38 and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 36, 37, 39-44, and 46-67 are under examination.
Claim Objections
2. Claim 60 is objected to because of the recitation “and or” in line 3. Correction to “and/or” is required.
3. Claim 60 is objected to because of the recitation “extracellular matrix in chondroprogenitor cells” in line 4. Since the extracellular matrix is extracellular and not inside cells, correction to “the extracellular matrix produced by the chondroprogenitor cells” is suggested.
Claim Rejections - 35 USC § 101
4. 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.
5. Claims 36, 37, 39-44, and 46-48 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claims recite chondroprogenitor cell, i.e., a product of nature. This judicial exception is not integrated into a practical application because the claims only recite a composition. The specification discloses that the claimed chondroprogenitor cell is an immature articular chondrocyte capable of maturation in vivo (see [0042]). There is nothing in the claims or specification differentiating the claimed chondroprogenitor from the naturally-occurring chondroprogenitor cells. As evidenced by Fergusson (Nature Comm., 2018, p. 1-16; IDS), the naturally-occurring chondroprogenitor cells express the recited SOX5, SOX6, SOX9, COL2A1, ACAN, ITGA4, and BMPR1B (see Abstract; p. 4, paragraph bridging columns 1 and 2; p. 5, Fig. 3g; p. 7; paragraph bridging p. 8 and 12).
Although claims 42-44 and 46-48 recite a composition comprising the chondroprogenitor cell and a collagen membrane, there is no evidence that presence of the collagen matrix induces a marked difference in the claimed chondroprogenitor cells as compared to the naturally-occurring chondroprogenitor cells.
While claims 40, 41, and 46-48 are product-by-process claims, the recited process steps do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there is no evidence that they result in a marked difference in structure, function, or other property as compared to the naturally-occurring counterpart.
Therefore, the rejection under 35 U.S.C. 101 is appropriate.
Claim Rejections - 35 USC § 102
6. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
7. Claim 36, 37, and 39-41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fergusson et al. (Nature Communications, 2018, p. 1-16; cited on the IDS filed on 11/15/2023).
Fergusson et al. disclose an isolated chondroprogenitor cell expressing SOX5, SOX6, SOX9, COL2A1, ACAN, ITGA4, and BMPR1B, which is capable of maturing in vivo (claims 36, 37, and 39-41) (see Abstract; p. 4, paragraph bridging columns 1 and 2; p. 5, Fig. 3g; p. 7; paragraph bridging p. 8 and 12). The product-by-process claims 40 and 41 are only limited by the structure implied by the process (see MPEP 2113 I). The structure implied by the process recited in claims 40 and 41 is the structure of the chondroprogenitor cell of claim 36, and thus, these claims are also anticipated by Fergusson et al.
Thus, Fergusson et al. disclose all claim limitations and anticipate the claimed invention.
Claim Rejections - 35 USC § 103
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
9. Claims 36, 37, 39-41, 53-61, and 64-67 are rejected under 35 U.S.C. 103 as being unpatentable over Fergusson et al., in view of all Lee et al. (FASEB J., 2015, 29: 3399-3410), Woods et al. (J. Cell. Physiol., 2007, 213: 1-8), and Zhou et al. (In Vitro Cell.Dev.Biol., 2016, 52: 356-364).
The teachings of Fergusson et al. are applied as above for claims 36, 37, and 39-41. In addition, Fergusson et al. teach a method for producing chondroprogenitor cells from human pluripotent cells (hESCs); the produced chondroprogenitor cells express SOX5, SOX6, SOX9, COL2A1, ACAN, ITGA4, and BMPR1B, are capable of maturing in vivo, and are suitable for regenerative medicine applications. The method comprises:
(1) maintaining the hESCs in mTESR medium;
(2) culturing the hESCs in MI-1 medium (X-Vivo medium comprising bFGF, activin A, and Wnt3a, each at 10 ng/ml) for 3 days;
(3) culturing in MI-2 medium (X-Vivo medium comprising 10 ng/ml bFGF; 10 ng/ml Wnt3a; 50 ng/ml Noggin) for 4 days;
(4) culturing in CI-A medium (10 ng/ml BMP4; 10 ng/ml FGF2) for 3 days;
(5) removing the cells expressing CD309 and CD326 via MACS using
anti-CD309/CD326 antibodies;
(6) culturing the CD309/CD326-depleted cells in CI-A medium supplemented with 10 ng/ml of the Rock inhibitor Y-27632, in a regular culture dish for 3 days;
(7) culturing in CI-B medium (10 ng/ml bFGF; 50 ng/ml SHH; 50 ng/ml BMP4), in a regular culture dish for 3 days;
(8) culturing the chondroprogenitor cells in a maintenance medium (X-vivo medium comprising 10 ng/ml IGF2; 10 ng/ml FGF2; 50 ng/ml LIF; 10 ng/ml TGF-β1; 1 ng/ml BMP4) for 14 days or up to 60 days.
(see paragraph bridging p. 6 and 7; p. 12, column 2, second full paragraph; p. 13, column 2; see the attached supplementary Fig. 3b; claims 36, 37, 39-41, 53-59, and 61).
While Fergusson et al. do not specifically teach an antimicrobial (claims 53 and 61), including antibiotics in the culture medium was the norm in the prior art of tissue culturing.
Fergusson et al. do not teach starting with hESCs aggregates, nor do they teach using Y-27632 in the MI-1 and CI-B media (claims 40, 41, 53, and 58). Lee et al. teach that starting with embryoid bodies (EBs; i.e., stem cell aggregates) in the presence of Y-27632 is the optimal initial step for differentiating toward the chondrogenic fate. Lee et al. teach that Y-27632 prevents cell-dissociation-induced apoptosis in hESCs and enhances differentiation toward a chondrogenic fate. Lee et al. teach obtaining the EBs from dissociated cells suspended in a Y-27632-comprising medium, followed by culturing the EBs in a mesoderm-inducing medium comprising 10 µg/ml Y-27632, bFGF, activin A, Wnt3a for the first 4 days (see p. 3400, column 2, first paragraph; paragraph bridging p. 3401 and 3402; p. 3402). Modifying Fergusson et al. by forming EBs in the presence of Y-27632 and culturing the resulting EBs in in their MI-1 medium supplemented with 10 µg/ml Y-27632 would have been obvious to one of skill in the art, with the reasonable expectation that doing so would enhance the chondroprogenitor cell yield. Furthermore, Woods et al. teach that ROCK signaling results in inhibition of chondrogenesis via inhibiting SOX9, which is responsible for initiating the expression of the genes encoding the ECM molecules Col2 and ACAN. Woods et al. teach that chondrocytes dedifferentiate in monolayer culture; inhibiting ROCK leads to SOX9 superinduction and rescue of the chondrocyte phenotype (see p. 1, column 2; paragraph bridging p. 3 and 4). Based on these teachings, one of kill in the art would have found obvious to also add 10 µg/ml Y-27632 to the CI-B medium, with the reasonable expectation that doing so would enhance the yield of chondroprogenitor cells. By doing so, one of skill in the art would have used an agent (Y-27632) which reduces the degeneration of the extracellular matrix produced by the chondroprogenitor cells (claim 60).
Fergusson et al., Lee et al., and Woods et al. do not teach using IGF-1 in the CI-B and the maintenance media (claims 40, 41, 53, and 58). Zhou et al. teach that the combination of IGF-1 and TGF-β1 induces greater expression of SOX9, Col2, ACAN in the mesodermal cells and enhances cartilage formation in vivo, compared to TGF-β1 alone (see Abstract; p. 360-361). Further including IGF-1 in the CI-B and the maintenance media would have been obvious to one of skill in the art, to achieve the predictable result of enhancing chondrogenesis and cartilage formation in vivo.
By doing so, one of skill in the art would have also practiced a method for producing a cartilage composition, as recited in claims 64-67.
With respect to claim 55, the cited prior art does not teach that the EBs are formed in by using spin culture and mTESR medium. However, it is noted that there is no evidence of record indicating that using spin culture/mTESR medium leads to unexpected results. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
With respect to claim 57, since Fergusson et al. teach that MI-1, MI-2, and the maintenance media are formed by adding the factors to the X-Vivo medium, one of skill in the art would have found obvious to do the same for the CI-A and CI-B media, to achieve the predictable result of obtaining chondroprogenitor cells.
Thus, the claimed invention was prima facie obvious at the time of its effective filling date.
10. Claims 36, 37, 39-41, 53-61, and 63-67 are rejected under 35 U.S.C. 103 as being unpatentable over Fergusson et al. taken with all Lee et al., Woods et al., and Zhou et al., in further view of Miyazaki et al. (Nat. Commun., 2012, 3: 1-10).
The teachings of Fergusson et al., Lee et al., Woods et al., and Zhou et al. are applied as above for claims 36, 37, 39-41, 53-61, and 64-67. Fergusson et al., Lee et al., Woods et al., and Zhou et al. do not specifically teach maintaining the hESCs in laminin-coated tissue culture dishes (claim 63). Miyazaki et al. teach that coating tissue culture dishes with laminin allows for robust proliferation of hESCs for therapeutic applications (see Abstract). Maintaining the hESCs in laminin-coated tissue culture dishes would have been obvious to one of skill in the art, to achieve the predictable result of sufficient numbers of hESCs to be used for differentiation toward the chondrogenic lineage.
Thus, the claimed invention was prima facie obvious at the time of its effective filling date.
11. Claims 36, 37, 39-44, 46-62, and 64-67 are rejected under 35 U.S.C. 103 as being unpatentable over Fergusson et al. taken with all Lee et al., Woods et al., and Zhou et al., in further view of Zheng et al. (Tissue Engineering, 2007, 13: 737-746).
The teachings of Fergusson et al., Lee et al., Woods et al., and Zhou et al. are applied as above for claims 36, 37, 39-41, 53-61, and 64-67. Fergusson et al., Lee et al., Woods et al., and Zhou et al. do not teach seeding the chondroprogenitor cells on a collagen membrane (claims 42-44 and 46-52). Zheng et al. teach treating injured/arthritic articular cartilage by implanting a type I/III collagen membrane seeded with autologous chondrocytes at the site of the injury (see Abstract; p. 745, column 1).
Furthermore, Lee et al. teach that, similar to hESCs, hiPSCs could be differentiated to chondroprogenitor cells. Lee et al, teach that patient-derived hiPSC constitute a limitless source for autologous cell transplantation (see Abstract; paragraph bridging p. 3399 and 3400; p. 3400, column 2, first paragraph; paragraph bridging p. 3401 and 3402). Based on these teachings, one of skill in the art would have found obvious to replace the hESCs with patient-derived hiPSCs, to achieve the predictable result of obtaining autologous chondroprogenitor cells for transplantation. One of skill in the art would have found obvious to further seed the autologous chondrogenic progenitors on a type I/III collagen membrane, to achieve the predictable result of obtaining a composition suitable to treat the injured/arthritic articular cartilage in the patient (claims 42-44 and 46-48). With respect to claims 49-52, one of skill in the art would have found obvious to further administer either the autologous chondroprogenitor cells or the type I/III collagen membrane seeded with the autologous chondroprogenitor cells to the patient, with the reasonable expectation that doing so would treat the treat the articular cartilage injury in the patient and reducing the risk of the patient developing osteoarthritis. With respect to claim 62, cryopreserving membranes seeded with the autologous chondroprogenitor cells by using a freezing medium comprising Y-27632 would have been obvious to one of skill in the art, to achieve the predictable result of obtaining a bank of ready to use therapeutic compositions.
Thus, the claimed invention was prima facie obvious at the time of its effective filling date.
12. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
