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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10-01-2025 has been entered.
Applicant's amendments to the claims and arguments filed on 10-01-2025 have been received and entered. Claims 18, 33 have been amended. Claims 4, 9-13, 16-17, 19-21, 23, 26, 34 are canceled. Claims 35 have been added. Claims 1-3, 5-8, 14-15, 18, 22, 24-25, 27-33, 35 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group II (Claims 18, 19, 22, and 24-26 and new claims 27-31), in the reply filed on 09-25-2024 is acknowledged.
Claims 1-3, 5-8, 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09-25-2024.
Claims 18, 22, 24-25, 27-33, 35 are under consideration.
Priority
This application is a 371 of PCT/KR2020/002919 filed on 02/28/2020 which claims priority from a foreign application filed in Republic of Korea, KR 10-2019-0050051 filed on 04/29/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Certified translation of Foreign Priority of Korean patent application of 10-2019-0050051 filed on 12-29-2025 is also acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10-01-2025 is in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn - Claim Rejections - 35 USC § 112
Claim 22 and claims 18, 24-25, 27-34 were 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. In view of Applicants' amendment and arguments, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn -Claim Rejections - 35 USC § 103
Claims 18, 25, 27-29, 31-34 were rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164). In view of Applicants' amendment of base claim 18, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as applied to claims 18, 25, 27-29, 31-34 above, and further in view of Komlos et al (Pub. No.: US 2013/0131701 A1, Pub. Date: May 23, 2013). The rejection is withdrawn for the reasons discussed above.
Claim 24 was rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as applied to claims 18, 25, 27-29, 31-34 above, and further in view of Li et al (Scientific Reports , 4 : 5600 ,DOI: 10.1038/srep05600, 18 July 2014). The rejection is withdrawn for the reasons discussed above.
Claim 30 was rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as applied to claims 18, 25, 27-29, 31-34 above, and further in view of Flynn (Pub. No.: US 2016/0051728 A1, Pub. Date: Feb. 25, 2016). The rejection is withdrawn for the reasons discussed above.
New-Claim Rejections - 35 USC § 112-New matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18, 22, 24-25, 27-33, 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. In the instant case, the recitation of “wherein 50% to 60% of the serum-induced protein is albumin” is considered new matter. Upon further review of the instant specification, examiner could only find “The term "serum-induced protein" used herein refers to a protein obtained by cross-linking a protein in serum by treating, with a reducing agent, a serum induced from fetal bovine serum (FBS), bovine calf serum (BCS) or other animals” (Page 3, line 16-19). There is no explicit or implicit support for “50% to 60% of the serum-induced protein is albumin”. On page 10 of the remark filed on 10-01-2025, applicant cited Wu et al. (MOLECULAR MEDICINE REPORTS, 29: 24, pages 1-15, 2024) to say “Among the proteins in serum, albumin accounts for about 50-60%”. However, there is no explicit or implicit support in the instant specification for 50-60% of albumin in the rerum to be induced (cross-linked) as cited in the claim. The serum in the claim encompasses any serum from human or other animals in any medical condition. While albumin is the most abundant protein in the blood of all vertebrates, its specific percentage of total protein varies significantly across species and life stages. While albumin is the most abundant protein in healthy human serum—typically making up 50–60% of total protein content—this percentage can drop significantly due to various medical conditions. It is also noted that applicant cited Wu et al who teach human blood plasma that contain human serum albumins accounting for ~50‑60% of total plasma protein while instant disclosure use “fetal bovine serum or bovine calf serum” (see instant specification on page 18, line 29, example 1).
Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of “wherein 50% to 60% of the serum-induced protein is albumin”. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for the limitation “wherein 50% to 60% of the serum-induced protein is albumin”. Claims 22, 24-25, 27-33, 35 are directly or indirectly depend from the rejected base claim. This is a new matter rejection.
New-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 18, 25, 27-29, 31-33, 35 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sawadkar et al (Pub. No.: US 2020/0164104 A1, Foreign Application Priority Data: Jul. 14 , 2017) and Liu et al (Scientific RePoRTs | 7: 9856 | DOI:10.1038/s41598-017-09563-w, 29 August 2017) and Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as evidenced by Transfusion Medicine (Transfus Med Hemother 2009;36:399–407, Chapter 5 Human Albumin).
Claim interpretation:
The specification of the claimed invention teaches that the term "serum-induced protein" used herein refers to a protein obtained by cross-linking a protein in serum by treating, with a reducing agent, a serum induced from fetal bovine serum (FBS), bovine calf serum (BCS) or other animals (for example, mammals or humans) (Page 3, lines 16-19). Thus, "serum-induced protein" is interpreted as protein obtained by cross-linking protein and treating with a reducing agent.
The specification of the claimed invention teaches that homogenization was performed thereon by using an electric tissue grinder (Homogenizer 01000, Benchmark Scientific) (Page 19, lines 4-5). Thus, tissue grinder is interpreted as homogenizer.
For the sake of compact prosecution, the term “aging” is interpreted as storing/incubating/drying in temperature-controlled condition.
Regarding to claim 18, Lee teaches methods for preparing albumin tissue scaffolds from animal albumins (Abstract). Tissue scaffolds are three-dimensional porous materials, support cell attachment, growth, and differentiation, directing new tissue formation in vitro or in vivo ([0004], page 1). Human mesenchymal stem cells can be sub-cultured to an albumin tissue scaffold ([0021], page 2) (For the preamble).
Lee teaches Albumin is a plasma protein ([0007], page 1). Two classes of albumin polymers are chemically cross-linked albumins and enzymatically cross-linked albumins, both can be applied ([0011], page 1). Also, preparation of the albumin polymer was done as follows: 0.05 g human, bovine, or porcine serum albumin was dissolved. Polymerization reaction was carried out by adding 0.5 mL of 1 mg/mL microbial transglutaminase (i.e., cross-linking agent) and 0.025 mL of 0.5 M DTT (i.e., reducing agent) into albumin solution. The resulted albumin solid (i.e., the reaction product) was homogenized. The homogenate was spun down , and the supernatant was discarded. The lactic acid washing step was repeated more twice ([0046], page 4) (For Claim 18, For the claimed: (i)“cross-linking proteins in a serum or plasma protein aqueous solution by treating the serum or plasma protein aqueous solution with a cross-linking agent”, (ii) “reacting the cross-linked proteins in the serum or plasma protein aqueous solution with a reducing agent to obtain a reaction product”, (iii) homogenizing the reaction product to obtain a homogenized serum-induced protein, (iv) recovering a suspension of the homogenized serum-induced protein by centrifuging, (v) washing the suspension of serum-induced protein obtained after the centrifuging to obtain a washed serum-induced protein.
Although Lee teaches polymerization reaction was carried out by adding microbial transglutaminase (i.e., cross-linking agent) and 0.025 mL of 0.5 M DTT (i.e., reducing agent) into albumin solution ([0046], page 4), Lee do not teach performing these step subsequently. Sawadkar et al cure the deficiency.
Sawadkar et al teach a tissue scaffold and a method for making a tissue scaffold (Abstract). Sawadkar et al teach that methods of the invention may comprise washing or cleaning to remove agents involved in solubilizing and /or cross-linking ([0069], page 4), and this may include contacting or washing with a reducing agent ([0070], page 4), and the presence of the reducing agent may stabilize the cross-linking process and result in a scaffold with enhanced biological efficacy. Furthermore, the presence of the reducing agent is likely to reduce the cytotoxic effects caused by the leaching of un-reduced cross -linking agent from the composition ([0071], page 4), and the step of washing to remove agents involved in solubilizing and/or cross-linking may be carried out for at least 5 hours, preferably at least 8 hours ([0071], page 4).
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 Lee by performing the step of washing to remove agents involved in cross-linking subsequently after the cross-linking step as taught by Sawadkar et al. 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 Sawadkar et al teach that presence of the reducing agent may stabilize the cross-linking process and result in a scaffold with enhanced biological efficacy. Furthermore, the presence of the reducing agent is likely to reduce the cytotoxic effects caused by the leaching of un-reduced cross -linking agent from the composition ([0071], page 4). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Sawadkar et al were successful in making a tissue scaffold with detailed instructions, working examples and data.
Although Lee teaches human, bovine, or porcine serum albumin can be used and homogenized ([0046], page 4), Lee do not teach 50% to 60% of the serum-induced protein is albumin. Liu et al cure the deficiency.
Liu et al teach quick fixation based on formaldehyde crosslinking (FC) was introduced into a two-step precipitation (TSP) procedure for real-time and comprehensive profiling of the human serum albuminome (Page 2, 2nd para.). Liu et al teach collection and delipidation of human serum samples: Whole blood was collected into blood tubes without additives from six healthy individuals, and centrifuged for 15 min at 3000 rpm. The resultant serum samples were pooled in equal volumes for subsequent experiments (Page 2, 3rd para.). Liu et al teach FC-based quick fixation: Quick fixation of human serum samples was initially performed using formaldehyde, and formaldehyde solution was added to 100 µL of serum samples. The solutions were gently mixed and incubated for various times at 4 °C, and the cross-linking times were strictly controlled (Page 2, 4th para.). As evidenced by Transfusion Medicine (Transfus Med Hemother 2009;36:399–407, Chapter 5 Human Albumin) that teaches albumin comprises about 50–60% of the total protein content of plasma (Page 400, right column of Transfusion Medicine).
Additionally, Lee teaches different preparation method for bovine serum albumin solution for preparation of the albumin tissue scaffold: 2 g bovine serum albumin was dissolved in 8.8 mL buffer of 50 mM BICINE ([0041], page 3); 0.05 g human, bovine, or porcine serum albumin was dissolved in 0.475 mL of 50 mL BICINE ([0046], page 4). Thus, it is indicating that amount/concentration of albumin in solution for cross-linking process was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to use different amount/concentration of albumin in solution out of the course of routine optimization in order to achieve a desired level of solid network. It is also noted that Lee teaches the use of any albumin solution ([0011], page 1) which encompass serum, and Lee made no mention that albumin solution has to be prepared from commercially available albumins or it should not use other albumin sources such as serum. Nevertheless, Liu et al reference was added as evidence for crosslinking human serum albumin.
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 Lee by performing cross-linking proteins in a serum as taught by Liu et al. 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 Liu et al teach quick fixation of human serum samples (Page 2, 4th para.), and a two-step precipitation (TSP) procedure consisting of an initial 12% PEG precipitation step followed by the addition of 42% ethanol is useful for isolating the serum albuminome (Page 4, 2nd para.). Liu et al concluded that “we first developed a modified TSP method to replace the conventional protein G-ethanol method for effective preparation of serum albuminome. To capture weak and transient interactions in real time, we further optimized the well-established protocol by combining FC and TSP. We have shown here that the newly developed FC-TSP approach can be used for comprehensive profiling of human serum albuminome. This method is simple, rapid, inexpensive and easy to use, and appropriate for albuminome preparation of multiple clinical samples. We anticipate that the FC-TSP-MS strategy will have widespread future applications for albuminome-based biomarker discovery” (Page 9, conclusion). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Liu et al were successful in preparation a human serum albuminome with simple, rapid, inexpensive and easy to use method, with detailed instructions, working examples and data.
Lee teaches the polymerization reaction was carried out at the temperature of 37°C. Extensive cross links among individual albumin molecules occurred during incubation. The proceeding of polymerization can be traced using stirring. The reaction, at first, became high viscous, and then it turned into a solid form. The time required for curing solution is vary, which greatly depend on the amounts of cross linkers and albumin that are used. The preferred time for reaction incubation is between 0.5 to 24 hours ([0033], page 3). Additionally, Lee teaches various concentrations of glutaraldehyde was combined with bovine serum albumin solution in fresh plastic tube, mixed up immediately by a Vortex mixer at top speed, and samples were incubated at 37°C ([0039], page 3). Also, the prepared tissue scaffold was stored in a dry box ([0041], page 4). Thus, it is indicating that the stirring/mixing and aging/incubating bovine serum albumin solution were recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the stirring/mixing and aging/incubating of serum protein such as serum albumin for a plurality of times during the process of preparation of the albumin polymer out of the course of routine optimization in order to increase the polymerization to achieve a desired level of strength. (For Claim 18, For the claimed: (vi) stirring the washed serum-induced protein to obtain a stirred serum-induced protein; (vi) aging the stirred serum-induced protein.
Although Lee teaches the preferred time for reaction incubation is between 0.5 to 24 hours ([0033], page 3), and Liu et al teach quick fixation of human serum samples with formaldehyde solution and incubating the solution for various times at 4 °C(Page 2, 4th para.), the references do not teach aging the serum-induced protein at a temperature of 1°C to 15°C for 8 hours. However, Sun et al cures the deficiency.
Regarding to claim 18 and 35, Sun et al teaches aging of a regenerative biologic scaffold during storage at elevated humidity and temperature (Title). Sun et al teach that tissue products stored at 75% RH and 85% RH changed significantly, including decreased elasticity. In comparison, changes were nondetectable in control products stored at 2oC to 8oC. Calorimetric analysis revealed that tissue products stored at 2oC to 8oC and at 33% RH and 40oC were in the glassy state, whereas the products stored at 75% RH, 85% RH, and 40oC were not in the glassy state, suggesting a role of the glassy state in preserving tissue products during storage (Abstract). Sun et al teach Figure 2 shows the accumulation of Maillard products (advanced glycation end-products) as a function of storage time in days. Additionally, Lee teaches the preferred time for reaction incubation is between 0.5 to 24 hours ([0033], page 3). Thus, storage/incubation time was recognized in the prior art references to be a result-effective variable. A person of ordinary skill in the art would have been motivated to incubate the biologic scaffold in different time duration out of the course of routine optimization in order to achieve a desired level of elasticity and stability such as for 8 hours.
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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 Lee by aging scaffold during storage at a temperature of 2oC to 8oC as taught by Sun et al. 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 Sun et al provide explicit advantage of tissue products stored at 2oC to 8oC which is in glassy state that plays an important role in preservation of tissue matrix products during storage (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Sun et al provides detailed instructions and data to show benefits of storing tissue products in temperature 2oC to 8oC.
Regarding to claim 25, Lee teaches the preferred mechanical homogenization method is selected from the group consisting of pestle homogenizer, motor-driven tissue homogenizer ([0034], page 3). Lee also teaches that the resulted albumin solid was homogenized in 9 mL of 6 Murea, 0.1 M sodium acetate, pH 5.0. The homogenate was spin down at 2,330 g for 5 min, and the supernatant was discarded ([0046], page 4).
Regarding to claim 27 and 28, Lee teaches polymerization (cross-linking) reaction was carried out by adding 0.5 mL of 1 mg/mL microbial transglutaminase (a cross-linking agent) and 0.025 mL of 0.5 M DTT (a reducing agent), into albumin solution ([0046], page 4).
Regarding to claim 29, Lee teaches surface pore size of albumin tissue scaffold is inversely proportional to the degree of albumin cross links. The results of pore geometry measurements have a range of about few µm to about few hundred µm in diameter, more preferably among 42 to 225µm ([0016], page 2).
Regarding to claim 31, Lee teaches human mesenchymal stem cells were sub-cultured to an albumin tissue scaffold, and a preferred source of cells is select from the group consisting of blood-derived, cord blood-derived, amniotic fluid-derived, skin-derived, adipose-derived, bone marrow-derived, and surgical biopsy-derived somatic cells and stem cells ([0021], page 2).
Regarding to claim 32, Lee teaches the polymerization can be traced using stirring ([0033], page 3). The bovine serum albumin solution in fresh plastic tube can mixed up immediately by a vortex mixer at top speed ([0039], page 3). Since stirring and vortexing using stirrer and vortexer have been used routinely in almost any life science laboratory, it is a matter of design for a person of ordinary skill in the art to optimize the parameters such as stirring for 20 minutes at 10,000 rpm.
Regarding to claim 33, Sun et al teaches that tissue products stored at 2oC to 8oC were in the glassy state, suggesting a role of the glassy state in preserving tissue products during storage (Abstract).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sawadkar et al (Pub. No.: US 2020/0164104 A1, Foreign Application Priority Data: Jul. 14 , 2017) and Liu et al (Scientific RePoRTs | 7: 9856 | DOI:10.1038/s41598-017-09563-w, 29 August 2017) and Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as evidenced by Transfusion Medicine (Transfus Med Hemother 2009;36:399–407, Chapter 5 Human Albumin) as applied to claims 18, 25, 27-29, 31-33, 35 above, and further in view of Komlos et al (Pub. No.: US 2013/0131701 A1, Pub. Date: May 23, 2013).
The teachings of Lee, Sawadkar et al, Liu et al, Sun et al are as described above and are incorporated herein in their entirety.
The above references do not teach cross-linking agent is treated with specific activity of 2 unit/mg to 100 unit/mg. However, Komlos et al cures the deficiency.
Regarding to claim 22, Komlos et al teaches the transglutaminase composition has a specific activity level (enzyme units/protein content) of about at least 15 U/mg. Most preferably, the transglutaminase has a specific activity level of at least about 25 U/mg ([0031], page 2).
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 Lee and Sun et al by using transglutaminase with a specific activity level of about at least 15 U/mg or 25 U/mg as taught by Komlos et al. 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 Komlos et al teaches hemostatic dressing that includes a layer of transglutaminase sandwiched between a first and a second layer of gelatin which is useful for treating wounds ([0214], page 11). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Komlos et al provides working examples and data for using transglutaminase as cross-linking agent.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sawadkar et al (Pub. No.: US 2020/0164104 A1, Foreign Application Priority Data: Jul. 14 , 2017) and Liu et al (Scientific RePoRTs | 7: 9856 | DOI:10.1038/s41598-017-09563-w, 29 August 2017) and Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as evidenced by Transfusion Medicine (Transfus Med Hemother 2009;36:399–407, Chapter 5 Human Albumin) as applied to claims 18, 25, 27-29, 31-33, 35 above, and further in view of Li et al (Scientific Reports , 4 : 5600 ,DOI: 10.1038/srep05600, 18 July 2014)
The teachings of Lee , Sawadkar et al, Liu et al, Sun et al are as described above and are incorporated herein in their entirety.
The above references do not teach reducing agent has a concentration of 5 mM to 50 mM. However, Li et al cures the deficiency.
Regarding to claim 24, Li et al teaches a novel albumin-based tissue scaffold for autogenic tissue engineering applications (title). Preparation of the albumin tissue scaffold: DTT was added to a final concentration of 12.5 mM in the reaction (Page 6, Method, last para. of left column to right column).
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 Lee and Sun et al by using 12.5 mM of DTT as reducing agent as taught by Li et al. 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 Li et al teaches a method for synthesizing an albumin-based tissue scaffold and characterized its cell compatibility, and the albumin tissue scaffold could be a good substrate for tissue culture and tissue engineering that can support human MSC attachment, growth, and differentiation (Page 6, left column). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Li et al teaches new methods of artificial fabrication of autogenic tissue substitutes (Abstract) with detailed instructions and data for using such albumin-based tissue scaffold.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Lee (Pub. No.: US 2014/0213765 A1, Pub. Date: Jul. 31, 2014) in view of Sawadkar et al (Pub. No.: US 2020/0164104 A1, Foreign Application Priority Data: Jul. 14 , 2017) and Liu et al (Scientific RePoRTs | 7: 9856 | DOI:10.1038/s41598-017-09563-w, 29 August 2017) and Sun et al (TISSUE ENGINEERING: Part C Volume 15, Number 1, 2009, DOI: 10.1089/ten.tec.2008.0164) as evidenced by Transfusion Medicine (Transfus Med Hemother 2009;36:399–407, Chapter 5 Human Albumin) as applied to claims 18, 25, 27-29, 31-33, 35 above, and further in view of Flynn (Pub. No.: US 2016/0051728 A1, Pub. Date: Feb. 25, 2016).
The teachings of Lee , Sawadkar et al, Liu et al, Sun et al are as described above and are incorporated herein in their entirety.
The above references do not teach elastic modulus of 1 kPa to 10 kPa. However, Flynn cures the deficiency.
Regarding to claim 30, Flynn teaches decellularized adipose tissue (DAT) is suitable for use in biomedical applications such as in soft tissue augmentation or as a bioscaffold ([0002], page 1). Flynn teaches a DAT bioscaffold, for adipose tissue engineering applications, may be soft, flexible, and elastic, with a Young's modulus similar to or the same as that of normal fat, i.e., in the range of about 3–4 kPa ([0059], page 5).
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 Lee and Sun et al by using elastic modulus of 1 kPa to 10 kPa as standard for bio-scaffold as taught by Flynn. 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 Flynn teaches the use of cross-linking the collagen with glutaraldehyde that may improve resiliency and decrease the immunogenicity of the material ([0005], page 1). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Flynn provides detailed instructions and working examples for generating bio-scaffold with decellularized adipose tissue.
Response to Arguments
Applicant's arguments filed on 10-01-2025 have been fully considered but they are not persuasive. The rejections necessitated by amendments have been described above. To the extent that Applicants' arguments are pertinent to the standing rejection of claim, they are addressed as follows:
1. Applicant argues essentially that cited references do not teach the claimed conditions: Lee fails to teach serum-derived proteins as the starting material. A person having ordinary skill in the art would be aware that the commercially available albumin as used by Lee would be significantly different in composition as compared to serum-derived proteins. Additionally, there is no disclosure or suggestion in Lee of performing an incubating step at 1°C to l 5°C for 8 hours. Sun fails to teach serumderived proteins as the starting material. There is no disclosure or suggestion of serum-derived proteins as the starting material in Komlos. There is no disclosure or suggestion in Li of serum-derived proteins as the starting material. Additionally, there is no disclosure or suggestion in Li of performing an incubating step at 1°C to l 5°C for 8 hours. There is no disclosure or suggestion in Flynn of serum derived proteins as the starting material (Remarks, page 8-9).
Response to Arguments:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, It is also noted that Lee teaches the use of any albumin solution ([0011], page 1) which encompass serum, and Lee provides proof of concept of preparing albumin tissue scaffolds from animal albumins (Abstract). Lee made no mention that albumin solution has to be prepared from commercially available albumins or it should not use other albumin sources such as serum. Nevertheless, Liu et al reference was added as evidence for crosslinking human serum albumin. Liu et al teach quick fixation based on formaldehyde crosslinking (FC) was introduced into a two-step precipitation (TSP) procedure with human serum albuminome (Page 2, 2nd para.) with the use of human serum samples (Page 2, 3rd para.). Transfusion Medicine provides evidence that in serum, albumin comprises about 50–60% of the total protein content of plasma (Page 400, right column of Transfusion Medicine). One of ordinary skill in the art would have been motivated to combine the references because Liu et al teach quick fixation of human serum samples (Page 2, 4th para.), and a two-step precipitation (TSP) procedure consisting of an initial 12% PEG precipitation step followed by the addition of 42% ethanol is useful for isolating the serum albuminome (Page 4, 2nd para.). Liu et al concluded that “we first developed a modified TSP method to replace the conventional protein G-ethanol method for effective preparation of serum albuminome. To capture weak and transient interactions in real time, we further optimised the well-established protocol by combining FC and TSP. We have shown here that the newly developed FC-TSP approach can be used for comprehensive profiling of human serum albuminome. This method is simple, rapid, inexpensive and easy to use, and appropriate for albuminome preparation of multiple clinical samples. We anticipate that the FC-TSP-MS strategy will have widespread future applications for albuminome-based biomarker discovery” (Page 9, conclusion).
Additionally, Lee teaches different preparation method for bovine serum albumin solution for preparation of the albumin tissue scaffold ([0041], page 3and ([0046], page 4). Thus, it is indicating that amount/concentration of albumin in solution for cross-linking process was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to use different amount/concentration of albumin in solution out of the course of routine optimization in order to achieve a desired level of solid network. Finally, there is no requirement that Sun et al, Komlos, Li, Flynn to teach that which is clearly taught by Lee or Liu et al.
2. Applicant argues essentially that serum refers to the component obtained by removing fibrinogen from plasma in blood, and contains water, glucose, inorganic salts, gamma globulins, other proteins, electrolytes, antibodies, antigens, and hormones. Among the proteins in serum, albumin accounts for about 50-60%. 3 In other words, the serum-derived proteins of the claimed method and the commercial albumin of Lee, for example, differ in composition such that serum has about 40-50% additional protein as compared to commercial albumin. Thus, in order to further distinguish the claimed method from the teachings of Lee, Claim 18 has been amended to recite, in part, ". .. wherein 50% to 60% of the serum-induced protein is albumin ...." Thus, the starting material used by Lee and the claimed method are different (Remarks, page 10).
Response to Arguments:
As mentioned above, it is also noted that Lee teaches the use of any albumin solution ([0011], page 1) which encompass serum, and Lee provides proof of concept of preparing albumin tissue scaffolds from animal albumins (Abstract). Lee made no mention that albumin solution has to be prepared from commercially available albumins or it should not use other albumin sources such as serum. Nevertheless, Liu et al reference was added as evidence for crosslinking isolated human serum albumin. Liu et al teach quick fixation based on formaldehyde crosslinking (FC) was introduced into a two-step precipitation (TSP) procedure with human serum albuminome (Page 2, 2nd para.) with the use of human serum samples (Page 2, 3rd para.). Transfusion Medicine provides evidence that in serum, albumin inherently comprises about 50–60% of the total protein content of plasma (Page 400, right column of Transfusion Medicine).
3. Applicant argues essentially that even if a person having ordinary skill in the art were to consider the teachings of Lee, which teaches commercial albumin as the starting material, it would not be possible for them to arrive at the cell scaffold of the claimed method. This is because the presence of additional proteins can significantly affect cell adhesion and proliferation efficiency. In support of this, BODIOU et al. 4 shows that, in the process of producing cultured meat under a serum-free environment, experiments were conducted to compare the degree of cell adhesion and proliferation when fibronectin, vitronectin, and laminin were included. Specifically, it was confirmed that all media contained bovine serum albumin, and that cell adhesion efficiency differed depending on whether fibronectin, vitronectin, and laminin, which are serum proteins, were additionally included. That is, even in the presence of albumin, the presence of additional serum proteins such as fibronectin, vitronectin, and laminin led to differences in cell adhesion and proliferation efficiency (Remarks, page 10)
Response to Arguments:
Applicant cited Bodiou et al reference that producing cultured meat under a serum-free environment is irrelevant to the scope of the instant claim. The claim is directed to producing a porous scaffold. The teaching Bodiou et al are in different context without the use of cross-linking agent or reducing agent as required by the claim. There is no requirement in the claim for cell culturing step or producing cultured meat under a serum-free environment or cell adhesion and proliferation. Applicant argument regarding it would not be possible for ordinary skill in the art to arrive at the cell scaffold of the claimed method using teachings of Lee is not persuasive because Lee was successful in preparing albumin tissue scaffolds from animal albumins (Abstract), and tissue scaffolds are three-dimensional porous materials, support cell attachment, growth, and differentiation, directing new tissue formation in vitro or in vivo ([0004], page 1).
Applicant also provide opinion for “even in the presence of albumin, the presence of additional serum proteins such as fibronectin, vitronectin, and laminin led to differences in cell adhesion and proliferation efficiency”. However, there is no explanation for how it would prevent ordinary skill in the art to be successful in preparing albumin tissue scaffolds using the method of Lee. As per 716.01(c), (II), arguments by applicant cannot take the place of evidence, Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
4. Applicant argues essentially that Amended Claim 1 recites "reacting the cross-linked proteins in the serum aqueous solution which has been treated with the cross-linking agent, subsequently with a reducing agent to obtain a reaction product." According to the claimed method, a reducing agent is applied after treatment with a crosslinking agent, i.e., the reducing agent and the crosslinking agent are added sequentially. In contrast, Lee discloses a step of adding transglutaminase and a reducing agent simultaneously to the albumin solution. Thus, the claimed method differs from Lee in that the order of the process steps is fundamentally different (Remarks, page 11).
Response to Arguments:
The description for amended claim with new limitation can be found above with the teachings of Sawadkar et al. Briefly, Sawadkar et al teach that methods of the invention may comprise washing or cleaning to remove agents involved in solubilizing and /or cross-linking ([0069], page 4), and this may include contacting or washing with a reducing agent ([0070], page 4), and the presence of the reducing agent may stabilize the cross-linking process and result in a scaffold with enhanced biological efficacy. Furthermore, the presence of the reducing agent is likely to reduce the cytotoxic effects caused by the leaching of un-reduced cross -linking agent from the composition ([0071], page 4), and the step of washing to remove agents involved in solubilizing and/or cross-linking may be carried out for at least 5 hours, preferably at least 8 hours ([0071], page 4). One of ordinary skill in the art would have been motivated to combine the references because Sawadkar et al teach that presence of the reducing agent may stabilize the cross-linking process and result in a scaffold with enhanced biological efficacy. Furthermore, the presence of the reducing agent is likely to reduce the cytotoxic effects caused by the leaching of un-reduced cross -linking agent from the composition ([0071], page 4).
5. Applicant argues essentially that First, the claims have been amended to replace the term "aging" with "incubating." Second, in Sun, the term "aging" refers to the phenomenon of quality degradation during storage of a cell scaffold, meaning that irreversible chemical reactions (Maillard reaction) and structural deterioration naturally occur while the scaffold is stored. In contrast, the term "incubating" generally refers to a process step in which a protein reaction product is left at a certain temperature for a specific period of time to induce structural homogenization or aggregation stability of the protein. Furthermore, Sun uses "aging" to describe the degradation phenomenon of an already completed scaffold during storage. In contrast, in the claimed method, "incubating" is used to describe a step in the manufacturing process of the final scaffold for the purpose of improving homogeneity and ensuring physical stability. Thus, although the same term may have been used, the "aging" step in Sun and the "incubating" step in the claimed method are directed to entirely different stages. Accordingly, a person having ordinary skill in the art would not be able to readily derive the conditions of the "incubating" step of the claimed method from the "aging" conditions used to prevent degradation of a finished scaffold in Sun. (Remarks, page 12)
Response to Arguments:
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. It also appears that applicant is attempting to attack each reference individually. However, Applicant’s arguments with opinion that the differences between the term “aging” and “incubating” are not persuasive because that both “aging” and “incubating” are interchangeably and routinely performed in the art. There is no distinction in definition of “aging” and “incubating” provided by the instant specification. In the instant case, Sun et al teaches aging of a regenerative biologic scaffold during storage at elevated humidity and temperature (Title). Sun et al teach that tissue products stored at 75% RH and 85% RH changed significantly, including decreased elasticity. In comparison, changes were nondetectable in control products stored at 2oC to 8oC. Calorimetric analysis revealed that tissue products stored at 2oC to 8oC and at 33% RH and 40oC were in the glassy state, whereas the products stored at 75% RH, 85% RH, and 40oC were not in the glassy state, suggesting a role of the glassy state in preserving tissue products during storage (Abstract). Sun et al teach Figure 2 shows the accumulation of Maillard products (advanced glycation end-products) as a function of storage time in days. Additionally, Lee teaches the preferred time for reaction incubation is between 0.5 to 24 hours ([0033], page 3). Thus, aging/incubating time at 2oC to 8oC was recognized in the prior art references to be a result-effective variable. A person of ordinary skill in the art would have been motivated to incubate the biologic scaffold in different time duration out of the course of routine optimization in order to achieve a desired level of elasticity and stability such as for 8 hours.
6. Applicant argues about unexpected advantages: (i) The scaffold produced by the claimed method stably supports long-term culture of functional cells: The porous cell scaffold prepared by the claimed method exhibits excellent effects in cell culture and in the production of functional proteins therefrom (Remarks, page 13); (ii) The scaffold produced by the claimed method yields cells with markedly improved in vivo engraftment: Cells cultured on the scaffold prepared by the claimed method also exhibit excellent in vivo engraftment (Remarks, page 14); (iii) The scaffold produced by the method of amended Claim 18 has remarkably superior utility. The porous cell scaffold prepared by the claimed method also demonstrates excellent commercial applicability (Remarks, page 15).
Response to Arguments:
As per MPEP § 716.02, [a]ny 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 this case, there is no evidence of record that specifically using cross-linking albumin directly from the serum, or using reducing agent subsequently after treating with the cross-linking agent, or incubating at a temperature of 1°C to l5°C for 8 hours would lead to superior results over cited prior arts. All the steps recited in the claims have been described above and rendered obvious over prior art references. Thus, it is expected to have the same functions and properties. Applicant’s arguments regarding limitations not recited in the claim are not commensurate with the scope of the claims.
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