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 .
1. Original claims 1-15 are pending and under examination.
Claim Objections
2. It is suggested that claims 1, 10, and 11 be amended to recite:
“synovium-derived mesenchymal stem cells expressing surface antigens selected from integrin β1 and/or platelet-derived growth factor receptor β.”
3. It is suggested that claims 2 and 12 be amended to recite:
“wherein the synovium-derived mesenchymal stem cells express both integrin β1 and platelet-derived growth factor receptor β.”
4. Claims 3 and 13 are objected to because of the recitation “a type II collagen [Symbol font/0x61]1 chain”. Correction to “type II collagen [Symbol font/0x61]1 chain” is required.
5. It is suggested that claim 4 and 14 be amended to recite:
“wherein the synovium-derived mesenchymal stem cells express on their surface FGFR3.”
6. It is suggested that claims 5 and 15 be amended to recite:
“wherein the therapeutic agent for arthrosis comprises at least 30% of the synovium-derived mesenchymal stem cells expressing integrin β1 and/or platelet-derived growth factor receptor β.”
7. Consistent with the specification, it is suggested that claim 6 be amended as follows:
“A method for producing the therapeutic agent for arthrosis according to claim 1, comprising:
step A of treating a synovial tissue with an enzyme to obtain an enzyme-treated mixture comprising synovial tissue and synovium-derived mesenchymal stem cells;
step B of recovering the synovium-derived mesenchymal stem cells from the enzyme-treated mixture by removing the synovial tissue and further using centrifugation to wash and collect the synovium-derived mesenchymal stem cells;
step C of culturing the collected synovium-derived mesenchymal stem cells on a base material; and
step D of separating the cultured synovium-derived mesenchymal stem cells from the base material.”
8. Claim 7 is objected to because of the recitation “a residual enzyme concentration in a supernatant”. Correction to “the residual enzyme concentration in the supernatant” is required.
9. Claim 8 is objected to because of the recitation “a period during which the synovium-derived mesenchymal stem cells are cultured is 28 days or less”. Correction to “the synovium-derived mesenchymal stem cells are cultured for 28 days or less” is required.
10. Claim 10 should recite “sorting out the synovium-derived mesenchymal stem cells expressing surface antigens selected from integrin β1 and/or platelet-derived growth factor receptor β.
Double Patenting
11. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 ( CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web- based eTerminal Disclaimer may be filled out completely online using web- screens. An eTerminal Disclaimer that meets all requirements is auto- processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying- online/eterminal-disclaimer.
12. Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18/145,922 (reference application), in view of both Tsuji et al. (Cell Transplantation, 2017, 26: 1089-1102) and Okamura et al. (Int. J. Mol. Sci., online 30 December 2020, 22: 1-16; cited on the IDS filed on 05/07/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same synovial mesenchymal stem cells and method for obtaining synovial mesenchymal stem cells. The specific enzymes and parameters recited in the application claims 1-15 anticipate the genus recited in the instant claims 6-10. The application specification discloses that the method comprises removing the synovial tissue after the enzyme treatment, followed by collecting washing the synovial mesenchymal stem cells (see [0019]-[0020]).
The application claims do not recite that the synovial mesenchymal stem cells express integrin β1 (CD29), PDGFR β (CD140b), FGFR3, and comprise the gene encoding type II collagen [Symbol font/0x61]1 chain (COL2A1). However, it was known in the prior art that synovial mesenchymal stem cells express CD29, CD140b, FGFR3, and comprise a gene encoding COL2A1. See for example Tsuji et al., teaching that synovial mesenchymal stem cells express the surface antigens CD29 and CD140 (see p. 1092, column 2, third paragraph; p. 1095, Table 3). See Okamura et al. teaching that synovial mesenchymal stem cells express FGFR3 and comprise a gene encoding COL2A1 (see p. 2; p. 4, Fig. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d). The application claims do not specifically teach a method for treating a joint. However, since the application claims 14, 15, and 17 define that the synovial mesenchymal stem cells are suitable for joint therapy, one of skill in the art would have found further claiming the method as an obvious variant. Thus, the instant claims and the application claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, and 10-16 of copending Application No. 18/146,109 (reference application), in view of both Tsuji et al. and Okamura et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same method for obtaining synovial mesenchymal stem cells. The specific enzymes and parameters recited in the application claims anticipate the genus recited in the instant claims 6-10.
The application claims do not recite that the synovial mesenchymal stem cells express integrin β1 (CD29), PDGFR β (CD140b), FGFR3, and also comprise a gene encoding type II collagen [Symbol font/0x61]1 chain (COL2A1). However, it was known in the prior art that synovial mesenchymal stem cells express CD29, CD140b, FGFR3, and comprise a gene encoding COL2A1. See for example Tsuji et al., teaching that synovial mesenchymal stem cells express the surface antigens CD29 and CD140 (p. 1092, column 2, third paragraph; p. 1095, Table 3). See Okamura et al. teaching that synovial mesenchymal stem cells express FGFR3 and comprise a gene encoding COL2A1 (p. 2; p. 4, Fig. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d). While the application claims do not recite synovial-mesenchymal stem cells, one of skill in the art would have reasonably concluded that practicing the method necessarily entails possession of these cells. Thus, further claiming synovial mesenchymal stem cells would have be considered an obvious variant by one of skill in the art.
The application claims do not specifically teach a method for treating a joint. However, since the application claims 15 and 16 define that the synovial mesenchymal stem cells are suitable for joint therapy, one of skill in the art would have found further claiming the method as an obvious variant. Thus, the instant claims and the application claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 101
14. 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.
15. Claims 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claims recite synovial mesenchymal stem cells, i.e., a product of nature. This judicial exception is not integrated into a practical application because they simply recite synovial mesenchymal stem cells. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there is no evidence that that claimed synovial mesenchymal stem cells are any different from their naturally-occurring counterpart.
While the claims recite cell surface markers such as integrin β1 (CD29), PDGFR β (CD140b), FGFR3, and a gene encoding type II collagen [Symbol font/0x61]1 chain (COL2A1), naturally occurring synovial mesenchymal stem cells express CD29, CD140b, FGFR3 on their surface gene markers; they also comprise the gene encoding COL2A1. See Tsuji et al. (Cell Transplantation, 2017, 26: 1089-1102; p. 1092, column 2, third paragraph; p. 1095, Table 3). See Okamura et al. (Int. J. Mol. Sci., online 30 December 2020, 22: 1-16; p. 2; p. 4, Fig. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d).
Although claim 5 recites that additional cells are present, there is no evidence that any of these additional cells induces a marked difference in the synovial mesenchymal stem cells as compared to the naturally-occurring RBCs. Therefore, the rejection under 35 U.S.C. 101 is appropriate.
Claim Rejections - 35 USC § 102
16. 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.
17. Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tsuji et al. (Cell Transplantation, 2017, 26: 1089-1102), as evidenced by Okamura et al. (Int. J. Mol. Sci., online 30 December 2020; cited in the IDS).
Tsuji et al. disclose human synovial mesenchymal stem cells (synovial MSCs) expressing CD29 and CD140b (claims 1 and 2) (see Abstract; p. 1090, column 2, first paragraph; p. 1091, Table 2; p. 1092, column 2, third paragraph; p. 1095, Table 3). As evidenced by Okamura et al., human synovial MSCs also express FGFR3 on their surface and comprise the gene encoding COL2A1 (claims 3 and 4) (see Abstract; p. 4, Fig. 2; p. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d).
Thus, Tsuji et al. disclose all claim limitations and anticipate the claimed invention.
18. Claims 1-4, 6, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ando et al. (Tissue Engineering, 2008, 14: 2041-2049), as evidenced by both Tsuji et al. and Okamura et al.
Ando et al. disclose human synovial MSCs isolated by treating human synovial tissue with collagenase for 2 h; neutralizing the collagenase with culture medium comprising 10% FBS; collecting the synovial MSCs by centrifugation, washing the synovial MSCs with PBS, resuspending the synovial MSCs in culture medium and plating them in culture dishes, culturing for 15-28 days, and detaching the MSCs with trypsin-EDTA (claims 1, 6, and 8) (see p. 2042, column 1). As evidenced by Tsuji et al. and Okamura et al., human synovial MSCs comprise the gene encoding COL2A1 and express CD29, CD140b, and FGFR3 on their surface. See Tsuji et al. (p. 1092, column 2, third paragraph; p. 1095, Table 3); see Okamura et al. (p. 2; p. 4, Fig. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d) (claims 1-4).
Thus, Ando et al. disclose all claim limitations and anticipate the claimed invention.
19. Claims 1-4 and 11-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sekiya et al. (Clin. Orthop. Relat. Res., 2015, 473: 2316-2326), as evidenced by both Tsuji et al. Okamura et al.
Sekiya et al. disclose human synovial MSCs and a method for treating knee cartilage defects in human patients by transplanting the human synovial MSCs into the defects (see paragraph bridging p. 2317 and 2318; p. 2318, column 2; p. 2319; p. 2320, column 2; p. 2322; p. 2324, column 2). As evidenced by Tsuji et al. and Okamura et al., human synovial MSCs comprise the gene encoding COL2A1 and express CD29, CD140b, and FGFR3 on their surface. See Tsuji et al. (p. 1092, column 2, third paragraph; p. 1095, Table 3); see Okamura et al. (p. 2; p. 4, Fig. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d) (claims 1-4 and 11-14).
Thus, Sekiya et al. disclose all claim limitations and anticipate the claimed invention.
Claim Rejections - 35 USC § 103
20. 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.
21. Claims 1-5 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Tsuji et al. as evidenced by Okamura et al.
The teachings of Tsuji et al. are applied as above for claims 1-4. Tsuji et al. do not specifically disclose using the human synovial MSCs to treat a joint (claims 11-14). However, Tsuji et al. teach that synovial MSCs were already used in clinical trials for regenerating the articular cartilage and meniscus (see p. 1090, column 1). One of skill in the art would have found obvious to transplant the human synovial MSCs taught by Tsuji et al. to a joint of a patient in need of therapy, with the reasonable expectation that doing so would result on the regeneration of the damaged articular cartilage or meniscus. With respect to claims 5 and 15, one of skill in the art would have reasonably concluded that the number of synovial MSCs is a result-effective variable. One of skill in the art would have found obvious to use routine experimentation and vary the number of the number of human synovial MSCs to be administered to achieve the predictable result of identifying the optimal conditions for therapy. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed concentration range was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
22. Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Ando et al. as evidenced by Okamura et al., in view of Tsuji et al.
Ando et al. teach human synovial MSCs isolated by treating human synovial tissue with collagenase for 2 h; neutralizing the collagenase with culture medium comprising 10% FBS; collecting the synovial MSCs by centrifugation, washing the synovial MSCs with PBS, resuspending the synovial MSCs in culture medium and plating them in culture dishes, culturing for 15-28 days, and detaching the MSCs with trypsin-EDTA (claims 1, 6, and 8) (see p. 2042, column 1). As evidenced by Tsuji et al. and Okamura et al., human synovial MSCs comprise the gene encoding COL2A1 and express CD29, CD140b, and FGFR3 on their surface. See Tsuji et al. (p. 1092, column 2, third paragraph; p. 1095, Table 3); see Okamura et al. (p. 2; p. 4, Fig. 2; paragraph bridging p. 4 and 5; p. 7, Fig. 5d) (claims 1-4).
Ando et al. do not specifically teach washing until the enzyme concentration in the supernatant is 0.5 ng/ml or less (claim 7) or sorting the cells (claim 10).
With respect to claim 7, since Ando et al. teach washing the synovial MSCs after collagenase treatment, one of skill in the art would have reasonably concluded that washing is performed to remove the enzyme. Thus, one of skill in the art would have found obvious to wash the synovial MSCs until the enzyme is removed.
With respect to claim 10, Tsuji et al. teach that, to achieve effective and reproducible transplantation purposes, it is important to control the numbers and purity of synovial MSCs, which can be achieved by FACS. Tsuji et al. also teach the necessity of choosing an adequate detachment enzyme to preserve the cell surface markers necessary for FACS; Tsuji et al. teach that detaching with trypsin alters the surface markers and should be replaced with detaching by using TrypLE within 120 min (see Abstract; p. 1090, column 1 and column 2, second paragraph; p. 1095, Table 3). Based on these teachings, one of skill in the art would have found obvious to modify Ando et al. by replacing trypsin with TrypLE and further using FACS to sort out the synovial MSCs, to achieve the predictable result of obtaining a composition with enhanced therapeutic potential. The specification defines that the cell stripper is a solution containing a trypsin-like enzyme and EDTA such as TrypLE (see [0036]). Thus, by modifying Ando et al. as set forth above, one of skill in the art would have enriched for synovial MSCs (claim 5) and would have used a cell stripper (claim 9).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
23. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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