DETAILED ACTION
Receipt is acknowledged of applicant’s Amendment/Remarks filed 7/3/2025.
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 .
Status of the Claims
Claim 10 has been amended. No claims are cancelled. Claim 11 is newly added. Accordingly, claims 1-11 remain pending in the application and are currently under examination.
Information Disclosure Statement
The IDS filed 8/15/2025 has been considered. A signed copy is enclosed herewith.
Withdrawn Rejections
Applicant’s amendment renders the rejections of claim 10 under 35 USC 101/112 moot. Specifically, the claim has been amended to remedy the non-statutory subject matter and indefinite issues. Thus, said rejections have been withdrawn.
Applicant’s amendment renders the rejection of claim 5 under 35 USC 112 moot. Specifically, Applicant’s arguments are found persuasive. See Remarks dated 7/3/2025, pages 7-8. Thus, said rejection has been withdrawn.
Maintained Rejections
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.
Claims 1 and 6-9 stand rejected and amended claim 10 and new claim 11 are newly rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (CN 113694253 A, Nov. 26, 2021, machine translation, hereafter as “Fan”) in view of Kong et a. (CN 111714248 A, Sep. 29, 2020, machine translation, hereafter as “Kong”) and Tan et al. (CN 104826169 A, Aug. 12, 2015, machine translation, hereafter as “Tan”).
The claimed invention is drawn to a tissue engineering blood vessel for in vivo rapid recellularization, wherein the tissue engineering blood vessel is prepared through the following steps:
S1: dissolving polyglycolic acid and polyethylene glycol separately in an organic solvent to prepare a polyglycolic acid spinning solution and a polyethylene glycol spinning solution, and preparing a tubular polymer composite scaffold having a special tube wall structure by electrospinning from the polyglycolic acid spinning solution and the polyethylene glycol spinning solution in a predetermined ratio, wherein a mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for an inner tube wall of the tubular polymer composite scaffold is higher than a mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for an outer tube wall of the tubular polymer composite scaffold; the mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for the inner tube wall of the tubular polymer composite scaffold is (15:1)-(50:1), and the mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for the outer tube wall of the tubular polymer composite scaffold is (5:1)-(15:1);
S2: seeding a seed cell on the tubular polymer composite scaffold, and culturing for 3 weeks to 3 months in a predetermined perfusion culture condition simulating an arterial pulsatile flow in a body to give an engineering blood vessel composed of the seed cell and an extracellular matrix; and
S3: decellularizing the engineering blood vessel to remove vascular cell components, so as to give the tissue engineering blood vessel composed of the extracellular matrix; and a method of making thereof.
It is important to note that instant claims 8 and 9 are deemed product-by-process claims due to the limitation, “wherein the tissue engineering blood vessel is prepared through the following steps…” and as such, determination of patentability is based on the product itself, not by the method in which it is made. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process (MPEP 2113).
Regarding instant claims 1 and 8, Fan teaches a preparation method of an artificial blood vessel comprising: 1) preparing a tubular bracket/scaffold; 2) inoculating smooth muscle cell in the tubular bracket; 3) putting the tubular bracket/scaffold inoculated with smooth muscle cell into the near physiological pulsating flow environment to culture to obtain the vascular stent; and 4) carrying out cell-free (decellularization) treatment to the vascular stent to obtain the artificial blood vessel (abstract). Fan teaches that the tubular bracket is prepared using a biodegradable polymer as a raw material by methods such as electrospinning (page 3, 4th para.). Fan also exemplifies putting the tubular bracket/scaffold inoculated with smooth muscle cell into the near physiological pulsating flow environment to culture for 2 months (page 7, 5th para.).
Fan is silent to the particular biodegradable polymers, polyglycolic acid and polyethylene glycol.
Kong teaches an artificial blood vessel comprising one or more degradable polymers, wherein the one or more degradable polymers is selected from a finite group of degradable polymers including polyglycolic acid and polyethylene glycol (title; 2nd to last para. of page 3 – 1st para. of page 4). Kong also teaches that the tubular polymer scaffold can be prepared by electrostatic spinning (page 4, 6th para.).
Fan and Kong are both drawn to artificial blood vessels and methods of making thereof, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the particular biodegradable polymer, polyglycolic acid and polyethylene glycol as suggested by Kong in the invention of Fan with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Kong teaches that said polymers are suitable for the same purpose of producing an artificial blood vessel via electrospinning. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination (MPEP 2144.07).
Fan is also silent to “a mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for an inner tube wall of the tubular polymer composite scaffold is higher than a mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for an outer tube wall of the tubular polymer composite scaffold; the mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for the inner tube wall of the tubular polymer composite scaffold is (15:1)-(50:1), and the mass ratio of the polyglycolic acid spinning solution to the polyethylene glycol spinning solution for the outer tube wall of the tubular polymer composite scaffold is (5:1)-(15:1)”.
Kong further teaches that the tubular scaffold can be a double layer structure (page 4, 3rd para.).
Tan teaches multi-layer artificial blood vessels that are made using electrostatic spinning (abstract). Tan teaches that the multi-layer artificial blood vessel is designed such that each layer is degrades at different rates and the outer layer specifically degrades more slowly such that it maintains its mechanical integrity while increasing porosity, said differing degradation rates allows for the growth of smooth muscle cells (page 2, 5th para.; page 3, para. 4-5; page 4, last full para.; claim 1).
The references are all drawn to artificial blood vessels and methods of making thereof, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include a multi-layer scaffold comprising an inner layer having a composition different from that of the outer layer of the scaffold as suggested by Tan into the invention of Fan/Kong with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Tan teaches that artificial blood vessels comprising electrospun layers that degrade at different rates allows the porosity of the vessel to increase while the mechanical integrity of the outer layer remains intact thereby allowing smooth muscle cells proliferate. Regarding the claimed ratios, degradation rates of polyglycolic acid and polyethylene glycol are understood in the art and a skilled artisan would be able to optimize the ratios of each polymer within each layer by way of routine experimentation to arrive at a desired degradation rate of each layer such that mechanical integrity of the artificial vessel remains intact while porosity can increase thereby allowing smooth muscle cells to proliferate.
Regarding instant claim 6, Fan further teaches smooth muscle cells from various mammals (Embodiments 1-3).
Regarding instant claim 7, Fan, as discussed above, teaches smooth muscle cells are directly recovered from a mammal donor (Embodiments 1-3) and, as such, reads on “primary” cells.
Regarding instant claim 9, Fan further teaches that stimulation of the smooth muscle cells express collagen (abstract). Kong also shows collagen deposition after smooth muscle cells were cultured, specifically collagen type I and type III (page 5, Fig. 4 description; paragraph bridging pages 12-13). The references indicate that the method necessarily results in an extracellular matrix material comprising type I and type III collagen.
Regarding instant claim 10, said claim is considered an intended use claim due to the recitation, “wherein the tissue engineering blood vessel serves as a replacement of an esophagus, a trachea, a ureter, a urethra, a bile duct, a fallopian tube, or a vas deferens, a use in preparing an allogenic biological heart valve, and/or a use as a surgical patch” and, as such, does not alone show patentable distinction. A recitation of intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. In other words, if the prior art structure is capable of performing the intended use, then it meets the claim. As discussed above, the cited art teaches/suggests the structural limitations of the claimed artificial blood vessel and, as such, a skilled artisan would reasonably expect that same blood vessel could be use in the same intended manner.
Regarding instant claim 11, the cited references are silent to the properties recited. However, a composition and it properties are inseparable (2112.01). MPEP 2112.01 also states,
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.
As discussed above, the cited art teaches/suggests a substantially identical product made by a substantially identical process. Accordingly, a prima facie case has been established. One of ordinary skill in the art would reasonably expect a substantially identical product made by a substantially identical process to possess the same properties including those recited in instant claim 11.
The combined teachings of Fan, Kong and Tan render the instant claims prima facie obvious.
Response to Arguments
Applicant's arguments, filed 7/3/2025, regarding the 103 rejection over Fan, Kong and Tan have been fully considered but they are not persuasive.
Applicant argues that while Kong teaches polyglycolic acid and polyethylene glycol, Kong teaches said polymers in a long list of possible degradable polymers in the alternative. Applicant also argues that the claim requires separate preparations of a polyglycolic acid spinning solution and a polyethylene glycol spinning solution and then a combined use of the two solution for electrospinning to product a tubular polymer composite scaffold. Remarks, pages 8-10.
In response, it is respectfully submitted that Kong teaches “one or more degradable polymers” which implies combinations of the listed polymers are permitted. Further, Kong teaches a finite list of 12 recited degradable polymers including polyglycolic acid and polyethylene glycol which is not a long list as applicant contends. Kong’s teachings suggest that the inclusion of both polyglycolic acid and polyethylene glycol because Kong teaches that said one or more polymers are suitable for the same purpose of producing an artificial blood vessel via electrospinning and the selection of the particular combination would have been based on routine experimentation of a finite number of identified and predictable solutions. Additionally, the references require dissolving the polymers prior to electrospinning and a skilled artisan would have readily understood that polymers, in general, would either be dissolved separately or together. Both options are equally obvious. A skilled artisan would have looked at the individual polymers and their solubilities and selected a particular solvent or solvents depending on their respective solubility properties. In this case, polyglycolic acid and polyethylene glycol are very different polymers having very different solubilities (i.e., highly crystalline, hydrophobic vs water-soluble, hydrophilic). Accordingly, a skilled artisan would have readily possessed this knowledge and dissolved each polymer, separately or in combination, in an appropriate solvent or solvents suitable for each polymer. With respect to the combined use of the two polymer solutions, Kong and Tan both teach utilizing different polymer solutions to form an artificial blood vessel and Tan specifically teaches forming different layers using the different polymer solutions such that said layers degrade at different rates allowing the porosity of the vessel to increase while the mechanical integrity of the outer layer remains intact thereby allowing smooth muscle cells to proliferate. Thus, for these reasons, applicant’s argument is unpersuasive.
Applicant argues that “Limitation B” defines inner and outer walls of the tubular polymer composite scaffold rather than the tubular polymer composite scaffold having a double layer structure of Kong. Remarks, pages 10-11.
In response, it is respectfully submitted that the claims require a tubular structure that has a particular first polymer composition electrospun for the inner tube wall and a particular second polymer composition that is electrospun for the outer tube wall. Kong teaches a double layer tubular structure, each layer is electrospun and have different polymer compositions (e.g., Example 4 of Kong) and Tan teaches a multiple layered tubular structure, each layer is electrospun and have a different polymer composition (e.g., page 4, last full paragraph of Tan). While the instant claims do not recite “layered”, the claims describe a layered structure. The cited references meet the limitations of the claim. Applicant’s argument is not persuasive.
Applicant argues that Tan merely discloses different layers that degrade at different times, but Tan is silent to any of polyglycolic acid and polyethylene glycol, let alone any ratio thereof. Remarks, page 11.
In response, it is respectfully submitted that Tan is not relied upon for the particular polymers, polyglycolic acid and polyethylene glycol. Kong is relied upon for the teachings of the particular polymers, polyglycolic acid and polyethylene glycol. 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). It is noted that Kong teaches degradable polymers in general and names not only the claimed polymers, polyglycolic acid and polyethylene glycol, but also polycaprolactone and gelatin which are utilized in the Tan reference. Tan is relied upon for the teaching of artificial blood vessels comprising electrospun polymeric layers that degrade at different rates for the purpose of allowing porosity of the vessel to increase while the mechanical integrity of the outer layer remains intact thereby allowing smooth muscle cells to proliferate. Regarding the claimed ratios, the rejection explains that the degradation rates of polyglycolic acid and polyethylene glycol are understood in the art and a skilled artisan would be able to optimize the ratios of the polymers within each layer by way of routine experimentation to arrive at a desired degradation rate of each layer such that mechanical integrity of the artificial vessel remains intact while the porosity can increase thereby allowing smooth muscle cells to proliferate as suggested by Tan. For these reasons, applicant’s argument is not persuasive.
Applicant argues that the selection of the two materials, polyglycolic acid and polyethylene glycol and the design for their mass ratio in the inner and outer tube walls are not arbitrary but crucial output of Applicant’s creative work and points to pages 8-9 of the instant specification to support their position. Applicant argues that the references do not suggest or imply the surprising function/role of polyglycolic acid or polyethylene glycol during different stages of cell culture and, as such, is unpredictable to those skilled in the art to combine the polymers in the manner defined in claim 1. Remarks, pages 11-15.
In response, it is respectfully submitted that the prior art need not recognize each of the functions/roles that applicant mentions so long as there is reasoning/motivation to combine the teachings of the references. Such reasoning and motivation have been discussed in the rejection as well as the preceding paragraphs. It should be noted that the prior art does in fact recognize at least some of the functions/roles that the instant specification describes including maintaining mechanical integrity while increasing porosity and allowing growth of smooth muscle cells.
Obviousness does not require absolute predictability, but at least some degree of predictability is required (MPEP 2143.02). Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness (MPEP 2143.02). Applicants have not provided evidence showing that there was no reasonable expectation of success. For these reasons, applicant’s argument is not persuasive.
Applicant argues that prior to the claimed invention, there were persistent problems existing in commercially available artificial blood vessels, namely, recellularization failure or slow recellularization, low patency rates, susceptibility to infection, and high degradation rates and the cited art does not identify such problems. Applicant argues that selecting the particular polymers in a particular ratio and configuration proved to be an effective solution to solving the aforementioned problems. Applicant asserts that the extra research and investigation conducted for the purpose of figuring out the creatively combined use of polyglycolic acid and polyethylene glycol would beyond doubt increase the cost of a tissue engineering blood vessel produced whereas a person of ordinary skill in the art had no reason to do so when not knowing the specific problems. Remarks, pages 15-16.
In response, it is respectfully submitted that the cited art need not identify such problems in order for a prima facie case of obviousness to be established. In a 103 rejection, "[T]he analysis that "should be made explicit" refers not to the teachings in the prior art of a motivation to combine, but to the court’s analysis. . . . Under the flexible inquiry set forth by the Supreme Court, the district court therefore erred by failing to take account of ‘the inferences and creative steps,’ or even routine steps, that an inventor would employ and by failing to find a motivation to combine related pieces from the prior art" (MPEP 2143). The rejection above explains the reasoning and motivation to combine/modify the references to arrive at the claimed invention. Additionally, insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Evidence of unexpected properties must also be commensurate in scope with the claims (MPEP 716.02(d)). For these reasons, applicant’s arguments are unpersuasive.
Applicant further argues that Fan does not disclose the additional limitation of claim 6 because Fan only mentions smooth muscle cells, but does not specify that the smooth muscle cells are vascular smooth muscle cells. Remarks, pages 16-17.
In response, it is respectfully submitted that in an anticipation teaching, a “reference must teach every aspect of the claimed invention either explicitly or impliedly” (MPEP 2120 (III)). Fan teaches a particular embodiment that smooth muscle cells are sourced from an abdominal aorta of a rat (i.e., mammal) (Embodiment 3). Smooth muscle cells from an abdominal aorta are known an vascular smooth muscle cells. Thus, while “vascular” is not explicitly stated, “vascular” is impliedly taught because Fan describes the source from which the smooth muscle cells are obtained. For these reasons, applicant’s argument is not persuasive.
Applicant further argues that Fan does not disclose the additional limitation of claim 7. Applicant states that Fan only teaches primary cells isolated from mammals and that primary cells are scarce in quantity and cannot meet the requirement for culturing one blood vessel. Applicant asserts that culturing on blood vessel requires cells from multiple donors. Applicant further asserts that, in the implementation of the present invention, passage 3 cells after subculture of seed cells are used for culturing. Remarks, page 17.
In response, it is respectfully submitted that the examiner agrees with applicant in that Fan teaches primary cells from mammals. The claim recites, “wherein the seed cells are primary to 10th-passage cells from one or more donors or a cell bank”. Fan reads on the claimed embodiment of primary cells from one donor. Applicant’s argument requiring multiple donors conflicts with the claim as it is currently written because the claim states, “one or more donors”. Further, applicant’s remark stating that “in the implementation of the present invention, passage 3 cells after subculture of seed cells are used for culturing” raises a potential enablement issue because it appears that applicant’s argument would imply that primary to 2nd-passage cells would not work in the present invention. As such, further clarification is requested. For these reasons, applicant’s argument is not persuasive.
Regarding claims 8 and 9, applicant relies on the same arguments discussed above regarding claim 1. Remarks, page 17.
For the same reasons as discussed above, applicant’s arguments are unpersuasive.
Thus, for these reasons, Applicant’s arguments are found unpersuasive. Said rejection is maintained.
Claim 2 stands rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (CN 113694253 A, Nov. 26, 2021, machine translation, hereafter as “Fan”) in view of Kong et a. (CN 111714248 A, Sep. 29, 2020, machine translation, hereafter as “Kong”) and Tan et al. (CN 104826169 A, Aug. 12, 2015, machine translation, hereafter as “Tan”), as applied to claim 1 above, and further in view of Kira (EP 0217115 A1, Apr. 8, 1987, hereafter as “Kira”).
The claimed invention is described above.
Fan, Kong and Tan teach the elements discussed above. Additionally, Fan teaches that the artificial blood vessel can be designed to have different sizes and lengths (page 8, 4th para.) and exemplifies a wall thickness of 0.2 mm and a diameter of 3 mm (Embodiment 1). Kong teaches that the tubular polymer fiber scaffold is a structure having a porous wall (claim 2). Kong also exemplifies tubular scaffolds having an inner diameter of 2-10 mm, a wall thickness of 200-1000 microns (0.2-1 mm) and a length of 5-40 cm (page 4, 2nd para.).
It would have been prima facie obvious to one of ordinary skill in the art to design an artificial blood vessel having the claimed dimensions with a reasonable expectation of success because Fan and Kong teach overlapping diameters, wall thicknesses, and lengths that are suitable for an artificial blood vessel. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (MPEP 2144.05 (I)).
Fan, Kong and Tan are silent to a wall porosity of 85-99.9%.
Kira teaches artificial vessels having a wall porosity of 75-95% (abstract). Kira teaches that the porosity percentage greatly affects the mechanical properties, especially compliance, and the blood compatibility of the contact surface with blood (col. 2, lines 15-25; col. 3, lines 42-52).
The references are all drawn to artificial blood vessels and methods of making thereof, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the claimed wall porosity as suggested by Kira in the invention of Fan/Kong/Tan with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Kira teaches that a porosity of 75-95% provides an artificial vessel with improved mechanical properties including compliance as well as blood compatibility. In addition, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the porosity by way of routine experimentation. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation” (MPEP 2144.05(II)(A)).
The combined teachings of Fan, Kong, Tan and Kira render the instant claim prima facie obvious.
Response to Arguments
Applicant's arguments, filed 7/3/2025, regarding the 103 rejection over Fan, Kong, Tan and Kira have been fully considered but they are not persuasive.
Applicant argues that while some of the parameters have some overlaps with the ranges disclosed by the prior art, they product surprising effects, particularly, the porosity of 85-99.9% is conducive to the adhesion and proliferation of seed cells as well as the transportation of nutrients and oxygen. Remarks, page 18.
In response, it is respectfully submitted that the examiner agrees that the parameters overlap with the teachings of prior art. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (MPEP 2144.05 (I)). With respect to porosity, Kira teaches artificial vessels having a wall porosity of 75-95% (abstract). Kira teaches that the porosity percentage greatly affects the mechanical properties, especially compliance, and the blood compatibility of the contact surface with blood (col. 2, lines 15-25; col. 3, lines 42-52). Accordingly, Kira provides an overlapping porosity range and provides the requisite motivation to incorporate such a porosity into the teachings of Fan, Kong and Tan. Insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims (see MPEP 716.02(d)). Thus, Applicant' s argument is found unpersuasive
For these reasons, said rejection is maintained.
Claim 3 stands rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (CN 113694253 A, Nov. 26, 2021, machine translation, hereafter as “Fan”) in view of Kong et a. (CN 111714248 A, Sep. 29, 2020, machine translation, hereafter as “Kong”) and Tan et al. (CN 104826169 A, Aug. 12, 2015, machine translation, hereafter as “Tan”), as applied to claim 1 above, and further in view of Neutel et al. (“High Pulsatile Load Decreases Arterial Stiffness: An ex vivo Study”, Frontiers in Physiology, Oct. 2021, Vol. 12, Article 741346, pp. 1-11; hereafter as “Neutel”).
The claimed invention is described above.
Fan, Kong and Tan teach the elements discussed above. Fan also teaches static in vitro culture for 24 hours and further culturing in an arterial pulsatile flow environment for 2 months (i.e., simulating canine/pig/rat pulse frequencies, pressures and flow waveforms) (Embodiments 1-3).
Fan, Kong and Tan are silent to the particular steps of: culture of 6-8 days in an arterial pulsatile flow at a pressure of 10-90 mmHg; culture in an arterial pulsatile flow at an increased pressure of 90-110 mmHg; and culture of one week in an arterial pulsatile flow at an increased pressure of 110-160 mmHg.
Neutel teaches that stiffness is a strong predictor of cardiovascular events (page 1, last para.). Neutel studied the effects of pulsatile load on overall stiffness of aortic tissue and vascular smooth muscle cell function (abstract). Neutel’s experimental protocol included increasing steps of pulse pressure starting at a physiological pressure of 40 mmHg and increasing up to 200 mmHg in steps of 20 mmHg (page 3, 1st full para.). Neutel found that increasing pulsatile pressure decreases arterial stiffness/improves compliance and altered the response of vascular smooth muscle cells to a contractile stimulus (title; abstract; paragraph bridging pages 5-7; conclusion).
The references are all drawn to the blood vessel art, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the claimed culture conditions including increasing arterial pulsatile pressures as suggested by Neutel in the invention of Fan/Kong/Tan with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Neutel teaches that increasing arterial pulsatile pressures in a blood vessel improves mechanical properties including stiffness/compliance as well as alters the response of vascular smooth muscle cells to a contractile stimulus. In addition, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the culture conditions including the pressures and duration by way of routine experimentation. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation” (MPEP 2144.05(II)(A)).
The combined teachings of Fan, Kong, Tan and Neutel render the instant claim prima facie obvious.
Response to Arguments
Applicant's arguments, filed 7/3/2025, regarding the 103 rejection over Fan, Kong, Tan and Neutel have been fully considered but they are not persuasive.
Applicant argues that Neutel took the descending aorta and abdominal aorta of mice to investigate the contraction/tension of vascular smooth muscle cells in mouse blood vessels in high-potassium ion solution under different pulse pressures, which differs from the design concept and principle of the present invention. Applicant argues that the culture conditions in claim 3 yields mechanical stability, promotes more abundant secretion of extracellular matrix proteins, and accelerate the maturation of the tissue-engineered blood vessels. Remarks, pages 19-20.
In response, it is respectfully submitted that Neutel teaches that stiffness is a strong predictor of cardiovascular events (page 1, last para.). Neutel studied the effects of pulsatile load on overall stiffness of aortic tissue and vascular smooth muscle cell function (abstract). Neutel’s experimental protocol included increasing steps of pulse pressure starting at a physiological pressure of 40 mmHg and increasing up to 200 mmHg in steps of 20 mmHg (page 3, 1st full para.). Neutel found that increasing pulsatile pressure decreases arterial stiffness/improves compliance and altered the response of vascular smooth muscle cells to a contractile stimulus (title; abstract; paragraph bridging pages 5-7; conclusion). Neutel provides general teachings of increasing steps of pulse pressure in particular ranges, similarly as recited in the claims, decreases arterial stiffness/improves compliance and altered the response of vascular smooth muscle cells to a contractile stimulus. Thus, the teachings of Neutel provide the requisite teachings and motivation to modify Fan, Kong and Tan. In addition, a skilled artisan would have been able to optimize the culture conditions including the pressures and duration by way of routine experimentation. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation” (MPEP 2144.05(II)(A)). Insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims (see MPEP 716.02(d)). Thus, Applicant' s argument is found unpersuasive
For these reasons, said rejection is maintained.
Claim 4 stands rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (CN 113694253 A, Nov. 26, 2021, machine translation, hereafter as “Fan”) in view of Kong et a. (CN 111714248 A, Sep. 29, 2020, machine translation, hereafter as “Kong”) and Tan et al. (CN 104826169 A, Aug. 12, 2015, machine translation, hereafter as “Tan”), as applied to claim 1 above, and further in view of Badylak et al. (WO 2017/123883 A1, Jul. 20, 2017, hereafter as “Badylak”).
The claimed invention is described above.
Fan, Kong and Tan teach the elements discussed above. Fan also teaches that the decellularization treatment involves processing the cultured scaffold with an aqueous solution comprising SDS, EDTA, NaCl, NaOH for 2 hours and repeating said processing 5 times (Embodiments 1-3). It is noted that Fan does not explicitly teach a temperature at which the decellularization takes place, however the lack of said teaching implies that the process takes place at room temperature. Additionally, Kong teaches a similar decellularization process and indicates that said process takes place at room temperature (page 5, 3rd para.). Thus, in light of the teachings of Fan and Kong, a skilled artisan would reasonably conclude that decellularization processes take place at room temperature.
Fan, Kong and Tan are silent to the particular decellularization agent, 3-[(3-cholamidopropyl)-diethylammonio]-propanesulfonate (CHAPS).
Badylak teaches a method of producing aortic extracellular matrix comprising decellularizing the extracellular matrix from blood vessels ([0006] and [0063]). Badylak teaches CHAPS and SDS are useful detergents for the decellularization process ([0063], [0068], [0078] and [0088]).
The references are all drawn to the blood vessel art, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include 3-[(3-cholamidopropyl)-diethylammonio]-propanesulfonate (CHAPS) as suggested by Badylak in the invention of Fan/Kong/Tan with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Fan and Badylak both teach decellularization of a vessel to obtain the extracellular matrix, Fan teaches SDS as a decellularization agent and Badylak teaches that both SDS and CHAPS are useful as decellularization agents. Badylak effectively teaches the SDS and CHAPS are functional equivalents and, as such, combining or substituting functional equivalents that are known to be used for the purpose is prima facie obvious (MPEP 2144.06).
The combined teachings of Fan, Kong, Tan and Badylak render the instant claim prima facie obvious.
Response to Arguments
Applicant's arguments, filed 7/3/2025, regarding the 103 rejection over Fan, Kong, Tan and Badylak have been fully considered but they are not persuasive.
Applicant argues that none of prior art discloses the combined use of CHAPS and EDTA. Applicant assets that CHAPS is used to gently disrupt cell nuclei and membranes while preserving the native conformation of proteins and EDTA binds to calcium and magnesium ions on cell membranes to disrupt intercellular junctions, promoting cell separation and achieving decellularization. Applicant asserts that the combined use ensures more thorough removal of cells from the tissue-engineered blood vessel while leaving the protein structure intact. Applicant further asserts that the mechanical properties of the tissue-engineered blood vessels remain unaffected before and after decellularization, however the references make no mention of these features. Remarks, pages 20-21.
In response, it is respectfully submitted that the prior art need teach each of the functions or benefits that applicant has mentioned. The references as a whole teach CHAPS and EDTA as known decellularization agents and combining or substituting functional equivalents that are known to be used for the purpose is prima facie obvious (MPEP 2144.06). Insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims (see MPEP 716.02(d)). Thus, Applicant' s argument is found unpersuasive
For these reasons, said rejection is maintained.
Claim 5 stands rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (CN 113694253 A, Nov. 26, 2021, machine translation, hereafter as “Fan”) in view of Kong et a. (CN 111714248 A, Sep. 29, 2020, machine translation, hereafter as “Kong”) and Tan et al. (CN 104826169 A, Aug. 12, 2015, machine translation, hereafter as “Tan”), as applied to claim 1 above, and further in view of Lancaster et al. (CA 3067558 A1, Dec. 20, 2018, hereafter as “Lancaster”).
The claimed invention is described above.
Fan, Kong and Tan teach the elements discussed above.
Fan, Kong and Tan are silent to a cell seeding density of 0.1-3.0 x 106 cells/cm.
Lancaster teaches engineered tissue compositions for supporting cell growth, maintenance, and/or differentiation featuring a scaffold, extracellular matrix (ECM) material, and optionally a population of ECM-generating cells (abstract). Lancaster teaches seeding the particular cells, smooth muscle cells ([0014]). Lancaster also teaches seeding ECM-generating cells in a scaffold at a density of between 5 x 105 to 5 x 107 cells/cm2 ([0020]).
The surface area formula of a tube is A = 2πRouterh + 2πRinnerh + 2π(Router² - Rinner²). Using the dimensions of, for example, Kong (inner diameter of 2-10 mm, wall thickness of 0.2-1 mm, and length of 5-40 cm), the surface area range can be calculated to about 13-5,288 cm2. Using the cell density information of Lancaster and length range of Kong, a linear cell density can be calculated to a range of approximately 0.12 x 105 - 1 x 107 cells/cm which encompasses the claimed range.
The references are drawn to tissue engineering scaffolds comprising extracellular matrix generating cells, thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the claimed cell density as suggested by Lancaster in the invention of Fan/Kong/Tan with a reasonable expectation of success. A skilled artisan would have been motivated to do so because Lancaster teaches that a cell density of 5 x 106 to 5 x 107 cells/cm2 effectively generates extracellular matrix on a scaffold. In addition, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the cell density by way of routine experimentation. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation” (MPEP 2144.05(II)(A)).
The combined teachings of Fan, Kong, Tan and Lancaster render the instant claim prima facie obvious.
Response to Arguments
Applicant's arguments, filed 7/3/2025, regarding the 103 rejection over Fan, Kong, Tan and Lancaster have been fully considered but they are not persuasive.
Applicant relies on the same arguments as presented for the 103 rejection over Fan, Kong and Tan. No further arguments regarding claim 5 are presented. Remarks, page 21.
For the same reasons as discussed above, Applicant’s arguments are not persuasive.
Thus, said rejection is maintained.
Conclusion
All claims have been rejected; no claims are 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CASEY HAGOPIAN whose telephone number is (571)272-6097. The examiner can normally be reached on M-F 9:00 am - 3:30 pm.
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Casey S. Hagopian
Examiner, Art Unit 1617
/CARLOS A AZPURU/Primary Examiner, Art Unit 1617
