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. Claims 1 – 3, 5 – 31, and 11 – 31 remain pending. Claims 1 – 3 and 5 – 10 are under consideration.
Withdrawn Claim Rejections
2. The rejection of claim 1 and dependents for reciting both “consists of” and “comprising” is withdrawn in view of Applicant’s amendment to claim 1.
3. The rejection of claim 10 for recitation of “includes” as it relates to claim 1 is withdrawn in view of Applicant’s amendment to claim 1 and 10 to recite “comprises”
4. The rejection of claims 1 – 3 and 7 – 8 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 requiring target molecules be covalently bound directly to the surface and/or in the pores of the said carrier.
5. The rejection of claims 5, 6, and 9 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 requiring target molecules be covalently bound directly to the surface and/or in the pores of the said carrier.
6. The rejection of claim 10 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1 requiring target molecules be covalently bound directly to the surface and/or in the pores of the said carrier.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
7. Claims 5, 6, 9, and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
8. Regarding claim 5, it is unclear how the limitations of claim 5 relate to claim 1 as claim 1 has been amended to require the target molecules be covalently bound directly to the surface and/or in the pores but claim 5 requires target molecules be covalently bound onto the functionalized nanoparticles. It is unclear if “target molecules” of claim 5 are a second group of target molecules in addition to the ones directly bound to the surface and/or pores and/or if the target molecules of claim 5 are located at a different location on the membrane compared to the target molecules of claim 1. Claim 9 is also rejected as it depends from claim 5 and does not clarify the grounds of rejection. For the purpose of applying prior art, claim 5 is interpreted as the membrane having integrated target molecules covalently bound directly to the surface and target molecules covalently bound onto the functionalized nanoparticles via surface functional groups on the nanoparticles.
9. Regarding claim 6, it is unclear how the limitations of claim 6 relate to claim 1 as claim 1 has been amended to require the target molecules be covalently bound directly to the surface and/or in the pores but claim 6 requires target molecules be covalently bound onto the functionalized nanoparticles. It is unclear if “target molecules” of claim 6 are a second group of target molecules in addition to the ones directly bound to the surface and/or pores and/or if the target molecules of claim 6 are located at a different location on the membrane compared to the target molecules of claim 1. For the purpose of applying prior art, claim 6 is interpreted as the membrane having integrated target molecules covalently bound directly to the surface and target molecules covalently bound onto the integrated functionalized nanoparticles via surface functional groups on the nanoparticles.
10. Regarding claim 10, it is unclear how the limitations of claim 10 relate to claim 1 as claim 1 has been amended to require the target molecules be covalently bound directly to the surface and/or in the pores but claim 10 requires target molecules be bound to the NiCu functionalized nanoparticles. It is unclear if “target molecules” of claim 10 are a second group of target molecules in addition to the ones directly bound to the surface and/or pores and/or if the target molecules of claim 10 are located at a different location on the membrane compared to the target molecules of claim 1. For the purpose of applying prior art, claim 10 is interpreted as the membrane having integrated target molecules covalently bound directly to the surface and target molecules covalently bound onto the functionalized nanoparticles of NiCu enclosed by a layer of silica via surface NH2 functional groups on the nanoparticles.
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.
11. Claim(s) 1 – 3 and 7 – 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee (Lee, HyeongJin, et al. Tissue Engineering Part C: Methods 19.10 (2013): 784-793; previously cited), hereinafter Lee in view of Nordon (Nordon, Robert E., et al. Cytometry: The Journal of the International Society for Analytical Cytology 24.4 (1996): 340-347), hereinafter Nordon.
Regarding claims 1 – 3 and 7, Lee teaches 3D printed multi-layered structures comprising polycaprolactone (“biocompatible polymer with pores” and “3D printed carrier structure”, “at least one layer of biocompatible polymer” of claim 1) and comprising polycaprolactone and alginate (“derivatives of at least one of polysaccharides” and “alginate” of claim 7) and polycaprolactone (S-1, S-2, and S-3 in Figure 1) where the pore size of each of the S-1, S-2, and S-3 structures is greater than 300 µm but less than 500 µm (“diameter in the range from 200 to 500 µm” of claim 1) (Abstract; Figure 1; page 785, right col. paragraph 1 and 5; page 786, left col. paragraph 3; Figure 3; page 787, right col. paragraph 3 – 4). Figure 3b shows the structures comprises multiple layers of polycaprolactone (PCL) struts arranged in a structured geometry (“woven and nonwoven materials” of claim 1, “a structured geometry with a shape, size and distribution of the pores uniform throughout the layer” of claim 2 and “several layers of structured” of claim 3). Applicant’s specification (page 7 – 8) discloses derivatives of polysaccharides including alginate and polycaprolactone are suitable biocompatible polymers (“inert” of claim 1).
Lee does not teach “integrated target molecules are covalently bound directly to the surface and/or in the pores of said carrier structure” of claim 1 or “said target molecule is an entire antibody or part of the antibody” of claim 8. However, Lee teaches the cells are viable in the S-1 structure in which the PCL struts are surrounded by alginate and in the S-3 structure comprising both PCL and alginate struts where cell viability is observed both on the PCL struts and alginate struts of S-3 (Figure 3b, 3c, 4h, and 5). Lee teaches tissue engineering is a rapidly growing interdisciplinary research area that may provide options for treating damaged tissues and organs (page 784, left col. paragraph 1).
Regarding “integrated target molecules are covalently bound directly to the surface and/or in the pores of said carrier structure” of claim 1 and “antibody” of claim 8, Nordon teaches a membrane for separation of CD34+ stem cells comprising multiple regenerated cellulose hollow fiber modules that have CD34 monoclonal antibody (claim 8) covalently bound directly to the surface (claim 1) (page 341, left col. para. 3 – 5 and right col. para. 1 – 2; Figure 1). Nordon teaches the antibody recognizes CD34+ stem cells and these cells are captured by the antibody covalently bound to the membrane (Abstract; page 344, left col.; Table 3; Figure 4). Nordon teaches in Table 1 the membrane specifications including an internal diameter of 200 µm and external diameter of 216 µm, and the membrane is cuprophan-anti-CD34 (Table 1). Nordon teaches in Table 2 a protocol for using the membrane for separating CD34+ stem cells from peripheral stem cells from patients (page 342, left col. para. 3 – 4; Table 2). Nordon teaches the purity of the CD34+ cells recovered was 94.4% (page 344, right col. para. 4). Nordon teaches that the hollow-fiber system provides a suitable platform for affinity cell separation (page 345, left col. para. 2). Nordon teaches the development of hematopoietic stem cell biology and related clinical therapies relies on efficient methods for the selection of cell subpopulations (page 340, left col. para. 1). Nordon teaches development of large-scale CD34+ cell enrichment technologies will enable the development of new strategies for hematopoietic reconstitution (page 340, left col. para. 1). Nordon teaches hollow-fiber systems provide a geometry that is suitable for the separation of adherent cell populations by using uniform shear fractionation and may provide sufficient surface area in a compact configuration for clinical separations (page 341, left col. para. 2).
It would have been obvious prior to the effective filing date for the person of ordinary skill in the art to combine the teachings of Lee regarding a 3D printed multi-layered structure of alginate and polycaprolactone where the pore size is greater than 300 µm but less than 500 µm where the structure comprises multiple layers of polycaprolactone struts arranged in a structured geometry with the teachings of Nordon regarding a membrane for separation of CD34+ stem cells comprising multiple regenerated cellulose hollow fiber modules that have CD34 monoclonal antibody covalently bound directly to the surface to arrive at the claimed membrane for separation of target stem cells from a single-cell suspension containing stem cells, whereby said single-cell suspension is obtained from a biological sample containing stem cells, wherein the membrane comprises a 3D printed carrier structure having at least one layer of biocompatible polymer with pores, wherein the biocompatible polymer is inert towards the target stem cells such that it does not influence the essential characteristics of the target stem cells, and wherein integrated target molecules are covalently bound directly to the surface and/or in the pores of said carrier structure and are capable of binding to characteristic antigens on the surface of the target stem cells to provide selective retrieval of target stem cells; wherein the pores have a diameter in the range from 200 to 500 μm, such that the single-cell suspension may free flow through the 3D carrier structure; and wherein the biocompatible polymer comprises woven and nonwoven materials. One would have been motivated to combine the teachings of Lee and Nordon in a membrane comprising a polysaccharide with covalently bound antibodies to separate CD34+ stem cells from a cell suspension for clinical therapies as Lee teaches tissue engineering is a rapidly growing interdisciplinary research area that may provide options for treating damaged tissues and organs and Nordon teaches the development of hematopoietic stem cell biology and related clinical therapies relies on efficient methods for the selection of cell subpopulations and Nordon teaches development of large-scale CD34+ cell enrichment technologies will enable the development of new strategies for hematopoietic reconstitution. One would have a reasonable expectation of success in combining the teachings as Nordon teaches the antibody recognizes CD34+ stem cells and these cells are captured by the antibody covalently bound to the membrane and Nordon teaches the purity of the CD34+ cells recovered was 94.4% and the alginate of Lee and the cellulose of Nordon are both polysaccharides.
12. Claim(s) 5, 6, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee (Lee, HyeongJin, et al. Tissue Engineering Part C: Methods 19.10 (2013): 784-793; previously cited), hereinafter Lee in view of Nordon (Nordon, Robert E., et al. Cytometry: The Journal of the International Society for Analytical Cytology 24.4 (1996): 340-347), hereinafter Nordon as applied to claims 1 – 3 and 7 – 8 above, and further in view of Kim (Kim, Jung-Ju, et al. Rsc Advances 4.33 (2014): 17325-17336; previously cited), hereinafter Kim in view of Odabas (Odabaş, S., et al. Journal of Chromatography B 861.1 (2008): 74-80; previously cited), hereinafter Odabas.
Lee in view of Nordon make obvious the limitations of claim 1 as set forth above. Lee and Nordon do not teach the membrane additionally includes functionalized nanoparticles integrated into the membrane structure, whereby target molecules are covalently bound onto the functionalized nanoparticles via their surface functional groups of claim 5 or the functionalized nanoparticles comprise at least one of a metal, metal alloy, metal oxide, or polymer with at least one functional group of claim 9.
Regarding claim 6, Lee teaches a 3D structure made of several layers of alginate and polycaprolactone with structured geometry with pores of 300 – 500 µm (Abstract; Figure 1; page 785, right col. paragraph 1 and 5; page 786, left col. paragraph 3; Figure 3; page 787, right col. paragraph 3 – 4). Lee does not teach “integrated functionalized nanoparticles to which target molecules are covalently bound via the surface functional groups”. However, Lee teaches preosteoblast cells were viable on the scaffold (Abstract; Figure 5).
Regarding “functionalized nanoparticles integrated” of claim 5, “integrated functionalized nanoparticles” of claim 6, and “at least one metal” of claim 9, Kim teaches composite porous scaffolds of polycaprolactone (PCL) and carboxyl group surface functionalized magnetite nanoparticles (“inorganic”, “magnetic”, “metal”, “metal oxide”, “functionalized nanoparticles have on their surface at least one functional group” of claim 9) (magnetic scaffolds) where the nanoparticles were well-distributed within the PCL matrix to enable homogenous nanocomposites with pores ranging from 250 – 500 µm (Abstract; page 17326, left col. paragraph 1 – 3; page 17327, right col. paragraph 3; page 17328, left col. paragraph 1 – 2 and right col. paragraph 1; Figure 2; page 17329, left col. para. 2 and right col. para. 1; page 17330, left col. paragraph 1; page 17335, left col. paragraph 2 and right col.; Table 2). Kim does not teach “whereby target molecules are covalently bound onto the functionalized nanoparticles via their surface functional groups” of claim 5 or “to which target molecules are covalently bound via their surface functional groups of claim 6. However, Kim teaches the nanoparticles have carboxyl groups present on the surface (page 17330, left col. para. 1). Kim teaches magnetic nanoparticles can be incorporated within polymeric scaffolds to provide additional magnetic properties to the scaffolds (page 17325, right col. para. 2). Kim teaches the incorporation of inorganic nanoparticles is considered a promising strategy to produce biopolymer-based bone scaffolds with properties more suitable for bone repair and regeneration (page 17325, right col. para. 2). Kim teaches pores larger than 300 µm are preferred for the induction of osteogenesis (page 17327, right col. para. 1). Kim teaches cell adhesion increased in the PCL-magnetite nanoparticles relative to PCL alone and these cells might experience more rapid proliferation-to-differentiation switch, i.e., undergo more active osteogenic differentiation processes (page 17332, right col. para. 2; Figure 9b; page 17333, right col. para. 1). Kim teaches the calcium level of the cells on the PCL-magnetite scaffold is 2.8-fold higher than on PCL alone indicating that cell mineralization was significantly enhanced on the magnetic scaffolds indicating that the surface-functionalized magnetite nanoparticles in the scaffolds helped cellular osteogenesis and the final stage of mineralization (page 17334, left col. para. 1). Kim teaches it is considered that the cells entering into an osteogenic differentiation could produce sufficient levels of bone matrix proteins, which are critically involved in subsequent cellular mineralization (page 17334, left col. and right col. para. 1). Kim teaches several studies have reported the influential role of magnetite nanoparticles incorporated within biomaterials and scaffolds in the cell proliferation and osteoblastic differentiation in vitro (page 17334, right col. para. 2). Kim teaches the PCL-magnetite nanoparticle scaffolds showed excellent tissue compatibility in vivo for 2 weeks, and the information delivers a minimal guideline of the possible use of the developed scaffolds for further biomedical applications (page 17335, left col. para. 2). One would have been motivated to combine the teachings of Lee, Nordon, and Kim because all three are drawn to structures for binding cells and Lee and Kim teach PCL structures and Kim teaches the PCL structures can have integrated carboxyl group surface functionalized magnetite nanoparticles that improves cell binding and osteogenesis, and Nordon teaches covalently bound antibodies to the structure via functional groups allows for selective binding of cells displaying an antigen recognized by the bound antibodies.
Regarding “whereby target molecules are covalently bound onto the functionalized nanoparticles via their surface functional groups” of claim 5 and “to which target molecules are covalently bound via their surface functional groups of claim 6, Odabas teaches magnetite nanoparticles functionalized with surface carboxyl groups to which CD105 and CD73 antibodies are covalently bound for separation of mesenchymal stem cells (MSCs) from cell suspensions (Abstract; Figure 1C – D; page 75, right col. 4 – 6; page 76, left col. last paragraph; page 77, left col. paragraph 2 – 4; page 78, left col. paragraph 2 – 3). Odabas teaches the immobilization of CD79 and CD105 antibodies to the nanoparticles was achieved with well-known carbodiimide chemistry with coupling efficiencies of 79.85% and 77.98%, respectively (page 77, right col. paragraph 4). Odabas teaches separation of CD105+ stem cells with the functionalized nanoparticles was greater than commercially available CD105 microbeads and quite high separation efficiencies were achieved (Table 2; page 78, right col. paragraph 2 – 3; page 80, left col. paragraph 2). Odabas teaches the first step in stem cell therapies is to obtain the required amount of specific stem cells where they have to be isolated and cultured in vitro in order to increase their number (page 74, right col. paragraph 2). Odabas teaches MSCs can be isolated from bone marrow where they represent a very small fraction of the total nucleated cell (page 74, right col. paragraph 2). Odabas proposes separating the target cells by magnetic nanoparticles and then culture them directly (page 80, left col. paragraph 1). Odabas teaches MSCs can differentiate into osteoblasts (page 74, left col. para. 2).
It would have been obvious prior to the effective filing date for the person of ordinary skill in the art to combine the teachings of Lee regarding a 3D printed multi-layered structure of alginate and polycaprolactone where the pore size is greater than 300 µm but less than 500 µm where the structure comprises multiple layers of polycaprolactone struts arranged in a structured geometry with the teachings of Nordon regarding a membrane with covalently bound antibodies directly to the surface via functional groups for separation of stem cells with the teachings of Kim regarding composite porous scaffolds of PCL and carboxyl group surface functionalized magnetite nanoparticles for that enhances cell binding and osteogenesis and that show excellent tissue compatibility in vivo with the teachings of Odabas regarding covalently bound antibodies to magnetite nanoparticles to separate mesenchymal stem cells that can differentiated into osteoblasts to arrive at the claimed membrane wherein the membrane additionally includes functionalized nanoparticles integrated into the membrane structure,
whereby target molecules are covalently bound onto the functionalized nanoparticles via their surface functional groups and wherein the membrane is carried out as a 3D carrier structure made of several layers of biocompatible polymer wherein each individual layer is of the structured geometry with pores with the diameter in the range from 200 to 500μm and whereby the individual layers of the carrier structure are made of the same biocompatible polymer with integrated functionalized nanoparticles to
which target molecules are covalently bound via the surface functional groups, and wherein the functionalized nanoparticles are magnetic and comprise a metal and comprise a functional group. One would have been motivated to combine the teachings of Lee, Nordon, Kim, and Odabas in a membrane comprising magnetite nanoparticles to capture MSCs that undergo osteogenesis for bone repair as Kim teaches the incorporation of inorganic nanoparticles is considered a promising strategy to produce biopolymer-based bone scaffolds with properties more suitable for bone repair and regeneration and Kim teaches several studies have reported the influential role of magnetite nanoparticles incorporated within biomaterials and scaffolds in the cell proliferation and osteoblastic differentiation in vitro and Odabas teaches the first step in stem cell therapies is to obtain the required amount of specific stem cells where they have to be isolated and Odabas teaches MSCs can differentiate into osteoblasts. One would have a reasonable expectation of success in combining the teachings as Kim teaches the magnetic scaffolds showed favorable tissue compatibility in vivo and thus support their use for bone repair and regeneration and Odabas teaches quite high separation efficiencies of CD105+ and CD73+ stem cells from bone marrow.
13. Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee (Lee, HyeongJin, et al. Tissue Engineering Part C: Methods 19.10 (2013): 784-793; previously cited), hereinafter Lee in view of Nordon (Nordon, Robert E., et al. Cytometry: The Journal of the International Society for Analytical Cytology 24.4 (1996): 340-347), hereinafter Nordon as applied to claims 1 – 3 and 7 – 8 above, and further in view of Calandrelli (Calandrelli, L., et. al. J Mater Sci: Mater Med 21, 2923–2936 (2010); previously cited), hereinafter Calandrelli in view of Qhobosheane (Qhobosheane, Monde, et al. Analyst 126.8 (2001): 1274-1278; previously cited), hereinafter Qhobosheane in view of Stergar (Stergar, J., et al J Sol-Gel Sci Technol (2017) 88:57–65; previously cited), hereinafter Stergar in view of Odabas (Odabaş, S., et al. Journal of Chromatography B 861.1 (2008): 74-80; previously cited), hereinafter Odabas.
Lee in view of Nordon make obvious the limitations of claim 1 as set forth above. Lee teaches a 3D printed layer-by-layer structure consisting of eight layers of polycaprolactone (PCL) with structured geometry with fixed pore size of 500 µm (“structured geometry and made of polycaprolactone”) (page 785, right col. paragraph 5; page 787, right col. paragraph 3; Figure 3). Lee teaches preosteoblast cells were viable on the structure and a pore size over 300 µm is recommended for osteoconduction and vascularization (Abstract; Figure 5; page 787, right col. para. 3). Lee teaches tissue engineering is a rapidly growing interdisciplinary research area that may provide options for treating damaged tissues and organs (page 784, left col. paragraph 1).
Lee does not teach “ten layers” or “with integrated functionalized nanoparticles of NiCu enclosed by a layer of silica with NH2 functional groups on the surface onto which the target molecules are bound”. However, a rationale for arriving at ten layers through routine optimization comes from the combined teachings of Lee and Nordon. Lee teaches the method of producing the structures comprises 3D printing layer upon layer (Figure 1; page 785, right col. para. 3) and Nordon teaches the monoclonal antibody covalently attached to the surface selectively adsorbs the cells (Abstract). Nordon teaches the development of hematopoietic stem cell biology and related clinical therapies relies on efficient methods for the selection of cell subpopulations (page 340, left col. para. 1). Nordon teaches development of large-scale CD34+ cell enrichment technologies will enable the development of new strategies for hematopoietic reconstitution (page 340, left col. para. 1). Therefore, it would be obvious to adjust the number of layers, since it is a result-effective variable dependent on the number of cells desired to be captured. Taken together, Lee and Nordon provide a rationale for one of ordinary skill in the art to arrive at the claimed ten layers because adding two additional layers to the structure of Lee would provide more cell capture sites to increase the number of target cells captured.
Regarding “integrated functionalized nanoparticles”, Calandrelli teaches nanocomposites of PCL and functionalized silica nanoparticles (Abstract; page 2923, right col. last paragraph; page 2924, left col. last paragraph and right col. last paragraph). Calandrelli teaches the silica particles have been functionalized with vinyl end group but not a NH2 group (page 2924, right col. last paragraph). However, Calandrelli teaches silica is generally inert in the body and can be modified easily using a variety of well-established chemical reactions including reaction with DETA to introduce NH2 groups on the surfaces of silica nanoparticles (page 2323, right col. paragraph 2 – 3). Calandrelli teaches bone marrow comprises mesenchymal stem cells (MSCs) that can give rise to precursors for bone (page 2924, left col. paragraph 2). Calandrelli teaches an ideal bone tissue engineering strategy implies the use of autologous bone marrow MSCs (page 2924, left col. paragraph 3). Calandrelli teaches PCL/silica nanocomposites appear promising for bone tissue engineering (page 2395, left col. last paragraph). Calandrelli does not teach “NiCu enclosed by a layer of silica”. One would have been motivated to combine the teachings of Lee and Calandrelli as Lee teaches preosteoblast cells were viable on the PCL structure and Calandrelli teaches PCL/silica nanocomposites appear promising for bone tissue engineering.
Regarding “NH2 functional groups on the surface onto which the target molecules are bound”, Qhobosheane teaches silica nanoparticles with NH2 functional groups on the surface onto which enzymes are bound (Scheme 1; page 1275, right col. paragraph 1 – 3; page 1276, right col. paragraph 2). Qhobosheane teaches silica nanoparticles are a good biocompatible support for enzyme immobilization (Abstract). Qhobosheane does not teach “NiCu enclosed by a layer of silica”. One would have been motivated to combine the teachings of Calandrelli and Qhobosheane as both are drawn to functionalized silica nanoparticles.
Regarding “NiCu enclosed by a layer of silica ” nanoparticles, Stergar teaches NiCu magnetic nanoparticles in a silica matrix (Abstract; page 58, left col. last paragraph; Figure 1). Stergar teaches NiCu nanoparticles are sustainable nanomaterials which are chemically stable, biocompatible and exhibit desired magnetic properties making them highly interesting for use in biomedicine (page 58, left col. paragraph 3).
Odabas teaches covalently bound CD105 and CD73 antibodies to surface functionalized magnetic nanoparticles for separation of MSCs from cell suspensions including bone marrow (Abstract; Figure 1C – D; page 75, right col. 4 – 6; page 76, left col. last paragraph; page 77, left col. paragraph 2 – 4; page 78, left col. paragraph 2 – 3). Odabas teaches the immobilization of CD79 and CD105 antibodies to the nanoparticles was achieved with well-known carbodiimide chemistry (page 77, right col. paragraph 4). Odabas teaches in Figure 1C coupling between carboxyl and amine groups using EDC (Figure 1C). Odabas teaches separation efficiencies of CD105+ and CD73+ stem cells were achieved (Table 2; page 78, right col. paragraph 2 – 3; page 80, left col. paragraph 2). Odabas teaches the first step in stem cell therapies is to obtain the required amount of specific stem cells where they have to be isolated and cultured in vitro in order to increase their number (page 74, right col. paragraph 2). Odabas teaches MSCs can be isolated from bone marrow where they represent a very small fraction of the total nucleated cell (page 74, right col. paragraph 2). Odabas proposes separating the target cells by magnetic nanoparticles and then culture them directly (page 80, left col. paragraph 1). Odabas teaches MSCs can differentiate into osteoblasts (page 74, left col. para. 2).
It would have been obvious prior to the effective filing date for the person of ordinary skill in the art to combine the teachings of Lee regarding a 3D printed multi-layered structure of alginate and polycaprolactone where the pore size is greater than 300 µm but less than 500 µm where the structure comprises multiple layers of polycaprolactone struts arranged in a structured geometry with the teachings of Nordon regarding a membrane with covalently bound antibodies directly to the surface via functional groups for separation of stem cells with the teachings of Calandrelli regarding nanocomposites of PCL and functionalized silica nanoparticles with the teachings of with the teachings of Qhobosheane regarding silica nanoparticles with NH2 functional groups on the surface onto which biomolecules are bound with the teachings of Stregar regarding NiCu magnetic nanoparticles in a silica matrix with the teachings of Odabas regarding covalently bound antibodies to magnetite nanoparticles to separate mesenchymal stem cells that can differentiated into osteoblasts to arrive at the claimed membrane wherein the membrane comprises a 3D carrier structure consisting often layers with structured geometry and made of polycaprolactone with the pore sizes of approximately 200 - 500μm and with integrated functionalized nanoparticles of Ni Cu enclosed by a layer of silica with NH2 functional groups on the surface onto which the target molecules are bound. One would have been motivated to combine the teachings of Lee, Nordon, Calandrelli, Qhobosheane, Stergar, and Odabas in a membrane to capture stem cells for osteoblastic differentiation for bone repair as Lee teaches tissue engineering may provide options for treating damaged tissues and organs and Calandrelli teaches PCL/silica nanocomposites appear promising for bone tissue engineering and Calandrelli teaches an ideal bone tissue engineering strategy implies the use of autologous bone marrow MSCs. One would have a reasonable expectation of success in combining the teachings as Lee teaches preosteoblast cells were viable on the PCL structure and a pore size over 300 µm is recommended for osteoconduction and vascularization and Calandrelli teaches silica is generally inert in the body and can be modified easily using a variety of well-established chemical reactions, Qhobosheane teaches silica nanoparticles are a good biocompatible support for biomolecule immobilization, Stergar teaches NiCu nanoparticles are biocompatible, and Odabas teaches quite high separation efficiencies of CD105+ and CD73+ stem cells from bone marrow with magnetic nanoparticles.
Applicant’s Arguments/ Response to Arguments
14. Applicant Argues: Applicant asserts that the sheer number of references that are utilized for the rejection points to the non-obviousness of the overall invention.
Response to Arguments: In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Applicant Argues: Applicant asserts that amended claim 1 requiring a direct covalent bond to the 3D printed carrier structure is not disclosed or suggested by the prior art.
Response to Arguments: This is not found persuasive because in the rejection set forth above, Nordon teaches a membrane for separation of CD34+ stem cells comprising multiple regenerated cellulose hollow fiber modules that have CD34 monoclonal antibody covalently bound directly to the surface (page 341, left col. para. 3 – 5 and right col. para. 1 – 2; Figure 1). Nordon teaches the antibody recognizes CD34+ stem cells and these cells are captured by the antibody covalently bound to the membrane (Abstract; page 344, left col.; Table 3; Figure 4).
Applicant Argues: Applicant asserts that Lee addresses fundamentally different technological problem using materially different structural and functional approaches and teaches away by not emphasizing actively functionalized affinity membranes. Applicant asserts that claim 1 is directed to a porous membrane bearing covalently bound antibodies for the selective capture and release of cells based on antigen-antibody interactions. Applicant asserts that nothing in Lee teaches or suggests covalently functionalizing a porous polymeric membrane with antigen-specific biomolecules or using the structure for affinity-based cell selection rather than in-scaffold culture.
Response to Arguments: This is not found persuasive because claim 1 recites an intended use for the claimed membrane (“for separation of target stem cells from a single-cell suspension containing stem cells”), which is not considered a limitation but merely a statement of intended use because the remainder of claim 1 fully sets forth all of the limitations of the claimed membrane. Therefore, the combined teachings of Lee in view of Nordon make obvious the limitations of amended claim 1, and further the structures comprising a polysaccharide (alginate) as taught by Lee with CD34 antibody covalently bound directly to the polysaccharide surface (cellulose) as taught by Nordon would be capable of separating target stem cells from a single-cell suspension containing stem cells.
Conclusion
No claims allowed.
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 ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 8:45 am - 5:45 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Z.M.B./Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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