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
Applicant's election of Group I, drawn to a product comprising mesenchymal stem cells and a hydrogel, in the reply filed on 5/29/2024 stands.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 20-21, 23, 26-31, 33-34 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Natesan et al (2011, Tissue Eng Part A, 17(7-8):941-53; reference U) in view of Harmon et al (U.S. PGUPB 2007/0292401; 1/23/23 IDS), Brenner et al (U.S. PGUPB 2013/0129688) and Stephenne et al (U.S. PGUPB 2013/030229).
Regarding claims 20-21, 23, 27, 29-31 and 33-34, Natesan teaches a composition for large surface area skin grafting treatment of wounds (reads on a sheet for skin regeneration or diabetic wound healing, and on planar sheet) comprising adipose-derived mesenchymal stem cells (MSCs) with a spindle-shaped morphology (reads on fibroblast-like shape and on fibroblast-type cells) in a bi-layer hydrogel comprising both a fibronectin based fibrin glue hydrogel and type I collagen hydrogel (reads on hydrogel and one support) in the absence of an immune response (see abstract, pages 942-943 & 948-949 and Figure 1); all supports are either biodegradable or undegradable. Regarding claim 26, Natesan teaches the fibrin glue had a concentration of 10 IU/ml thrombin (see page 943). Regarding claim 20, Natesan teaches 50,000 cells were seeded on a gel in a 12-well plate, using a seeding density of 50,000 cells/ml (see pages 943-944 & 949), and Figure 4 shows that the cell number more than doubled by day 3, more than tripled by day 5, and more than quadrupled by day 7; reads on at least 20,000 cells per cm2. Regarding claims 20 and 30, Natesan teaches the cell/gel construct can be cryopreserved, and made with human adipose-derived MSCs (see page 942-943 and 949).
Figure 2 of Natesan clearly teaches undifferentiated ASC and thus would express the same growth factors. It is noted that in applicant’s response, applicant states undifferentiated ASCs secrete the claimed growth factors.
Natesan does not teach the thickness of the composition, that the composition is cryopreserved in a cryopreservation medium comprising human serum albumin (HSA) and DMSO, or that the composition comprises a support includes laminin or the materials listed in claims 28.
Regarding claim 20, Harmon is directed to methods involving stem cells on scaffolds for regeneration and repair of soft tissue, and Harmon teaches that preferably when the scaffold construct is used in skin grafting, the scaffold is about 0.5 to about 3 millimeter thick and is in the form of a flat sheet (see abstract and paragraph [0188]). Regarding claims 27-28 and 40, Harmon teaches that suitable support structures for stem cells include combinations of basement membrane proteins such as laminin and collagen, nonwoven fiberous scaffolds, biodegradable materials of PLA and/or PGA, and other supporting medium or hydrogels (see paragraphs [0042], [0166] and [0170]-[0171]).
Regarding claim 20, Brenner is drawn to method for preparing MSCs from different sources including adipose tissue derived MSCs, for transplantation for tissue and skin repair, and Brenner teaches that MSCs can be cryopreserved for long-term storage prior to use (see paragraphs [0025]-[0026], [0049]-[0050] and [0093] and Example 7). Regarding claims 20-21, Brenner teaches that for freezing, the MSCs are, 5 to 10% human serum albumin (HSA) and 5 to 10% DMSO and that after thawing, the MSC viability remains greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or 100% (see paragraphs [0093] and [0094] and Example 7). Regarding claim 20, Brenner also teaches an example wherein the MSCs are cryopreserved with 10% DMSO by volume and 20% HSA by volume (see Example 7). Regarding claim 31, Brenner does not teach that cryopreservation changes the shape of MSCs nor that strength.
Regarding claim 20, Stephenne is drawn to method for preparing MSCs from different sources including adipose tissue derived MSCs, for transplantation for tissue and skin repair, and that MSCs can be cryopreserved for storage prior to use (see paragraphs [0109], [0125], [0141] and [0164]). Regarding claims 20-21, Stephenne teaches that the MSCs can be combined with components that can maintain or enhance the viability of cells such as human albumin, that the MSC compositions may be either liquid or may be semi-solid or solid, such as a gel or may exist on solid support or scaffold, and that for freezing cryopreservatives such as DMSO are well known in the art to be useful for protecting the cells during freezing (see paragraph [0141] and [0148]). Regarding claim 31, Stephenne does not teach that cryopreservation changes the shape of MSCs nor that strength of any of the components.
It would have been obvious to combine Natesan and Harmon to include different combinations of support materials in Natesan’s stem cell composition for skin grafting, and to use a graft with a thickness of 0.5 to 3 mm. A person of ordinary skill in the art would have had a reasonable expectation of success in including different combinations of support materials, as taught by Harmon, and to use a graft with a thickness of 0.5 to 3 mm in Natesan’s stem cell composition for skin grafting because Harmon specifically teaches that these materials are useful for supporting stem cells and that this is a preferred thickness for skin graft materials. The skilled artisan would have been motivated to include different combinations of Harmon’s support materials and to use a graft with a thickness of 0.5 to 3 mm in Natesan’s stem cell composition for skin grafting because Harmon specifically teaches that these materials are useful in methods involving stem cells for regeneration and repair of soft tissue including skin, and that this is a preferred thickness for skin grafts, and Natesan composition is for skin grafting.
It would have been obvious to combine Natesan in view of Harmon with Brenner and Stephenne to cryopreserve Natesan’s MSC transplant composition in a cryopreservation medium comprising HSA and DMSO. A person of ordinary skill in the art would have been motivated to cryopreserve Natesan’s MSC transplant composition in a cryopreservation medium comprising HSA and DMSO because both Brenner and Stephenne establish that MSCs can be cryopreserved for storage and later use, and that cryopreservation with HSA and DMSO can maintain the viability of the MSCs for transplantation. The skilled artisan would have had a reasonable expectation of success in cryopreserving Natesan’s MSC transplant composition in a cryopreservation medium comprising HSA and DMSO because both Brenner and Stephenne specifically teaches that these materials are useful in methods involving MSCs for transplantation and tissue repair as they can preserve the viability of the MSCs, and Natesan composition is for transplantation and tissue repair. Additionally, Stephenne establish that MSCs can be in various forms including with solids and gels, with cryopreservation.
Regarding the claimed range of 1 to 20 w/v% DMSO and the claimed range of 1 to 50 w/v% HSA, as stated in the rejection Brenner teaches the use of 5 to 10% DMSO and 5 to 20% HAS, which are fully encompassed by the claimed ranges. Furthermore, both Brenner and Stephenne teach that HSA and DMSO function to promote viability and have cryoprotective functions, which renders the amount a result effective variable as both components have a known function of promoting viability of the cryopreserved MSC composition. Therefore, it is obvious to modify the amounts of HSA and DMSO to achieve the desired level of MSC viability.
Claims 20 and 29 limit to the use of the composition being for wound healing. Since the claims are drawn to a product, and not a method of use the product, these limitations only further limit the product to having a structure that could be used in wound healing (see MPEP 2111.02 II). Since Natesan specifically teaches the composition is useful for tissue engineering, and because Natesan anticipates the structure of the product, Natesan’s teachings also read on these use limitations.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Natesan et al (2011, Tissue Eng Part A, 17(7-8):941-53) in view of Harmon et al (U.S. PGUPB 2007/0292401; 1/23/23 IDS), Brenner et al (U.S. PGUPB 2013/0129688) and Stephenne et al (U.S. PGUPB 2013/0302291) as applied to claims 20-21, 23, 26-31, 33-34 and 40 above, and further in view of Peterbauer-Scherb et al (2012, J. Tissue Eng. Regen. Med., 6:434-442).
Natesan does not teach the amount of fibrinogen.
Regarding claims 24-25, like Natesan, Peterbauer-Scherb teaches a tissue engineering composition comprising adipose-derived MSCs with an elongated shape in a fibrin glue on a solid support in the absence of an immune response (see sections 2.2 and 3.2, and Figure 2). Regarding claims 24-25, Peterbauer-Scherb teaches the fibrin glue had a final concentration of 2 IU/ml thrombin and 6.25 mg/ml fibrinogen (see section 2.2).
It would have been obvious to combine Natesan with Peterbauer-Scherb to use Peterbauer-Scherb’s amount of fibrinogen and thrombin in Natesan’s composition. A person of ordinary skill in the art would have had a reasonable expectation of success in using Peterbauer-Scherb’s amount of fibrinogen and thrombin in Natesan’s composition because both references teach a tissue engineering composition comprising adipose-derived MSCs with an elongated shape in a fibrin glue on a solid support. The skilled artisan would have been motivated to use Peterbauer-Scherb’s amount of fibrinogen and thrombin in Natesan’s composition because Peterbauer-Scherb specifically teaches that these amounts are are useful for making fibrin supports in methods involving stem cells for regeneration and repair of soft tissue.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 10/28/2025 have been fully considered but they are not persuasive.
Applicant argues that the prior art teaches differentiated cells and the differentiated adipose derived MSCs do not secrete the claimed growth factors. Applicant argues that undifferentiated adipose derived MSCs do secrete the claimed growth factors.
This argument is unpersuasive. Figure 2 of Natesan clearly teaches undifferentiated ASC and thus would express the same growth factors. These undifferentiated cells are loaded into the hydrogel matrix and then differentiate later, day 7. See Figure 3. Note Natesan clearly teaches the ASC maintain their spindle shaped morphology as the migrate. Thus, the undifferentiated ASCs are secreting the claimed growth factors, at least at day 6. Natesan teaches controlling differentiation by matrix manipulation. Page 942. The inventive endeavor is to provide the ASC to a wound sire so the cells can proliferate and differentiate in use for re-epithelialization and wound healing. The instant claims only recite “the adipose-derived MSCs have a fibroblast-like shape and secrete Serpin E1 (PAI-1), Serpin F1 (PEDF), TIMP-1, CXCL8 (IL-8), FGF-2, and DPPIV (CD26)”. The claims do not state that the cells do not differentiate over time. Clearly Natesan teaches loading undifferentiated ASCs to a hydrogel matrix which meets the claim limitation.
It is further noted that instant example 2 assesses the biological characteristics of the adipose derived MSCs after culturing for 72 hours and the secretion of the claimed factors promote angiogenesis and cell proliferation. Thus, Natesan’s adipose derived MSCs at day 3 would also have the same characteristics. Note Figure 3 in which the cells are not differentiated. The prior art cells are also taught to promote angiogenesis for wound healing. It is noted that the instant specification teaches the isolation of the cells is from KR 10-1328604. See instant example 1. KR states that up to 10 passages the cells do not change in proliferation or phenotype. The isolation process is the same as taught by Natesan. Natesan teaches isolating the cells and using a passage of 2-4. The instant invention utilizes at least two passage. Thus, it appears both the prior art and instant invention use the same process of isolating the cells and incorporate the same cells into a hydrogel for wound healing.
If applicant is intending to claims cells that do not differentiate overtime and the cells remain undifferentiated, then it is suggested applicant amend the claims accordingly given adequate support and written description is found in the instant specification. It is noted that the instant specification does not provide the biological characteristics over time to show differentiation does not occur in the instantly claimed invention. Nowhere does the specification discuss that the cells are undifferentiated cells and/or do not differentiate over time. A written description rejection is not made at this time since applicant demonstrates that at day 3 (72 hours) the cells secreted the claimed growth factors, same as the prior art, Natesan. If applicant amends the claim to recite that the cells do not differentiate over time, applicant is requested to point out support.
Note the recently filed NPL of 10/28/2025 has not been considered; it is suggested applicant file an IDS so that the NPL may be considered.
Conclusion
No claims are free of the art. No claims are allowed.
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/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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