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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 reply filed 12/22/2025 has been received and entered into the application file. Applicant’s amendment and arguments have been fully considered. Claims 13-14, 18-19 and 21-24 are currently pending. Claims 1-12, 15-17 and 20 are cancelled. Claims 13 and 22-23 are currently amended. Claim 24 is newly added.
REJECTIONS WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claim 22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
Applicant’s amendment submitted 11/24/2025 amended claim 22 to now recite the limitation “wherein the graft comprises a decellularized pig aorta” and thus provides sufficient clarity.
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13 and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 13, Applicant’s amendment submitted 11/24/2025 has amended claim 13 to recite the limitation “…wherein the cell-derived TSP2-null ECM is deposited onto the lumen by TSP-null ECM producing cells in contact with the lumen…”
It is noted this limitation renders the claim indefinite since it is unclear if the newly recited limitation is directed to the source of the deposited ECM, from TSP-null cells, or if Applicant means for cells to be present on the lumen of the claimed vascular graft.
Likewise, regarding claim 24, claim 24 recites the limitation, “wherein the TSP-null ECM producing cells are in contact with the lumen for about 7 days” and thus renders claim 24 indefinite since it is unclear whether or not the cells remain on the claimed graft beyond 7 days, or are removed from the claimed graft.
In the interest of compact prosecution, the amended limitations are considered product-by-process limitations that define the manner by which the vascular graft has been produced thus depositing/coating TSP2-null ECM on the lumen of the vascular graft, and does not require the presence of cells. Thus, a non-thrombogenic vascular graft comprising a lumen and exogenous cell-derived ECM lacking TSP2 (i.e., TSP2-null ECM), wherein the cells used for depositing the ECM are no longer on the vascular graft, would appear to read on the claimed vascular graft.
However, despite the above interpretation, such treatment does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action. The rejection to claims 13 and 24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, stands and must be addressed.
Appropriate clarification is appreciated.
REJECTION(S) MAINTAINED/UPDATED
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 remains 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.
Regarding claim 23, it is noted that Applicant’s amendment submitted 11/24/2025 has amended claim 23 to now recite the limitation “wherein following transplantation of the graft in the recipient, blood flow is present through the graft two weeks after transplantation.”
It is noted this limitation renders the claim indefinite since the claim is directed to a composition per se. The claims are not directed to a method of transplantation, thus said limitation appears to be directed to the intended use of the composition, i.e., transplanted in the recipient. Thus, it is unclear if the claimed graft requires the presence of blood.
In the interest of compact prosecution, the amended limitation is considered to be directed to the intended use of the composition, i.e., transplanted in the recipient.
However, despite the above interpretation, such treatment does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action. The rejection to claim 23 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, stands and must be addressed.
Appropriate clarification is appreciated.
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.
Claim(s) 13-14, 18-19, 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Calabro (previously cited, “Calabro”), in view of Dimitrievska et al., (previously cited, “WO ‘835”).
The rejection has been updated in view of Applicant’s claim amendments submitted 11/24/2025.
Regarding claims 13 and 18, Calabro teaches that tissue and cell-derived ECM can be used as a bioactive substrate upon decellularization of the tissue or cell cultures. Decellularization can be conducted using a variety of protocols such as chemical or enzymatic decellularization. Calabro teaches the decellularized ECM is injectable or insertable when formulated as a hydrogel (i.e., graft) (page 2400, 6. Cell-derived ECM as a potential substrate for in vitro studies and in vivo applications, first sentence).
Calabro teaches the TSP2-null ECM can be formed by either: (1) TSP2-null fibroblasts or (2) WT (wild type) fibroblasts treated with TSP2 siRNA/shRNA (6. Cell-derived ECM as a potential substrate for in vitro studies and in vivo applications, second paragraph, page 2400 at right col).
Calabro teaches the TSP2-null ECM can be used to generate therapeutic coatings for vascular applications (i.e., exogenous cell-derived TSP2-null ECM), as well as useful for preparing hydrogels for treating wounds (6. Cell-derived ECM as a potential substrate for in vitro studies and in vivo applications, page 2400).
Calabro further teaches the TSP2-null ECM is non-thrombogenic (page 2399, right col, second paragraph).
Thus, Calabro teaches of insertable/injectable biomaterials and vascular grafts comprising the decellularized extracellular matrix lacking thrombospondin-2 (TSP2-null ECM), wherein the graft is non-thrombogenic. However, Calabro differs from the instant invention in that Calabro does not further exemplify the vascular graft comprises a lumen (claims 13 and 18) and Calabro does not further exemplify a step of administering (e.g., transplanting) the graft modified with the anti-thrombogenic TSP2-null ECM to a subject (claim 18).
WO ‘835 teaches there is an unmet need for non-thrombogenic vascular grafts, that is the vascular grafts do not cause thrombosis in the recipient patient (page 1, Background of the Invention).
WO ‘835 is directed to anti-thrombogenic vascular grafts and teaches vascular grafting employs transplanting of the prepared grafts (page 1, lines 15-19). Like Calabro, WO ‘835 teaches of modifying the decellularized vascular grafts by coating the vascular graft with an anti-thrombogenic composition (i.e., non-thrombogenic graft). The anti-thrombogenic agent reduces or eliminates the thrombogenicity of the vascular graft (Abstract; page 13, lines 26-27, page 14, lines 8-10, page 16, lines 7-19, and page 19, lines 24-26). WO ‘835 teaches the anti-thrombogenic vascular grafts are decellularized tubular grafts (e.g. rat aortas, tissue engineered vessels) that include a luminal surface and a hollow passageway (i.e., comprise a lumen) (page 15, lines 24-26, 29-32; page 35, lines 11-21; Figures 14-16) wherein the luminal surface of the tubular vascular graft is coated with the non-thrombogenic coating that prevents thrombosis (page 16, lines 4-6).
WO ‘835 additionally teaches a method of treating a diseased blood vessel in a subject comprising transplanting (i.e., administering) the anti-thrombogenic tubular vascular graft into the subject, wherein the lumen of the tubular vascular graft has been coated with the anti-thrombogenic coating, wherein the anti-thrombogenic coating comprises two layers. The first layer comprises hyaluronic acid and the second layer comprises the anti-coagulant heparin (page 2, lines 16-33 to page 3, lines 1-2; page 7, lines 15-24).
WO ‘835 teaches the anti-thrombogenic vascular graft is used to treat an aneurysm (page 15, lines 10-11).
Thus, WO ‘835 has established it was known that anti-thrombogenic vascular grafts comprise lumen, wherein the lumen is coated with the anti-thrombogenic agent.
WO ‘835 has established it was known to transplant (i.e., administer) non-thrombogenic tubular vascular grafts to humans since doing so improves or restores vital blood flow to organs and tissues without causing undesired thrombosis (page 1, lines 19-20).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use Calabro’s non-thrombogenic TSP2-null ECM for coating tubular vascular grafts comprising lumen for treating damaged or obstructed blood vessels by transplanting (i.e., administering) the vascular grafts to replace obstructed or damaged vessels therefore restoring vital blood flow to organs and tissues without causing undesired thrombosis.
It is submitted that because each of the types of anti-thrombogenic coatings disclosed by Calabro and WO ‘835 were known to individually reduce thrombogenicity in vascular grafts, it would further have been obvious to one having ordinary skill in the art to combine the TSP2-null ECM of Calabro with the anti-thrombogenic coating of WO ‘835 for the purpose of producing a transplantable tubular vascular graft that reduces undesired thrombogenicity thus improving the quality of the vascular graft. Combination of multiple products (anti-thrombogenic coatings) each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
The person of ordinary skill in the art would have been motivated to modify the transplant method of WO ‘835 to include further coating the vascular graft with TSP2-null ECM, as taught by Calabro, for the predictable result of successfully improving or restoring obstructed blood flow without causing undesired thrombosis, thus meeting the limitations of claims 13 and 18.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Calabro and WO ‘835 because each of these teachings are directed at non-thrombogenic vascular grafts.
Further regarding claim 13 and the limitation “wherein the graft is less adhesive for von Willebrand Factor (vWF) as compared to a reference graft comprising a lumen, wherein the reference graft is modified with a decellularized ECM not lacking TSP-2”, it is noted that Calabro does not further comment on whether or not the graft is less adhesive for von Willebrand Factor (vWF) as compared to a reference graft comprising a lumen and modified with a decellularized ECM not lacking TSP-2.
However, although Calabro does not state the graft is less adhesive for von Willebrand Factor (vWF) as compared to a reference graft comprising a lumen and modified with a decellularized ECM not lacking TSP-2, the fact that Calabro teaches the same extracellular matrix lacking thrombospondin-2 (TSP2-null ECM) as the instant application (Example 5, TSP2 KO ECM) means, 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. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).
Any properties exhibited by or benefits provided the composition are inherent and are not given patentable weight over the prior art. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not inherently possess the same properties as instantly claimed product. MPEP 2112.01
Further regarding claim 13 and the limitation “wherein a risk of developing a thrombosis in a recipient of the graft is reduced when the graft is transplanted into the recipient”, it is noted that claim 13 is directed to a composition per se. Claim 13 is not directed to a method of transplanting and does not positively recite a step of transplanting. Thus, said limitation is interpreted as functional language and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Additionally, “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).” See MPEP 2112.01 (I).
Further regarding claim 13 and the limitation “wherein the cell-derived TSP2-null ECM is deposited onto the lumen by TSP-null ECM producing cells in contact with the lumen”, it is noted this limitation is directed to the manner by which the claimed vascular graft is produced, i.e. a product-by-process limitation.
Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, if the product by process limitations are considered, the process imparts the feature of the vascular graft having TSP-null ECM deposited (coated) on the lumen of the vascular graft. Thus, a non-thrombogenic vascular graft comprising a lumen and exogenous ECM lacking TSP2 (i.e., TSP2-null ECM), wherein the cells used for depositing the ECM are no longer on the vascular graft, would appear to read on the claimed vascular graft.
The combined prior art teaches the anti-thrombotic agent is disposed on the lumen of the tubular vascular graft, thus meeting the limitation of claim 13 (See WO ‘835, page 16, lines 4-6).
Further regarding claim 18 and the limitation that the graft is pretreated with a therapeutic agent in a pharmaceutically acceptable carrier, it is noted that WO ‘835 teaches the vascular graft can be further treated prior to transplant (i.e., pretreated) and thus further include growth factors (e.g., VEGF, FGF) and immune modulating agents, as well as additional agents that modify the coagulation cascade, such as aspirin (page 18, lines 23-30). Thus, the method disclosed by WO ‘835 further administers therapeutic agents, such as aspirin, to the subject upon transplanting the vascular graft (claim 8), as well as pretreats the vascular graft with growth factors and immune modulating agents prior to transplantation. Given the vascular grafts are transplanted to humans to restore blood flow, the therapeutic agents are considered to be provided in a pharmaceutically accepted carrier. Thus, WO ‘835 meets the limitations of claim 18.
Regarding claim 14 and the limitation “wherein, when the graft is transplanted into the recipient, the graft is reendothelialized by the recipient's endothelial cells”, it is noted claim 14, which depends from claim 13, is directed to a composition per se. Claim 14 is not directed to a method of transplanting and does not positively recite a step of transplanting. Thus, said limitation is interpreted as functional language and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Additionally, “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).” See MPEP 2112.01 (I).
Regarding claim 19, WO ‘835 teaches the tubular grafts comprise outer diameters ranging from about 1 mm to about 25 mm (page 16, lines 14-15), thus the claimed range overlaps the prior art range. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Regarding claim 21, the combined prior art teaches the graft is an aortic graft (See WO ‘835 page 35, lines 11-21).
Regarding claim 23, the combined prior art renders obvious claim 13.
Further, as set forth above at the rejection under 35 USC 112(b), the limitation directed to “wherein following transplantation of the graft in the recipient, blood flow is present through the graft two weeks after transplantation”, is considered to be directed to the intended use of the composition, i.e., transplanted in the recipient to restore blood flow. Such limitations do not further define or limit the composition, per se. Compositions are defined by their physical, structural, and chemical properties, not by an intended use or application. Please note that it is well settled that “intended use” of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In re Hack 114, USPQ 161. See MPEP 2111.02
Regarding claim 24 and the limitation “wherein the TSP-null ECM producing cells are in contact with the lumen for about 7 days”, it is noted as set forth above at the rejection under 35 USC 112, said limitation is directed to the manner by which the vascular graft has been produced thus depositing/coating TSP2-null ECM on the lumen of the vascular graft, and does not require the presence of cells. Thus, a non-thrombogenic vascular graft comprising a lumen and exogenous cell-derived ECM lacking TSP2 (i.e., TSP2-null ECM), wherein the cells used for depositing the ECM are no longer on the vascular graft, would appear to read on the claimed vascular graft.
As such, claim 24 does not further limit parent claim 13 and is thus included in the rejection of claim 13.
The combined prior art teaches the anti-thrombotic agent is disposed on the lumen of the tubular vascular graft.
Claim(s) 22 is rejected under 35 U.S.C. 103 as being unpatentable over Calabro, in view of WO ‘835, as applied to claims 13-14, 18-19, 21 and 23-24 above, and further in view of Funamoto et al., (Biomaterials, Vol. 31, Issue 13, May 2010, pages 3590-3595; previously cited) (“Funamoto”).
The teaching of Calabro, in view of WO ‘835 is set forth above.
Regarding claim 22, it is noted that, although WO ‘835 teaches the vascular graft is a decellularized rat aorta, WO ‘835 does not further teach preparing the decellularized aortas from pigs. However, Funamoto is directed to preparing decellularized vascular grafts from pig aortas for subsequent transplantation as a vascular graft (Abstract; 2.3 Preparation of decellularized aortic scaffold by detergent treatment, page 3591; 2.4.4 Xeno-transplantation (pig to rat), page 3591; Fig. 3 and Fig. 6). Thus, Funamoto has established it was known in the art that decellularized pig aortas are useful as vascular grafts.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute decellularized pig aortas for the decellularized rat aortas since both types of decellularized aortas are known to be useful as vascular grafts. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of decellularized aorta for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Response to Remarks
Rejections under 35 USC 103:
Applicant has argued that the cited prior art is distinct from the claimed invention where the claims recite a graft modified by contacting its lumen with live cells that produce and deposit the TSP-null ECM onto the lumen (Remarks, pages 6-8).
As to Applicant’s remarks regarding the newly amended limitation directed to the manner by which the vascular graft has been produced to comprise TSP2-null ECM on the lumen of the vascular graft, it is noted that Applicant’s remarks have been fully considered, but are not found persuasive for the reasons set forth above at the rejections under 35 USC 112 and 35 USC 103.
As currently written, claims 13 and 24 do not require the presence of ECM producing cells or that the ECM has been deposited by ECM producing cells. Claims 13 and 24 as currently written do not exclude the TSP2-null ECM has been lyophilized, grinded or formulated as a hydrogel. Claims 13 and 24 are directed to a composition, per se, and compositions are defined by their physical, structural, and chemical properties. As set forth above, a non-thrombogenic vascular graft comprising a lumen and exogenous ECM lacking TSP2 (i.e., TSP2-null ECM), would read on the claimed vascular graft.
Conclusion
No claim is allowed. No claim is free of the prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633