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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 6, 2026, has been entered.
DETAILED ACTION
The amended claims filed on March 6, 2026, have been acknowledged. Claims 3, 5, 7-25, 27-55, 57, 59-60, 63-65, and 67-70 were cancelled. Claims 1-2, 4, 6, 26, 56, 58, 61-62, and 66 are pending and examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on March 6, 2026, has been considered.
Specification
The prior objection to the specification is withdrawn in light of Applicant’s amendments to the specification to provide appropriate symbols indicating use in commerce and generic terminology.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/741,933, filed October 5, 2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-2, 4, 6, 26, 56, 58, 61-62, and 66 receive domestic benefit from U.S. provisional application No. 62/741,933, filed October 5, 2018.
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.
Claims 1-2, 4, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2017132358 (Weiss; referenced in IDS) and further in view of Mennan et al. (Osteoarthritis and Cartilage 26: S146-S147. 2018; Published April 2018; previous art of record), Rojewski et al. (Cell Transplantation 22: 1981–2000. 2013), and Kandoi et al. (Scientific Reports 8: 1-12. 2018; Published August 2018). Applicant’s traversal is addressed below.
Regarding claims 1 and 26, Weiss teaches a method of expanding umbilical cord derived mesenchymal stem cells (MSCs; also identified as mesenchymal stromal cells) (page 1, line 15-page 4, line 20, Examples 1-2, and claims 1-11).
Weiss teaches that as part of their method, they isolated umbilical cords from births, isolated MSCs from the umbilical cord using enzymatic digestion, culturing MSCs in tissue culture plates for using DMEM media supplemented with 1% glutamax, 1% Antibiotic-Antimycotic, and 10% human platelet lysate until approximately 80-90% confluency. Once they reach 80-90% confluency, they were replated in fresh media. Weiss teaches that the confluent cells can be transferred from static culture conditions in a cell culture plate to a dynamic culture system by seeding cells on a microcarrier and culturing them in a bioreactor, such as a stirred tank bioreactor, with media containing human platelet lysate. Weiss teaches that they achieved an average cell yield of 4.2 x 107 ± 1.4 x 107 cells from their dynamic culture conditions after 6-7 days of culturing (Examples 1-2, page 8, lines 14-26, and claims 1-11).
Weiss does not teach expanding their MSCs in a functionally closed system that is either hermetically sealed or provides sterile barrier filters at all connections (Instant Specification paragraph 0037).
However, Mennan teaches a method of expanding umbilical cord MSCs comprising isolating UC-MSCs from UC matrix, culturing the UC-MSCs on tissue culture plates for ~14 days, then loading 5 x 106 cells into a Quantum bioreactor (Terumo BCT), an automated hollow fibre system, and culturing the cells in the bioreactor for 7.7 ± 2.2 days. Mennan teaches that they achieved harvests of 9-20 x 107 cells at the end of culturing in the bioreactor. Mennan teaches that their expanded UC-MSCs adhered to the ISCT criteria for MSCs and had comparable chondrogenic potency and immunomodulatory immunoprofiles before and after proinflammatory stimulation (page S146, column 2, paragraph 5-page S147, column 1, paragraph 3).
Regarding the functionally closed system limitation, the instant specification discloses that MSCs may then be expanded in a functionally closed system, such as a bioreactor. Expansion may be performed in a Quantum Bioreactor (paragraph 0065) which is used in Applicant’s Example 1, as well.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the stirred tank bioreactor of Weiss with the Quantum automated hollow fibre bioreactor of Mennan to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Weiss and Mennan use a similar general method for expanding UC-MSCs comprising isolating MSCs from umbilical cord, culturing them in a static culture condition on culture plates, then transferring the cells to a dynamic culture bioreactor, a stirred tank bioreactor in Weiss and a Quantum hollow fibre bioreactor in Mennan. Additionally, Mennan has successfully reduced to practice that UC-MSCs can be expanded in a Quantum bioreactor to produce large quantities of UC-MSCs that are ~2-5 times the amount achieved using the stirred tank bioreactor of Weiss. Furthermore, Mennan teaches that their expanded UC-MSCs adhered to the ISCT criteria for MSCs and had comparable chondrogenic potency and immunomodulatory immunoprofiles before and after proinflammatory stimulation. As such, the increased yield of Mennan did not lead to a reduction in the quality of the MSCs. Therefore, it would have been obvious to use the bioreactor and methods of running the bioreactor of Mennan to achieve a higher yield of UC-MSCs while maintaining a similar cell quality. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Although Weiss teaches that they included platelet lysate as part of their dynamic culture conditions, Mennan is silent as to whether they used platelet lysate in their Quantum hollow fibre bioreactor. Furthermore, Weiss teaches that UC-MSCs had higher viability and cell yields when grown in media comprising platelet lysate (page 16, line 17-page 23, line 24).
However, Rojewski teaches that they expanded bone marrow MSCs in a Quantum bioreactor with either fetal calf serum (FCS) or platelet lysate and found that they achieved an average of more than 10 x 107 of MSCs using platelet lysate. They achieved similar yields in the FCS and platelet lysate (xenogeny-free) expansion systems (abstract). Rojewski teaches that using a xenogen-free system affords a higher level of health protection and serve as an ethical advantage and that platelet lysate has already been proven to be a safe and feasible alternative to animal-derived serum as supplement for MSC cultivation (page 1982, column 1, paragraph 4).
Kandoi teaches that ex-vivo expansion of MSCs using a xenogeneic supplement such as fetal bovine serum (FBS) carries the risk of transmission of zoonotic infections and immunological reactions. Platelet lysate (PL) is a xeno-free, allogeneic replacement for FBS that generates the same yield of cells following enzymatic dissociation (abstract and Figure 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used platelet lysate as part of expanding the UC-MSCs in a Quantum bioreactor to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to expand UC-MSCs with platelet lysate in the Quantum bioreactor with a reasonable expectation of success because Weiss teaches that UC-MSCs had higher viability and cell yields when grown in media comprising platelet lysate and Rojewski and Kandoi teach that using a xenogen-free serum replacement reduces the risk of transmission of zoonotic infections and immunological reactions, improving health protection for use in clinical settings. Furthermore, Rojewski successfully reduces to practice that platelet lysate can be used to expand MSCs (using bone marrow derived MSCs) in a Quantum bioreactor with similar yields with FBS and similar yields to what was found with UC-MSC expansion of Mennan. Therefore, it would have been obvious that platelet lysate could be used during expansion of UC-MSCs in the Quantum bioreactor.
Regarding the at least 85% confluency limitation and the 6 to 8 days of expansion of claim 1 and wherein expanding is performed for less than 7 days of claim 26, Weiss, as stated supra, teaches that they waited until the cells reach 80-90% confluency before moving them to dynamic culture conditions and Mennan, as stated supra, teaches culturing the cells in the bioreactor for 7.7 ± 2.2 days.
As such, the combined method of expanding UC-MSCs of Weiss, Mennan, Rojewski, and Kandoi is considered to fall within the limitations of claims 1 and 26 as the range for confluency (80-90%) and the range of days for expansion in the bioreactor (5.5-9.9 days) overlaps with the claimed ranges.
Furthermore, MPEP 2144.05 states that In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range).
Regarding claim 2, Weiss teaches that cryopreserved umbilical cords could be used for isolating MSCs (page 4, line 21-page 5, line 11).
Regarding claims 71 and 4, Weiss teaches that as part of their isolation method, they can contact the umbilical cord tissue with digestive enzyme solutions, including a mixture of a collagenase and hyaluronidase enzyme solution (page 5, lines 12-28).
Response to Arguments
Applicant's arguments filed March 6, 2026, are acknowledged.
Applicant argues that the presently claimed invention is not obvious based on the combination of references. To be able to arrive at the particular elements of the currently claimed invention, the skilled artisan would have to select different elements from the various methods disclosed in the present combination of references while at the same time also excluding elements from the same methods disclosed therein. To do such indiscriminate selecting from each of the references, which themselves report to their peers the success of those individual methods, cannot render the currently claimed invention obvious.
To illustrate this, Applicant provides a table that reflects different elements from the presently claimed invention and the corresponding references from the combination that either disclose or do not disclose such particular elements. For each element with respect to the combination, there are conflicting teachings whether the method should utilize it, so it cannot be obvious which of the choices to use or not to use.
In addition, certain teachings in the references are mutually exclusive with respect to what is required in the presently claimed method. For example, the claims require that the expanding step occurs in a functionally closed system, and yet two of the references (Weiss and Kandoi) in the combination instruct the skilled artisan instead to utilize open systems. They also conflict with Mennan and Rojewski from the combination, and so it is self-evident that the skilled artisan would not find it obvious whether or not to use a closed system.
Inclusion of platelet lysate was not a requirement for the methods of Mennan that still produced over 200M cells, and yet the claimed invention and the other combined teachings require it. The teachings of the references are also incompatible with regards to the percentage of confluency and the duration of expansion times. Such contradictions within the teachings of the combined references, and particularly with respect to the presently claimed invention, leads to no clear indication what the methods should entail. The elements from the combination that would have to be picked and chosen, or excluded, are not obvious (page 9, paragraph 5-page 11, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, Applicant is reminded that a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, the combined teachings of Weiss, Mennan, Rojewski, and Kandoi do not require combining together all of their individual methods of expanding MSCs into an amalgam of all of the methods. It is well understood in the field that one can learn from other group’s protocols and incorporate individual methods steps into their own protocol that may prove beneficial without undergoing a wholesale change of all the steps because of the differences between the two protocols. Furthermore, as identified in the rejection above, Weiss serves as the base method being modified. Weiss teaches all the limitations of step a: culturing MSCs in a medium comprising platelet lysate to at least 85% confluency (Examples 1-2, page 8, lines 14-26, and claims 1-11) before moving the cells to a bioreactor. As identified by the Applicant, Weiss does not teach using a functionally closed system to expand their MSCs.
However, Mennan teaches a method of expanding umbilical cord MSCs comprising isolating UC-MSCs from UC matrix, culturing the UC-MSCs on tissue culture plates for ~14 days, then loading 5 x 106 cells into a Quantum bioreactor (a functionally closed system), an automated hollow fibre system, and culturing the cells in the bioreactor for 7.7 ± 2.2 days. Mennan teaches that they achieved harvests of 9-20 x 107 cells at the end of culturing in the bioreactor. Mennan teaches that their expanded UC-MSCs adhered to the ISCT criteria for MSCs and had comparable chondrogenic potency and immunomodulatory immunoprofiles before and after proinflammatory stimulation (page S146, column 2, paragraph 5-page S147, column 1, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the stirred tank bioreactor of Weiss with the Quantum automated hollow fibre bioreactor of Mennan to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Weiss and Mennan use a similar general method for expanding UC-MSCs comprising isolating MSCs from umbilical cord, culturing them in a static culture condition on culture plates, then transferring the cells to a dynamic culture bioreactor, a stirred tank bioreactor in Weiss and a Quantum hollow fibre bioreactor in Mennan. Additionally, Mennan has successfully reduced to practice that UC-MSCs can be expanded in a Quantum bioreactor to produce large quantities of UC-MSCs that are ~2-5 times the amount achieved using the stirred tank bioreactor of Weiss. Furthermore, Mennan teaches that their expanded UC-MSCs adhered to the ISCT criteria for MSCs and had comparable chondrogenic potency and immunomodulatory immunoprofiles before and after proinflammatory stimulation. As such, the increased yield of Mennan did not lead to a reduction in the quality of the MSCs. Therefore, it would have been obvious to use the bioreactor and methods of running the bioreactor of Mennan to achieve a higher yield of UC-MSCs while maintaining a similar cell quality. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
As such, this makes it clear that the change to the Weiss protocol is to use a functionally closed bioreactor for expanding the MSCs as this leads to an increased yield compared to the method of Weiss while maintaining the quality of the MSCs.
Regarding using platelet lysate during the expansion step in the Quantum bioreactor, although Weiss teaches that they included platelet lysate as part of their dynamic culture conditions, Mennan is silent as to whether they used platelet lysate in their Quantum hollow fibre bioreactor. Furthermore, Weiss teaches that UC-MSCs had higher viability and cell yields when grown in media comprising platelet lysate (page 16, line 17-page 23, line 24).
However, Rojewski teaches that they expanded bone marrow MSCs in a Quantum bioreactor with either fetal calf serum (FCS) or platelet lysate and found that they achieved an average of more than 10 x 107 of MSCs using platelet lysate. They achieved similar yields in the FCS and platelet lysate (xenogeny-free) expansion systems (abstract). Rojewski teaches that using a xenogen-free system affords a higher level of health protection and serve as an ethical advantage and that platelet lysate has already been proven to be a safe and feasible alternative to animal-derived serum as supplement for MSC cultivation (page 1982, column 1, paragraph 4).
Kandoi teaches that ex-vivo expansion of MSCs using a xenogeneic supplement such as fetal bovine serum (FBS) carries the risk of transmission of zoonotic infections and immunological reactions. Platelet lysate (PL) is a xeno-free, allogeneic replacement for FBS that generates the same yield of cells following enzymatic dissociation (abstract and Figure 2).
As identified above, Weiss teaches that UC-MSCs had higher viability and cell yields when grown in media comprising platelet lysate and Rojewski and Kandoi teach that using a xenogen-free serum replacement reduces the risk of transmission of zoonotic infections and immunological reactions, improving health protection for use in clinical settings. Furthermore, Rojewski successfully reduces to practice that platelet lysate can be used to expand MSCs (using bone marrow derived MSCs) in a Quantum bioreactor with similar yields with FBS and similar yields to what was found with UC-MSC expansion of Mennan. Therefore, it would have been obvious that platelet lysate could be used during expansion of UC-MSCs in the Quantum bioreactor.
As such, this makes it clear that the modification to the method of Weiss and Mennan is to include platelet lysate during expansion of the MSCs in the bioreactor and Rojewski and Kandoi provide motivation for making this change.
Therefore, the rejection identifies the specific steps of the Wiess protocol or Weiss and Mennan protocol that are being modified and the motivation for doing so. And one of ordinary skill in the art would be able to identify these modifications as being specific to each step, without requiring all steps to be modified to create an amalgam of each of the individual protocols used by Weiss, Mennan, Rojewski, and Kandoi.
Thus, Applicant’s arguments are considered unpersuasive.
Claims 1, 4, 7, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2017132358 (Weiss), Mennan et al. (Osteoarthritis and Cartilage 26: S146-S147. 2018; Published April 2018), Rojewski et al. (Cell Transplantation 22: 1981–2000. 2013), and Kandoi et al. (Scientific Reports 8: 1-12. 2018; Published August 2018) as applied to claims 1, 4, and 71 above and further in view of Min et al. (Chinese Journal of Tissue Engineering Research 16: 8406-8412. 2012; previous art of record). Applicant’s traversal has been fully consider and was addressed above.
The teachings of Weiss, Mennan, Rojewski, and Kandoi are as discussed above. As stated supra, Weiss teaches that as part of their isolation method, they can contact the umbilical cord tissue with digestive enzyme solutions, including a mixture of a collagenase and hyaluronidase enzyme solution. Furthermore, Weiss teaches that the umbilical cord tissue can be sequentially contacted with two or more digestive enzyme solutions and directly identifies collagenase, hyaluronidase, and DNase as known digestive enzyme solutions (page 5, lines 12-28).
The combined teachings of Weiss, Mennan, Rojewski, and Kandoi do not directly teach wherein the enzyme cocktail comprises hyaluronidase, collagenase, and DNase.
However, Min teaches that in this study they aimed to optimize the protocol for the isolation of MSCs from umbilical cord. They found that the combination of collagenase Ⅱ, collagenase Ⅳ, hyaluronidase, trypsin and DNAase can lead to the complete digestion of umbilical cord tissue and reduce the viscosity, and human umbilical cord mesenchymal stem cells (HUCMSCs) can be effectively isolated and cultured from umbilical cord (page 8407, column 1, paragraph 3). Min teaches that their results showed that the combination of collagenase Ⅱ and Ⅳ, hyaluronidase, trypsin and DNAase which were used to digest umbilical cord could significantly improve the yield, viability and colony-forming ability of HUCMSCs. In addition, the time for HUCMSCs to adhere and grow to confluence is less by using their combined digestion method than common digestion method (page 8411, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the enzymatic isolation method of umbilical cord MSCs of Weiss which only used collagenase and hyaluronidase with the method of isolating MSCs from cord blood tissue of Min to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Min teaches that their results showed that the combination of collagenase Ⅱ and Ⅳ, hyaluronidase, trypsin and DNAase which were used to digest umbilical cord could significantly improve the yield, viability and colony-forming ability of HUCMSCs. In addition, the time for HUCMSCs to adhere and grow to confluence is less by using our combined digestion method than common digestion method. As such, it would have been obvious to use an enzyme cocktail including collagenase, hyaluronidase, and DNase to isolate MSCs as it allows for MSCs to be more effectively isolated and cultured from umbilical cord. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2017132358 (Weiss), Mennan et al. (Osteoarthritis and Cartilage 26: S146-S147. 2018; Published April 2018), Rojewski et al. (Cell Transplantation 22: 1981–2000. 2013), and Kandoi et al. (Scientific Reports 8: 1-12. 2018; Published August 2018) as applied to claim 1 above, and further in view of Capelli et al. (Immunology Letters 168: 222-227. 2015; previous art of record). Applicant’s traversal has been fully consider and was addressed above.
The teachings of Weiss, Mennan, Rojewski, and Kandoi are as discussed above.
Although Weiss teaches that MSCs are important for treating immunological disorders, such as graft-versus-host-disease and clinical trials for cellular therapy (page 1, line 15-page 2, line 14) and Mennan teaches that they intended to use their expanded MSCs for cellular therapies for cartilage repair, they do not take the next step of making pharmaceutical compositions comprising the cells.
However, Capelli teaches their manufacturing experience on 103 consecutive clinical-grade in vitro expansions of umbilical cord-derived mesenchymal stromal cells together with description of methods and reagents utilized in their Cell Factory. The same animal- and serum-free medium, additioned with human platelet lysate, has been used for all the expansions performed (abstract). Capelli teaches that umbilical cord MSCs were used to treat steroid resistant Graft versus Host Disease (Clinical Trial NCT02032446) (Table 3). NCT02032446 teaches that three Umbilical Cord Mesenchymal stromal cells (UC-MSC) infusions (1-3 x 106 cells/kg) were given in weekly intervals starting from day 5 (page 6). Although Capelli does not specifically identify that the MSCs are comprised with a pharmaceutically acceptable carrier, it is well understood that the infusions would comprise a formulation of MSCs with a pharmaceutically acceptable carrier such as a saline solution.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of expanding MSCs of the combined teachings of Weiss, Mennan, Rojewski, and Kandoi with pharmaceutical infusion composition of Capelli to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Weiss and Mennan contemplate administering expanded MSCs to treat diseases and Capelli successfully reduces to practice that expanded MSCs have been administered to patients to treat Graft versus Host Disease. As such, it would have been obvious that the expanded MSCs from the combined method of Mennan, Rojewski, and Kandoi could be used as part of a pharmaceutical composition to treat a disease. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 58, 61, 62, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2017132358 (Weiss), Mennan et al. (Osteoarthritis and Cartilage 26: S146-S147. 2018; Published April 2018), Rojewski et al. (Cell Transplantation 22: 1981–2000. 2013), and Kandoi et al. (Scientific Reports 8: 1-12. 2018; Published August 2018) as applied to claim 1 above, and further in view of Capelli et al. (Immunology Letters 168: 222-227. 2015), as evidenced by NCT02032446, version 1, submitted 1/08/2014 (previous art of record). Applicant’s traversal has been fully consider and was addressed above.
Regarding claims 58 and 62, the teachings of Weiss, Mennan, Rojewski, and Kandoi are as discussed above.
Although Weiss teaches that MSCs are important for treating immunological disorders, such as graft-versus-host-disease and clinical trials for cellular therapy (page 1, line 15-page 2, line 14) and Mennan teaches that they intended to use their expanded MSCs for cellular therapies for cartilage repair, they do not take the next step of making pharmaceutical compositions comprising the cells.
However, Capelli teaches their manufacturing experience on 103 consecutive clinical-grade in vitro expansions of umbilical cord-derived mesenchymal stromal cells together with description of methods and reagents utilized in their Cell Factory. The same animal- and serum-free medium, additioned with human platelet lysate, has been used for all the expansions performed (abstract). Capelli teaches that umbilical cord MSCs were used to treat steroid resistant Graft versus Host Disease (Clinical Trial NCT02032446) (Table 3). NCT02032446 teaches that three Umbilical Cord Mesenchymal stromal cells (UC-MSC) infusions (1-3 x 106 cells/kg) were given in weekly intervals starting from day 5 (page 6). Although Capelli does not specifically identify that the MSCs are comprised with a pharmaceutically acceptable carrier, it is well understood that the infusions would comprise a formulation of MSCs with a pharmaceutically acceptable carrier such as a saline solution.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of expanding MSCs of the combined teachings of Weiss, Mennan, Rojewski, and Kandoi with the method of treating Graft-versus-host-disease of Capelli to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Weiss and Mennan contemplate administering expanded MSCs to treat diseases, Weiss specifically identifies Graft-versus-host-disease as a disease that has been treated by administering MSCs, and Capelli successfully reduces to practice that expanded MSCs have been administered to patients to treat Graft versus Host Disease. As such, it would have been obvious that the expanded MSCs from the combined method of Weiss, Mennan, Rojewski, and Kandoi could be used Graft-versus-host-disease. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 61, Weiss teaches that cryopreserved umbilical cords could be used for isolating MSCs (page 4, line 21-page 5, line 11). Furthermore, Capelli teaches that they cryopreserved MSCs (i.e. 78 banked vials (P2) (At P2 detachment they freeze intermediate vials for future expansions (P2 banking). Ten of such vials have been subsequently expanded to give other 47 bags (21 given to patients). Overall 8 patients have so far been treated, with UC-MSCs (page 223, column 2, paragraph 4 and page 224, column 1, paragraph 1).
Regarding claim 66, NCT02032446 teaches that Pentostatin will be given by intravenous infusion at a dose of 1 mg/m3 for 3 consecutive days. Thereafter, three Umbilical Cord Mesenchymal stromal cells (UC-MSC) infusions will be given at weekly intervals starting from day 5 (page 6). As the Applicant has not defined conjunction, the method of NCT02032446 is considered to fall within the limitations of claim 66.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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