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 .
This action is responsive to papers filed 03/16/2026.
Claims 1, and 8-11 have been amended. Claim 2 has been newly canceled and no claims have been newly added.
Claims 1 and 3-17 are currently pending.
Claims 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/11/2025.
Claims 1 and 3-15 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities:
The phrase “treating the synovial tissue with an enzyme comprising a collagenase class I, a collagenase class II and a neutral protease” is grammatically incorrect with regard to “an enzyme”.
The article “an” indicates a single enzyme is being referred to which conflicts with the requirement of multiple enzymes.
Suitable alternatives would be “an enzyme mixture” or “a mixed enzyme composition”.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites the phrase “without causing the synovial tissue to undergo a disinfection step” in lines 6-7.
This phrase is interpreted as excluding a step that kills off microbial contamination such as subjecting the cells to isodine solution for 1 minute as a tissue disinfection step (Applicant’s Specification page 3 paragraph 8 and pages 14-15 paragraphs 50-51). Filtering of the cells with a device such as a cell strainer is not excluded from the method as it is not considered to be disinfection (Applicant’s Specification page 15 paragraph 52).
Claim Rejections - 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-6, 8, 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Yamaguchi (JP 2020 78282-abstract from IDS filed 03/20/2023, using machine translation) in view of Wood (Newcastle University PhD Thesis, 2017) and Sugita et al (Regenerative Therapy, 2016-from IDS filed 11/05/2025).
Regarding claim 1, Yamaguchi disclose a method of separating and culturing MSCs from preserved synovial tissue (abstract). The synovial tissue is digested with an enzyme mixture (protease solution) of collagenase and dispase (neutral protease) (page 4, paragraphs 1-2) for 1-3 hours. Yamaguchi disclose wherein the MSCs seeded at a cell density of 5,000 to 10,000 cells/cm2 (page 8 last paragraph and page 9 last paragraph) which overlaps with the claimed seeding range. In cases involving overlapping ranges, the courts have consistently held that even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Yamaguchi do not specifically include an embodiment wherein the synovial tissue is treated with the enzyme mixture comprising collagenase I, collagenase II and a neutral protease for 2 hours or more.
Wood disclose a method of producing synovium-derived cells comprising treating the synovial tissue with an enzyme mixture, specifically Liberase which according to Applicant’s disclosure contains collagenase I, collagenase II and a neutral protease, for 2 hours or more (either one 2 hour digestion or three 45 minute digestions adding up to more than 2 hours total) without causing (without requiring) the synovial tissue to undergo a disinfection step (pages 24-25, section 2.3.3, page 38 section 3.4, page 39 Fig. 3.5 and 3.6, page 153, last paragraph).
Although Wood does not explicitly disclose that mesenchymal stem cells are produced by this enzymatic treatment, since they are carrying out the same claimed steps they are deemed to produce the same claimed cells.
Providing guidance on instances where the method steps of the prior art and instant claims are the same, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) states “[T]hat since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims.”
Sugita disclose a method for the optimization of human mesenchymal stem cells isolation from synovial tissue for subsequent tissue engineering (Title). Sugita disclose that the synovial tissue is treated with collagenase for 3 hours or more (Page 80, section 2.1, column 2, first paragraph).
One of ordinary skill in the art would have been motivated to treat the synovial tissue in the method of Yamaguchi with an enzyme mixture such as Liberase for about 3 hours because Wood teach that Liberase is a suitable enzyme mixture for digesting synovial tissue for cell isolation and Sugita teach and suggest that this is a suitable time for digesting synovial tissue with a collagenase enzyme. The substituting of the enzyme mixture Liberase taught by Wood for the enzyme mixture of collagenase and a neutral protease used by Yamaguchi is merely the exchange of one art recognized equivalent for another as both enzyme mixtures are known to digest synovial tissue for cell isolation and thus an obvious modification (see MPEP 2144.06). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Yamaguchi also suggest the use of an enzyme mixture with collagenase and a neutral enzyme and also suggest a digestion time of 3 hours is suitable for synovial tissue as well.
Regarding claim 3, Yamaguchi disclose wherein the concentration of the enzyme treatment is 1 to 2 mg/ml collagenase and 3000 to 7000 units/ml dispase or 1.3-1.8 mg/ml collagenase and 4000 to 6000 units/ml dispase (page 4 paragraph 2).
These concentrations appear to fall within the claimed concentration range, however, even if they did not, they would provide for starting points for arriving at the claimed concentration range through routine optimization and experimentation.
With regard to the concentrations of enzymes in the enzyme composition, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05).
The selection of specific concentrations clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the amount and viability of the cells obtained would have been affected by these concentrations.
Regarding claims 4-6, 14-15, Yamaguchi do not specifically identify human patients as a source for the synovial tissue, but do suggest that the MSCs obtained from synovial tissue are intended for therapeutic methods of cell transplantation in joints such as the knee (page 2).
Sugita disclose that mesenchymal stem cells isolated from human synovial tissue are beneficial and desirable for cartilage repair (Title, abstract, pages 79-80). Sugita teach the cells are from multiple individual human donors (page 80). Since the individual donor cells are treated separate from other donor cells the synovial tissue is deemed to be derived from a single donor.
One of ordinary skill in the art would have been motivated to use human synovial tissue in the method of Yamaguchi because Sugita teach and suggest that human patients are a suitable source for such tissue. The beneficial use of autologous cells is well known in the art of cell therapy and thus human synovial MSCs from a single donor for administration to the same subject would have been motivated by the desire to avoid the risks of graft versus host disease and potential infection by any viruses or bacteria from a different individual donor. Since Yamaguchi suggest the knee joint as a potential site in need of the MSC administration, formulation for injection into the knee would provide a medical treatment for meniscus injury repair as the meniscus is located in the knee joint. One of ordinary skill in the art would have had a reasonable expectation of success because both Yamaguchi and Sugita are producing mesenchymal stem cells from synovial tissue for use in cell therapy.
Regarding claim 8, Yamaguchi does not teach culturing the MSCs for 10 days or more.
Sugita disclose that the best yields for expanding synovial derived MSCs are when seeding at a low density and culturing for 21 days (page 82, Discussion).
One of ordinary skill in the art would have been motivated to culture the synovial derived MSCs in the method of Yamaguchi for 21 days because Sugita disclose that the best yields of 5-fold more cells are obtained when cells are seeded at a lower density of 1000 cells/cm2 and cultured for 21 days (more than 10 days). One of ordinary skill in the art would have had a reasonable expectation of success because both Yamaguchi and Sugita are producing mesenchymal stem cells from synovial tissue for use in cell therapy.
Regarding claims 11-12, Yamaguchi disclose wherein the MSCs seeded at a cell density of 5,000 to 10,000 cells/cm2 (page 8 last paragraph and page 9 last paragraph) which overlaps with the claimed seeding range. In cases involving overlapping ranges, the courts have consistently held that even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
However, one of ordinary skill in the art would have been motivated to seed at a lower density of 1000 cells/cm2 and skipping a filtering step in the MSC expansion method of Yamaguchi because Sugita disclose that the best yields of 5-fold more cells (5 times more cells which falls into Applicant’s claimed range for expansion) are obtained when cells are seeded at a lower density of 1000 cells/cm2, without a filtering step and cultured for 21 days (more than 10 days). One of ordinary skill in the art would have had a reasonable expectation of success because both Yamaguchi and Sugita are producing mesenchymal stem cells from synovial tissue for use in cell therapy.
Regarding claim 13, Yamaguchi do not produce their synovial-derived MSCs by co-culturing with any cell other than a synovial-derived MSCs.
Therefore, the combined teachings of Yamaguchi, Wood and Sugita would have rendered obvious Applicant’s invention as claimed.
Claim(s) 7 is rejected under 35 U.S.C. 103 as being unpatentable over Yamaguchi (JP 2020 78282-abstract from IDS filed 03/20/2023, using machine translation) in view of Wood (Newcastle University PhD Thesis, 2017) and Sugita et al (Regenerative Therapy, 2016-from IDS filed 11/05/2025) as applied to claim 1, 3-6, 8, 11-15 above, and further in view of Novagen (2008, ProteoExtract Collagenase Set).
Regarding claim 7, the combined teachings of Yamaguchi, Wood and Sugita render obvious the claimed invention as described above, but do not particularly disclose that the mass ratio between the synovial tissue to the enzyme as being 1,000:1 to 10:1.
One of ordinary skill in the art would have been motivated to optimize the mass ratio between the tissue and the enzyme in the method of Yamaguchi in order to obtain the desired dissociation of the synovial tissue to release the synovium-derived MSCs using no more than routine experimentation. One of ordinary skill in the art would have been able to arrive at the claimed range with a reasonable expectation of success because according to Novagen, the starting point for the concentration of collagenase is about 10,000 units per g of tissue (p.3), and considering the activity of collagenase per mg of dry weight being more than 100, 125 or 160 (see Table at p. 2), 10,000 units would be about 60-100 mg (or 0.06-0.1 g). From this calculation, the mass ratio of the tissue to enzyme would be 1 g of tissue to 0.06-0.1 g of collagenase, which is 17:1 to 10:1.
Therefore, the combined teachings of Yamaguchi, Wood, Sugita and Novagen would have rendered obvious Applicant’s invention as claimed.
Claim(s) 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Yamaguchi (JP 2020 78282-abstract from IDS filed 03/20/2023, using machine translation) in view of Wood (Newcastle University PhD Thesis, 2017) and Sugita et al (Regenerative Therapy, 2016-from IDS filed 11/05/2025) as applied to claim 1, 3-6, 8, 11-15 above, and further in view of Hatakeyama et al (Stem Cells International, 2017).
Regarding claims 8-9, Yamaguchi does not teach culturing the MSCs for 10-28 days.
Hatakeyama disclose a method of isolating synovial mesenchymal stem cells (Title) and include wherein the synovial derived MSCs are seeded and cultured for 3-4 days and then the adherent cells (MSCs) were then cultured for 14 days without refeeding (10 days or more without culture medium exchange) (page 2 column 2 third paragraph).
Sugita disclose that the best yields for expanding synovial derived MSCs are when seeding at a low density and culturing for 21 days (page 82, Discussion).
One of ordinary skill in the art would have been motivated to culture the synovial derived MSCs in the method of Yamaguchi for 19 days or more because Sugita disclose that the best yields of 5-fold more cells are obtained when cells are seeded at a lower density of 1000 cells/cm2 and cultured for 21 days (more than 10 days). One of ordinary skill would have been motivated to include culturing for 10 days or more without refeeding because Hatakeyama suggest that this is suitable for the expansion and isolation of synovial-derived MSCs and this would have also provided the benefit of minimizing the expense of culture medium used as well. One of ordinary skill in the art would have had a reasonable expectation of success because Yamaguchi, Hatakeyama and Sugita are all producing mesenchymal stem cells from synovial tissue for use in cell therapy.
Therefore, the combined teachings of Yamaguchi, Wood, Sugita and Hatakeyama would have rendered obvious Applicant’s invention as claimed.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Yamaguchi (JP 2020 78282-abstract from IDS filed 03/20/2023, using machine translation) in view of Wood (Newcastle University PhD Thesis, 2017) and Sugita et al (Regenerative Therapy, 2016-from IDS filed 11/05/2025) as applied to claim 1, 3-6, 8, 11-15 above, and further in view of Nimura et al (Arthritis and Rheumatism, 2008, from IDS filed 01/03/2024).
Regarding claim 10, Yamaguchi disclose wherein the serum used can be bovine serum, fetal bovine serum, horse serum, human serum or the like (page 4, second to last paragraph). Yamaguchi do not specifically teach or suggest the use of autologous serum in their method.
Nimura discloses that synovial mesenchymal stem cells (MSCs) are a promising cell source for cartilage regeneration due to their high chondrogenic potential. Nimua state that for clinical safety autologous human serum should be used instead of fetal bovine serum (FBS). Nimura also state that human synovial MSCs demonstrated increased proliferation and expanded more in human serum than in FBS (abstract, page 504, Figure 1, page 509 end of column 1 to top of column 2).
Therefore, one of ordinary skill in the art would have been motivated to use autologous human serum in the method of Yamaguchi because Nimua teach and suggest that autologous human serum is preferred to other serum, such as FBS, because it provides added clinical safety (avoidance of contaminating microorganisms and prions) and because the cells expand better with autologous human serum as well. One of ordinary skill in the art would have had a reasonable expectation of success because Yamaguchi already indicate that human serum is suitable for their method and both Yamaguchi and Nimura are producing mesenchymal stem cells from synovial tissue for further culture and use in cell therapy.
Therefore, the combined teachings of Yamaguchi, Wood, Sugita and Nimura would have rendered obvious Applicant’s invention as claimed.
Double Patenting
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.
Claims 1, 3-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-8, 10-15 of copending Application No. 18/146109 in view of Wood (Newcastle University PhD Thesis, 2017), Yamaguchi (JP 2020 78282-abstract from IDS filed 03/20/2023 and Sugita et al (Regenerative Therapy, 2016-from IDS filed 11/05/2025).
The copending claims of patent application ‘109 are also drawn to a production method for a synovium-derived mesenchymal stem cell comprising treating a synovial tissue with a mixed enzyme including one or more kinds of collagenase and one or more kinds of neutral proteases for 2 hours or more.
The copending claims also include wherein the enzyme comprises a collagenase I, a collagenase II and a neutral protease which renders obvious a Liberase enzyme mixture which is a well-known enzyme mixture that contains those enzymes as well as disclosed and suggested by Wood (pages 24-25, section 2.3.3, page 38 section 3.4, page 39 Fig. 3.5 and 3.6, page 153, last paragraph).
The copending claims also include the claimed enzyme concentration range, wherein the synovial tissue is human, wherein the tissue is from a single donor, wherein the donor and subject are the same, wherein the mass ratio is in the same range, wherein the culturing is for 10 or more days, cultured 10 or more days without culture medium exchange, wherein the culturing is with autologous serum, wherein the cells are produced without being co-cultured with a different cell type, a production method for joint medical treatment for a meniscus injury.
The co-pending claims do not specifically include the seeding density or the proliferation ratio range.
Yamaguchi disclose wherein the MSCs seeded at a cell density of 5,000 to 10,000 cells/cm2 (page 8 last paragraph and page 9 last paragraph) which overlaps with the claimed seeding range. In cases involving overlapping ranges, the courts have consistently held that even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
However, one of ordinary skill in the art would have been motivated to seed at a lower density of 1000 cells/cm2 and skipping a filtering step in the MSC expansion method of the copending claims because Sugita disclose that the best yields of 5-fold more cells (5 times more cells which falls into Applicant’s claimed range for expansion) are obtained when cells are seeded at a lower density of 1000 cells/cm2, without a filtering step and cultured for 21 days (more than 10 days). One of ordinary skill in the art would have been motivated to use Liberase which includes collagenase I, collagenase II and a neutral protease because Wood disclose that this is a suitable enzyme mixture to use when digesting synovial tissue for cell isolation. One of ordinary skill in the art would have had a reasonable expectation of success because the copending claims, Yamaguchi and Sugita are producing mesenchymal stem cells from synovial tissue for use in cell therapy.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments with respect to the rejection(s) filed 12/16/2025 have been fully considered and are persuasive. Therefore, the rejections have been withdrawn as indicated above. However, a new ground(s) of rejection is necessitated based on the instant amendment to the claims that requires limitations in combinations not examined previously.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nakamura et al., “Initial Cell Plating Density Affects Properties of Human Primary Synovial Mesenchymal Stem Cells”, Journal of Orthopaedic Research, published online August 2018, 37(6), pp. 1358-1367.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631