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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10-29-2025 has been entered.
Applicant's amendments to the claims and arguments filed on 10-29-2025 have been received and entered. Claims 13 has been amended. Claims 4-9, 11-12, 26-28 have been canceled. Claims 1-3, 10, 13-25, 29-31 are pending in the instant application. The 37 C.F.R. 1.132 declaration by Dr. Blocki submitted on 10-29-2025 is acknowledged and has been considered in full. The arguments presented therein are discussed below in the Response to Arguments section of this action.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-3, 10, and 13-19) in the reply filed on 10-29-2024 is acknowledged. The traversal is on the ground(s) that as amended, claim 1 is drawn to a method for producing an extracellular matrix (ECM) material produced by mesenchymal stem cells, adipose-derived cells, or fibroblasts following their stimulation by dextran sulfate at a concentration of about 0.10 µg/ml to about 10 µg/ml. Applicant submits that a "single general inventive concept" is present among all claims now pending in this application. This is not found persuasive because even though the claims have been amended, the method for producing an extracellular matrix material is rendered obvious in view of Raghunath et al (Pub. No.: US 2012/0322152 Al, Pub. Date: Dec. 20, 2012) and Blocki et al (Biomaterials 53 (2015) 12-24, Doi: 10.1016/j.biomaterials.2015.02.075) as described in the U.S.C 103 rejection below. Additionally, the limitation of claim 1“wherein the extracellular matrix material has anti-inflammatory and/or pro-angiogenic properties” was also taught by previously cited Blocki et al reference (Applicant own work) as also described below. Thus, the groups of inventions are not so linked as to form a single general inventive concept under PCT Rule 13.1 : Group I is directed to a method for producing an extracellular matrix material; Group II is directed to an extracellular matrix material; Group III is directed to a method for enhancing tissue healing and/or regeneration. Groups I-III lack unity of invention. The requirement is still deemed proper and is therefore made FINAL.
Claims 20-25 and 29-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10-29-2024.
Claims 1-3, 10, 13-19 are under consideration.
Priority
This application is a 371 of PCT/CN2020/089991 filed on 05/13/2020 which claims priority from US provisional application no. 62/848,971 filed on 05/16/2019.
Claim Objections
Claim 15, 16, 17 are objected to because of the following informalities:
Claims 15 and 16 are depending from claim 1; however, the term “decellularizing” lack a clear antecedent basis in claim 1. It is noted that claim 14 provides a clear antecedent basis for the term “decellularizing” because it recites a step of decellularizing the extracellular matrix produced by the method of claim 1. It would be remedial to amend claims 15-16 to depend from claim 14 rather than claim 1.
Claim 17 appears to be grammatically confusing with the Markush group. It would be remedial to amend “wherein the lysing agent is an ionic detergent, non-ionic and non-denaturing, zwitterionic detergent, or a combination thereof.
Appropriate correction is required.
Maintained in modified form- Claim Rejections - 35 USC § 103 - necessitated by amendments
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.
Claims 1-3, 10, 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over Raghunath et al (Pub. No.: US 2012/0322152 A1, Pub. Date: Dec. 20, 2012 (Applicant own work)) and Blocki et al (Biomaterials 53 (2015) 12-24, Doi: 10.1016/j.biomaterials.2015.02.075, Available online 7 March 2015 (Applicant’s own work)).
Claim interpretation:
The specification of the claimed invention teaches that the collected cell-de1ived ECM is incorporated or processed otherwise into an applicable structure, for example, microcapsule, etc. ([0013], page 4). Thus, extracellular matrix (ECM) is interpreted to be able to incorporate into applicable structure such as microcapsules.
The specification of the claimed invention teaches that dextran sulfate is denoted as DxS ([0003], page 1).
Regarding to claim 1, Raghunath et al teaches a method of producing an extracellular matrix comprising a) contacting fibroblasts, mesenchymal stem cells or a combination thereof with one or more carbohydrate-based macromolecules, thereby producing a cell culture, and b) maintaining the cell culture under conditions in which the fibroblasts or mesenchymal stem cells or combination thereof proliferate and produce an extracellular matrix (e.g., claim 17, page 25); wherein the one or more carbohydrate-based macromolecule is a polymer of glucose, sucrose or a combination thereof (e.g., claim 20, page 25); wherein the polymer is Ficoll 70, Ficoll 400, dextran sulfate or a combination thereof (e.g., claim 21, page 25); comprising c) contacting the cell culture with one or more agents that lyse the cells, thereby producing a cell-free extracellular matrix (e.g., claim 25, page 25).
Although Raghunath et al teaches the use of dextran sulfate (e.g., claim 21, page 25), Raghunath et al does not teach dextran sulfate at a concentration of about 0.10 µg/ml to about 10 µg/ml. However, Blocki et al cures the deficiency.
Blocki et al (Applicant’s own work) teaches that Dextran sulfate, a negatively charged polycarbohydrate, was added to mimic glycosaminoglycans in the ECM. Cell viability assays showed that a combination of all components is necessary to support long-term survival and proliferation of MSCs within microcapsules (Abstract). Microcapsules consisting of DxS (Dextran sulfate) supported cell proliferation and survival in long-term cultures (Fig. 4a) (see page 18, left column, 1st para.). Blocki et al teach the use of a range of dextran sulfate (DxS) in Figure 1B (Page 15, see below).
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Raghunath et al by using 10 µg/ml of dextran sulfate as taught by Blocki et al, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Blocki et al teaches microcapsules consisting of DxS (Dextran sulfate) supported mesenchymal stem cells (MSCs) cell proliferation and survival in long-term cultures (see page 18, left column, 1st para , and Figure 1B). Additionally, since various amounts of Dextran sulfate from 0 to 1000 µg/ml (Figure 1B) have been used by Blocki et al to support the MSCs cell survival, thereby indicating that the various Dextran sulfate concentrations were recognized in the prior art to be a result-effective variable. Thus, a person of ordinary skill in the art would have been motivated to perform cell culturing with concentration of 0 to 1000 µg/ml Dextran sulfate concentrations out of the course of routine optimization. One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Blocki et al was successfully in improving cell survival with 10 various dextran sulfate concentrations in PBS medium (Page 15, Figure 1B).
Regarding to claim 1 the claimed: “wherein the extracellular matrix material has anti-inflammatory and/or pro-angiogenic properties”, Blocki et al (Applicant’s own work) teaches microcapsules supplemented with extracellular matrix (ECM) proteins collagen and fibrin (Abstract), and cells positive for the mannose receptor (CD206) an M2 marker were prominent around the biomaterial (microcapsules), indicating an anti-inflammatory and ‘wound-healing’ state around the biomaterial (Fig. 6c) (See page 21, left column, 1st para., and Figure 6C). Additionally, Blocki et al teaches collagen I and fibrin can polymerize to form a gel, increasing the stability of the capsule, and Fibrin is an early matrix component produced during wound healing, is pro-angiogenic and provides further wound-healing signals to the encapsulated cells. Supplementation of ECM proteins into hydrogel microcapsules have shown to improve the overall cell survival (Page 13, right column, 1st para.)
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Regarding to claim 2-3, Raghunath et al teach stem cells include embryonic stem cells, adult stem cells (e.g., hematopoietic stem cells, bone marrow stromal stem cells (mesenchymal stem cells)…… the stem cells are mammalian stem cells (e.g., primate, canine, feline, bovine, murine, and the like). In a particular aspect, the stem cells are human stem cells ([0080], page 5).
Regarding to claim 10, Raghunath et al teach additional macromolecular crowders can be added to the cell culture medium. In one aspect, the additional crowder(s) is a negatively charged crowder (e.g., Dextran sulfate 500 kDa) ([0105], page 8).
Regarding to claim 13, as described above, Blocki et al teach the use of a range of 0- 1000 µg/ml of dextran sulfate (DxS) in Figure 1B (Page 15). Additionally, since various amounts of Dextran sulfate from 0 to 1000 µg/ml (Figure 1B) have been used by Blocki et al to support the MSCs cell survival, thereby indicating that the various Dextran sulfate concentrations were recognized in the prior art to be a result-effective variable. Thus, a person of ordinary skill in the art would have been motivated to perform cell culturing with concentration of 0 to 1000 µg/ml Dextran sulfate concentrations out of the course of routine optimization.
Regarding to claim 14, Raghunath et al teach FIG. 34 that shows complete decellularization to obtain matrices ([0063], page 4).
Regarding to claim 15-16, Raghunath et al teach deposition and decellularization of Matrices (Lysis): For lysis, monolayers were first washed with PBS twice then treated with 0.5% DOC (deoxycholate) supplemented with 0.5x complete Protease Inhibitor in water, and monolayers were then incubated with DNAse ([0173], page 16).
Regarding to claim 17-18 , Raghunath et al teach contacting the cell culture with one or more agents that lyse the cells, thereby producing a cell-free extracellular matrix (Claim 25, page 25). …. wherein the one or more agents is deoxycholate (DOC), NP40, DNase or a combination thereof (Claim 26, page 25).
Regarding to claim 19, Raghunath et al teach Fibroblasts that were cultured with either DxS or Fc were lysed with the NP40 protocol to obtain DxSNP40 or FcNP40 matrices. ……. Cells that had settled on the bottom of detached easily removed by mechanical disturbances (FIGS. 29A and 29B) ([0200], page 21).
Response to Arguments
Applicant's arguments and the Blocki’s declaration filed 10-29-2025 have been fully considered but they are not persuasive.
The declaration stated that although Raghunath teaches methods of making ECM from
cell cultures, for example, by adding macromolecules such as dextran sulfate to a fibroblast or mesenchymal stem cell culture, the reference contains no indication or even suggestion regarding the resultant ECM' s properties in terms of anti-inflammation or pro-angiogensis. On the other hand, Blocki describes injectable microcapsules for delivering mesenchymal stem cells (MSCs), which also contain dextran sulfate, agarose, collagen, and fibrin. Even though the Examiner points to certain passages in Blocki (page 21, left column, pt paragraph, Figure 6c, and page 13, right column, pt paragraph) as indication of the biomaterial formed from the microcapsules after injection as anti-inflammatory or pro-angiogenic, these findings do not relate to and certainly cannot translate to producing ECM with anti-inflammatory and/or pro-angiogenic properties from cell cultures. This is because the purported anti-inflammatory and pro-angiogenic properties of the biomaterial are understood as due to the inclusion of collagen and fibrin in an artificial and simplified environment (microcapsules), which is entirely different from the much more complex environment in which Raghunath would use dextran sulfate to produce ECM, namely a culture of live cells capable of producing countless other molecules. Thus, the effects of adding dextran sulfate to such a complex system are not predictable based on Blocki' s observations. A skilled person in the pertinent technical field would recognize that whatever is reported by Blocki cannot be directly and simply extrapolated to put into Raghunath' s method. The skilled person therefore would have no reasonable expectation to successfully obtain ECM with anti-inflammatory and/or pro-angiogenic properties by combining Raghunath and Blocki (the Blocki’s declaration, page 2-3)
Response to Arguments:
As applicants admitted above “Raghunath teach methods of making ECM from cell cultures, for example, by adding macromolecules such as dextran sulfate to a fibroblast or mesenchymal stem cell culture”. Applicants disagree that “the reference contains no indication or even suggestion regarding the resultant ECM' s properties in terms of anti-inflammation or pro-angiogensis”; however, as per MPEP 2112 (II), inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999).
Blocki et al (Applicant’s own work) were cited to teach microcapsules supplemented with extracellular matrix (ECM) proteins collagen and fibrin (Abstract), and cells positive for the mannose receptor (CD206) an M2 marker were prominent around the biomaterial (microcapsules), indicating an anti-inflammatory and ‘wound-healing’ state around the biomaterial (Fig. 6c) (See page 21, left column, 1st para., and Figure 6C). Additionally, Blocki et al teach collagen I and fibrin can polymerize to form a gel, increasing the stability of the capsule, and Fibrin is an early matrix component produced during wound healing, is pro-angiogenic and provides further wound-healing signals to the encapsulated cells. Supplementation of ECM proteins into hydrogel microcapsules have shown to improve the overall cell survival (Page 13, right column, 1st para.). Applicants stated that “these findings do not relate to and certainly cannot translate to producing ECM with anti-inflammatory and/or pro-angiogenic properties from cell cultures. This is because the purported anti-inflammatory and pro-angiogenic properties of the biomaterial are understood as due to the inclusion of collagen and fibrin in an artificial and simplified environment (microcapsules), which is entirely different from the much more complex environment in which Raghunath would use dextran sulfate to produce ECM, namely a culture of live cells capable of producing countless other molecules. Thus, the effects of adding dextran sulfate to such a complex system are not predictable based on Blocki' s observations”. However, it appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention. However, it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. In the instant case, it is clear that Blocki et al provide evidence for cells positive with CD206 an M2 marker around the biomaterial (microcapsules supplemented with extracellular matrix (ECM) proteins collagen and fibrin) as an indicator for anti-inflammatory state: “cells positive for the mannose receptor (CD206) an M2 marker were prominent around the biomaterial, indicating an anti-inflammatory and ‘wound-healing’ state around the biomaterial (Fig. 6c)” (See page 21 of Blocki et al, left column, 1st para., and Figure 6C). Finally, it is noted that this argument from Applicant is conclusory in nature and unsupported by any convincing rationale or evidence for the assertion that the environment taught by Raghunath et al is so much more complex than the relatively simple capsular environment taught by Blocki et al that the teachings of Blocki et al regarding the efficacious effects observed by Blocki et al would not apply for the extracellular matrix made according to the combined teachings of Rahunath et al and Blocki et al as proposed.
2. The declaration stated that in contrast to the disclosure by Raghunath and Blocki, the method of this invention is the first that enables one to produce ECM with anti-inflammatory and/or pro-angiogenic properties from a culture of mesenchymal stem cells, adipose-derived cells, or fibroblasts. We performed experiments to assess effectiveness of dextran sulfate at different concentrations for promoting ECM formation from a cell culture, especially ECM with desirable characteristics such as pro-angiogenic and/or anti-inflammatory properties. In one such experiment, four types of mesenchymal stem cell (MSC) derived extracellular matrix material (ECM) were first made: they were synthesized and assembled from MSC cultures in the presence of dextran sulfate (DxS, 500 kDa) at the concentration of 0.1, 1, 10, or 100 µg/ml, respectively. Human umbilical vein endothelial cells (HUVECs) were then seeded on each of the four different types of ECM and on tissue culture polystyrene (TCP). After they were cultured for two days, HUVEC proliferation on all five substrates was evaluated by CCK8 assay (a colorimetric assay used for determining the number of viable cells in a sample). All four matrices, despite varying concentration of dextran sulfate used during their production, showed significant effectiveness in promoting endothelial cell proliferation, indicating that they all possessed a pro-angiogenic property. Results of this experiment are shown in Figure 1 below.
What's particularly surprising is our observation that, dextran sulfate is effective across a broad range of 0.10 - 100 µg/ml. Even at a very low concentration of 0.10 µg/ml, dextran sulfate was able to induce the production of an ECM with a level of pro-angiogenic property indistinguishable from those produced at much higher concentrations of 1, 10, and 100 µg/ml.
Moreover, we also performed experiments using different cell types for producing ECM by the method of this invention. Figure 2 below shows the results: in one HUVEC seeding experiment, the ECM produced by bone marrow stem cells (bmMSCs), adipose-derived cells (ADSCs), or fibroblasts (Fbs) following stimulation by about 10 µg/ml dextran sulfate yielded similar performance in CCK8 assay, yet each significantly better than the control material (TCP). This indicates that all three matrices, regardless of cell source, possessed pro-angiogenic properties (the Blocki’s declaration, page 3-5)
Response to Arguments:
It is noted that Blocki et al teach the use of Dextran sulfate to improve cells survival and proliferation in the culture of mesenchymal stem cells: “Dextran sulfate, a negatively charged polycarbohydrate, was added to mimic glycosaminoglycans in the ECM. Cell viability assays showed that a combination of all components is necessary to support long-term survival and proliferation of MSCs within microcapsules” (Abstract) and “Microcapsules consisting of DxS (Dextran sulfate) supported cell proliferation and survival in long-term cultures” (Fig. 4a) (see page 18, left column, 1st para.) and the use of range of dextran sulfate (DxS) concentrations in Figure 1B (Page 15, see below).
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Applicant argue that “What's particularly surprising is our observation that, dextran sulfate is effective across a broad range of 0.10 - 100 µg/ml. Even at a very low concentration of 0.10 µg/ml, dextran sulfate was able to induce the production of an ECM with a level of pro-angiogenic property indistinguishable from those produced at much higher concentrations of 1, 10, and 100 µg/ml.”. However, as per MPEP 716.02, Allegations of Unexpected Results: Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Blocki et al clearly teach the use of wide range of Dextran sulfate concentrations to improve cells survival in the culture of mesenchymal stem cells (See Figure 1B above). It is clear that the method steps, MSC cells, material (Dextran sulfate) recited in the prior art references are the same as the claimed invention. Thus, it is expected that extracellular matrix material generated by the method of the prior art references have the same properties and characteristic. Applicants has not provided evidences for culturing MSC cells in presence of Dextran sulfate as taught by Raghunath et al and Blocki et al would not generate extracellular matrix material with the same anti-inflammatory and/or pro-angiogenic properties as the claimed invention. Applicant clearly stated that “Even at a very low concentration of 0.10 µg/ml, dextran sulfate was able to induce the production of an ECM with a level of pro-angiogenic property indistinguishable from those produced at much higher concentrations of 1, 10, and 100 µg/ml”. Since Raghunath et al teaches a method of producing an extracellular matrix comprising contacting fibroblasts, mesenchymal stem cells or a combination thereof with one or more carbohydrate-based macromolecules (e.g., claim 17, page 25) such as dextran sulfate (e.g., claim 21, page 25), and Blocki et al teach wide range of dextran sulfate concentrations that can improve MSC cells survival and proliferation, a person of ordinary skill in the art would be able to generate an extracellular matrix with pro-angiogenic property. Therefore, applicants’ arguments regarding unexpected/superior results over the use of dextran sulfate in the culture of mesenchymal stem cell is not persuasive.
3. The arguments from the remarks stated that “Applicant disagrees with the conclusion of prima facie obviousness, at least because the requisite reasonable expectation of success is missing….
A careful review of the passages in Blocki identified by the Examiner as purportedly teaching the anti-inflammatory and pro-angiogenic properties of the biomaterial (page 21, left column, pt paragraph, Figure 6c, and page 13, right column, pt paragraph) indicates that these properties are due to the inclusion of collagen and fibrin in an artificial and simplified environment (microcapsules). This is entirely different from the much more complex environment in which Raghunath would use dextran sulfate to produce ECM, namely a culture of live cells, capable of producing countless other molecules. The effects of adding dextran sulfate to such a complex system are not predictable based on Blocki's observations. Thus, there is no logical or scientific basis for any reasonable expectation that, by combining the teaching of Raghunath and Blocki, one would be able to obtain ECM with anti-inflammatory and/or pro-angiogenic properties. This point is explained in detail in the Rule 132 declaration signed by lead inventor Dr. Blocki submitted with this response, see, e.g., paragraphs 5 of the declaration ……
Moreover, experimental data presented in the Rule 132 declaration show that surprising and unexpected results are achieved by the method of this invention” (Remarks, page 6-7)
Response to Arguments:
In response to applicant's argument pertaining to Raghunath et al and Blocki et al, it appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention. However, it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. In the instant case, as described above, Raghunath et al teach a method of producing an extracellular matrix comprising contacting fibroblasts, mesenchymal stem cells or a combination thereof with one or more carbohydrate-based macromolecules (e.g., claim 17, page 25) such as dextran sulfate (e.g., claim 21, page 25), and Blocki et al teach the use of Dextran sulfate to improve cells survival and proliferation in the culture of mesenchymal stem cells: “Microcapsules consisting of DxS (Dextran sulfate) supported cell proliferation and survival in long-term cultures” (Fig. 4a) (see page 18, left column, 1st para.) and the use of range of dextran sulfate (DxS) concentrations in Figure 1B (Page 15). Also, it is clear that Blocki et al provide evidence for cells positive with CD206 an M2 marker around the biomaterial (microcapsules supplemented with extracellular matrix (ECM) proteins collagen and fibrin) as an indicator for anti-inflammatory state: “cells positive for the mannose receptor (CD206) an M2 marker were prominent around the biomaterial, indicating an anti-inflammatory and ‘wound-healing’ state around the biomaterial (Fig. 6c)” (See page 21 of Blocki et al, left column, 1st para., and Figure 6C).
Additionally, applicants argue that the anti-inflammatory and pro-angiogenic properties of the biomaterial cited from Blocki et al (page 21, left column, pt paragraph, Figure 6c, and page 13, right column, pt paragraph) indicates that these properties are due to the inclusion of collagen and fibrin in an artificial and simplified environment (microcapsules), and the effects of adding dextran sulfate to such a complex system are not predictable based on Blocki's observations. However, there is no evidence in record to support applicant conclusion that the anti-inflammatory and pro-angiogenic properties of the biomaterial on cells with the presence of dextran sulfate would not occur in complex system. In fact, it is not persuasive to assume Blocki et al only teach anti-inflammatory and pro-angiogenic properties that occur only within the microcapsule: Blocki et al teach “Fig. 6. Col-Fb-DxS100 microcapsules exhibit sufficient mechanical stability for intramuscular injection and induce a wound-healing tissue response in vivo…… c) IHC of rat calf muscles with injected TRITC-labeled agarose-containing microcapsules.”. Blocki et al teach cells positive for the mannose receptor (CD206) an M2 marker were prominent around the biomaterial, indicating an anti-inflammatory and ‘wound-healing’ state around the biomaterial (Fig. 6c) (page 21, left column, 1st para.). Thus, it is clear that Fig. 6c teach in vivo anti-inflammatory effect of injected microcapsules containing DxS (dextran sulfate). In vivo environment is quite a complex system and not simple. Thus, the arguments are not persuasive and not commensurate with the scope of the claims.
The responses to surprising and unexpected results arguments can be found above.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632