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 .
The preliminary amendment of 12/29/2023 has been received and entered into the application file. Claims 28-37 are pending, all of which have been considered on the merits.
Priority
Acknowledgement is made of Applicants’ claim for benefit under 35 USC 121 as a divisional of prior-filed US Application No. 17/411718 (filed 10/14/2025, now US Patent 12440603), which claims benefit of prior-filed US Provisional Application No. 63/071635 (filed 8/28/2020).
Claim Interpretation
The following definitions from the specification are highlighted:
The term “substantially free of a protein” is defined as the tissue (treated tissue) comprising less than about 0.1 nmol/g of the protein, based on the mass of the respective tissue (treated tissue) or graft (See ¶0026 of PGPub).
Claims 28 and 30 recite collagen chains, however a variety of different formats are used, e.g. collagen I alpha-1 chain, collagen alpha-2(I) chain, etc. It is understood that all species are describing collagen, type, subunit. That is, “collagen I alpha-1 chain” is referring to collagen, type I, subunit alpha I. It is recommended to synchronize the species to all use the same format for consistency.
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 29 is 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 29: There is insufficient antecedent basis for “the nerve graft” in line 1. Parent claim 28 only describes a tissue graft.
Note: If claim 29 should be interpreted as further limiting the tissue graft to be a nerve graft, then claim 29 would be a duplicate of claim 37.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following rejection is made for the interpretation that use of “nerve graft” was in error in claim 29, and it should be interpreted as referring to the “tissue graft” of claim 28:
Claim 29 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 29: When interpreting claim 29 as replacing “nerve graft” with “tissue graft” in line 1, then claim 29 does not further limit parent claim 28. Parent claim 28 requires the tissue graft to be substantially free of one or more of the same proteins.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 28-31 and 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wolfinbarger, Jr (US 2003/0219417).
Wolfinbarger, Jr teaches a device and process for recellularizing and reendothelializing an essentially acellular or devitalized graft, specifically vascular grafts, for use in replacement of defective tissues (See ¶0009). Wolfinbarger, Jr disclose a 14-step method (¶0010-0023). Based on the method of production, the resulting graft is considered to be: devoid of endogenous cells and basement membrane, but contains exogenous fibroblasts and endothelial cells as well as exogenous collagen matrix. Steps 5 (¶0014), 7 (¶0016), and 9 (¶0018) are particularly relevant to defining the end product: Step 5 involves debriding the basement membrane using proteolytic enzymes to achieve total or partial removal of the basement membrane lining the luminal surface of the acellular graft. Wolfinbarger, Jr expand on this step in ¶0044. Step 7 involves seeding the recellularized graft with a fibroblast cell population (See step 7, ¶0016). More details are on step 7 are provided at ¶0046-0048). Step 9 involves seeding the recellularized graft with an endothelial cell population using a collagenous mixture containing endothelial cells (See step 9, ¶0018). More details on step 9 are provided at ¶0049-0050. Specifically, the endothelial cells are provided in a collagenous/non-collagenous solution that can contain collagen types IV, I, II, V, VII and X.
Regarding claim 28: The graft produced by the method of Wolfinbarger, Jr et al reads on a tissue graft. Noting that the method of production comprises (specifically at step 5) debriding the basement membrane using proteolytic enzymes to achieve, inter alia, total removal of the basement membrane. The proteins recited in lines 2-5 of claim 28 are basement membrane proteins. Thus, the tissue graft produced by Wolfinbarger, Jr will necessarily be free of each of these proteins.
The method further comprises (specifically at step 8) seeding the recellularized graft with an endothelial cell population using a collagenous mixture containing endothelial cells. The endothelial cells are provided in a collagenous/non-collagenous solution that can contain collagen types IV, I, II, V, VII and X. It is submitted that providing, inter alia, collagen types I and V to the tissue graft, the tissue graft will ultimately contain collagen types I and V (including all subunits thereof, including collagen type I alpha-1 chain, collagen type I alpha-2 chain, collagen type V alpha-3 chain, collagen type V alpha-1 chain).
Regarding claim 29: The following rejection is made for the interpretation that use of “nerve graft” was in error in claim 29, and it should be interpreted as referring to the “tissue graft” of claim 28: For the reasons set forth above, the graft of Wolfinbarger, Jr is free of basement membrane proteins.
Regarding claim 30: Following the discussion of claim 28 above, while Wolfinbarger, Jr et al does not quantify the final amount of collagen, given that Wolfinbarger, Jr et al deliver the endothelial cells in collagenous solution comprising collagen type I, and given that collagen type I is the main type of protein found in extracellular matrix (i.e. the native retained ECM of the vascular graft), there is a reasonable basis to conclude that the final graft comprises at least 0.1 nmol/g of all subunits of collagen type I.
Regarding claim 31: Following the discussion of claim 28 above, in preparation step 3, Wolfinbarger, Jr teaches the acellular graft can be treated with, inter alia, hyaluronins (which are glycosaminoglycans). Thus the resulting graft will further comprise glycosaminoglycans.
Regarding claim 35: Wolfinbarger, Jr et al teach the tissue graft can comprise, inter alia, small vein or artery grafts, which have inner diameters of 3-6 mm (See ¶0038). These species fall within the size range of having a diameter of about 1 mm to about 10 mm.
Claims 28-30, and 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Archibald et al (J Neuroscience, 1995).
Archibald et al discloses nerve guides conduits fabricated from highly purified type I collagen from bovine deep flexor tendon (See Pg 4110, “Surgery”).
Regarding claims 28, 29 and 37: The type I collagen nerve guide reads on a tissue graft, and specifically a nerve graft. As the graft is purified type I collagen, the graft is free of the basement membrane proteins recited in lines 2-6 of claim 1 (and in claim 29). The graft contains type I collagen, and thus all the subunits of type I collagen, including collagen I alpha-1 chain, and collagen alpha-2(I) chain.
Regarding claim 30: Following the discussion of claim 28 above, while Archibald et al does not quantify the final amount of type I collagen, given that the nerve graft is made completely of collagen type I, there is a reasonable basis to conclude that the final graft comprises at least 0.1 nmol/g of all subunits of collagen type I.
Claims 28-31, 33, and 35-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al (J Bone Joint Surg Am, 2012), evidenced by Yannas et al (PNAS, 1989).
Lee et al discloses nerve guides conduits fabricated from highly purified type I collagen from bovine deep flexor tendon (See Pg 2085 “Fabrication of collagen…”). Lee et al teach the collagen-GAG matrix ‘was prepared according to a process similar to Yannas et al.’ (See Lee et al, Pg 2085, “Fabrication of Collagen…”). Yannas et al teaches type I collagen and chondroitin 6-sulfate (See Yannas et al, Pg 933, “Preparation of CG Copolymers”). Thus the collagen-GAG matrix of Lee et al includes collagen type I and chondroitin 6-sulfate.
Regarding claims 28, 29 and 37: The type I collagen nerve guide reads on a tissue graft, and specifically a nerve graft. As the graft is purified type I collagen, the graft is free of the basement membrane proteins recited in lines 2-6 of claim 1 (and in claim 29). The graft contains type I collagen, and thus all the subunits of type I collagen, including collagen I alpha-1 chain, and collagen alpha-2(I) chain.
Regarding claim 30: Following the discussion of claim 28 above, while Lee et al does not quantify the final amount of collagen, given that Lee et al teach the nerve conduit is purified Type I collagen, and it is filled with a combination of type I collagen and chondroitin sulfate, there is a reasonable basis to conclude that the final graft comprises at least 0.1 nmol/g of all subunits of collagen type I.
Regarding claims 31 and 33: Following the discussion of claim 28 above, the nerve graft further comprises chondroitin 6-sulfate (a glycosaminoglycan).
Regarding claim 35: Following the discussion of claim 28 above, Lee et al teaches the nerve grafts have an inner diameter of 1.5 mm, which is within the claimed range.
Regarding claim 36: Following the discussion of claim 35 above, Lee et al teach 12 mm lengths of the nerve conduit were used (See Pg. 2085 “Surgical Procedures”). At a diameter of 1.5 mm, and a length of 12 mm, the conduit has a volume of approximately 21mm3, which is within the claimed range.
Claim Rejections - 35 USC § 103
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 28-31, 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Wolfinbarger, Jr et al (US 2003/0219417).
The teachings of Wolfinbarger, Jr et al are set forth above.
Regarding claim 36: Wolfinbarger, Jr et al does not teach the volume of the tissue graft. However, they do teach the tissue grafts can be small vein or artery grafts, with internal diameter of 3-6 mm, or large pulmonary or aortic valves with diameters of 28-35 mm (See ¶0038). While the volume will depend on the length and thickness of the grafts, production of version of each grafts having volumes within the claimed range of 5 to 55,000 mm3 are considered to be prima facie obvious. The length of the grafts would be dependent on downstream application. Grafts of several millimeters in length would have been reasonably appropriate for valve tissue replacements, and given the diameters, there is a reasonable basis to conclude the volume would fall within the claimed range.
Claims 28-30 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Archibald et al (J Neuroscience, 1995).
The teachings of Archibald et al are set forth above.
Regarding claim 35: Following the discussion of claim 28 above, Archibald et al does not teach the exact size of the nerve conduits, but they do state they were used to bridge median nerve gaps of 5 mm, and ulnar nerve gaps of 15 mm (See Pg 4110, “Surgery”). Based on this, there is reasonable basis to conclude that the nerve guide conduits had a length of slightly longer than 5 mm or slightly longer than 15 mm in order to bridge the gaps, respectively. It would have at least been prima facie obvious to have provided nerve grafts having lengths of slightly longer than 5 mm or 15 mm in order to bridge the gaps, but for the grafts to have a length of less than 100 mm because graft conduits with lengths significantly longer than the nerve gap would be problematic to insert, as it would cover substantial portions of healthy nerve. Therefore, selection of nerve graft sizes within the claimed range are considered to have been prima facie obvious. Regarding claim 36: Archibald et al does not teach the volume of the nerve graft conduits. However, for reasons discussed above with regards to claim 35, selection of nerve graft conduits having lengths ranging from slightly longer than 5 mm to slightly longer than 15 mm would have been prima facie obvious. Modification of the lengths to accommodate different nerve gap sizes would also have been prima facie obvious. While the volume will depend on the length and thickness of the grafts, production of version of each grafts having volumes within the claimed range of 5 to 55,000 mm3 are considered to be prima facie obvious.
Claims 28-31 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Archibald et al (J Neuroscience, 1995), in view of Xue et al (Artif Organs, 2016).
The teachings of Archibald et al are set forth above.
Regarding claim 31: Archibald et al does not teach inclusion of a calcium channel blocker in the nerve graft conduit.
Xue et al teach injection of calcium channel blocker verapamil to anastomosed peripheral nerves inhibited scar formation, thereby eliminating hurdles to the nerve repairing process (See Pg 519, col. 2).
Given that Archibald et al and Xue et al are both directed to therapies to restore peripheral nerves following dissection injury, it would have been prima facie obvious to have combined the treatments in order to provide additive therapeutic outcome. Specifically, it would have been prima facie obvious to have included calcium channel blocker verapamil to the nerve graft conduit of Archibald et al. The nerve conduit of Archibald et al would provide physical scaffolding, and the calcium channel blocker therapy reduces scar formation. Both result in nerve repair. There would have been reasonable basis to expect the combination would yield additive effects. This conclusion of obviousness is based on the ‘combining prior art elements according to known methods to yield predictable results’. MPEP 2143(I)(A).
Claims 28-32 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Archibald et al (J Neuroscience, 1995), in view of George et al (Journal of Neuroscience, 1995).
The teachings of Archibald et al are set forth above.
Regarding claims 31 and 32: Archibald et al does not teach inclusion of one of cobalt, manganese, lanthanum or nitrendipine (calcium channel blockers) in the nerve graft conduit.
George et al calcium channel blockers cobalt and manganese are effective to prevent axonal degeneration in axotomized axons (See Pg 6447, “Calcium channel blockers….”).
Given that Archibald et al and George et al are both directed to therapies to restore peripheral nerves following dissection injury, it would have been prima facie obvious to have combined the treatments in order to provide additive therapeutic outcome. Specifically, it would have been prima facie obvious to have included calcium channel blocker cobalt and/or manganese to the nerve graft conduit of Archibald et al. The nerve conduit of Archibald et al would provide physical scaffolding, and the calcium channel blocker therapy would reduce axonal degeneration. Both promote nerve repair. There would have been reasonable basis to expect the combination would yield additive effects. This conclusion of obviousness is based on the ‘combining prior art elements according to known methods to yield predictable results’. MPEP 2143(I)(A).
Claims 28-31 and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over Archibald et al (J Neuroscience, 1995), in view of Tomita et al (Glia, 2007).
The teachings of Archibald et al are set forth above.
Regarding claims 31 and 34: Archibald et al does not teach inclusion of a one or more glycoproteins, wherein the glycoprotein is myelin-associated glycoprotein (MAG) in the nerve graft conduit.
Tomita et al teach that application of MAG enhances functional recovery of transected sciatic nerves (See abstract).
Given that Archibald et al and Tomita et al are both directed to therapies to restore peripheral nerves following dissection injury, it would have been prima facie obvious to have combined the treatments in order to provide additive therapeutic outcome. Specifically, it would have been prima facie obvious to have included glycoprotein MAG to the nerve graft conduit of Archibald et al. The nerve conduit of Archibald et al would provide physical scaffolding, and the MAG therapy improves quality of axonal regeneration and enhances functional recovery. Both result in nerve repair. There would have been reasonable basis to expect the combination would yield additive effects. This conclusion of obviousness is based on the ‘combining prior art elements according to known methods to yield predictable results’. MPEP 2143(I)(A).
Claims 28-31, 33 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (J Bone Joint Surg Am, 2012), evidenced by Yannas et al (PNAS, 1989).
The teachings of Lee et al are set forth above.
Regarding claim 36: Lee et al does not teach the volume of the nerve graft conduits. Lee et al does not teach the exact size of the nerve conduits, but they do state they were used to bridge nerve gaps of 10 mm, and ulnar nerve gaps of 15 mm (See Pg 4110, “Surgery”). Based on this, there is reasonable basis to conclude that the nerve guide conduits had a length of slightly longer than 5 mm or slightly longer than 15 mm in order to bridge the gaps, respectively. It would have at least been prima facie obvious to have provided nerve grafts having lengths of slightly longer than 5 mm or 15 mm in order to bridge the gaps, but for the grafts to have a length of less than 100 mm because graft conduits with lengths significantly longer than the nerve gap would be problematic to insert, as it would cover substantial portions of healthy nerve. Therefore, selection of nerve graft sizes within the claimed range are considered to have been prima facie obvious.
Claims 28-31, 33 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (J Bone Joint Surg Am, 2012), evidenced by Yannas et al (PNAS, 1989), and in view of Xue et al (Artif Organs, 2016).
The teachings of Lee et al are set forth above.
Regarding claim 31: Lee et al does not teach inclusion of a calcium channel blocker in the nerve graft conduit.
Xue et al teach injection of calcium channel blocker verapamil to anastomosed sciatic nerves inhibited scar formation, thereby eliminating hurdles to the nerve repairing process (See Pg 519, col. 2).
Given that Lee et al and Xue et al are both directed to therapies to restore sciatic nerves following dissection injury, it would have been prima facie obvious to have combined the treatments in order to provide additive therapeutic outcome. Specifically, it would have been prima facie obvious to have included calcium channel blocker verapamil to the nerve graft conduit of Lee et al. The nerve conduit of Lee et al would provide physical scaffolding, and the calcium channel blocker therapy reduces scar formation. Both result in nerve repair. There would have been reasonable basis to expect the combination would yield additive effects. This conclusion of obviousness is based on the ‘combining prior art elements according to known methods to yield predictable results’. MPEP 2143(I)(A).
Claims 28-33 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (J Bone Joint Surg Am, 2012), evidenced by Yannas et al (PNAS, 1989), and in view of George et al (J Neuroscience, 1995).
The teachings of Lee et al are set forth above.
Regarding claims 31 and 32: Lee et al does not teach inclusion of one of cobalt, manganese, lanthanum or nitrendipine (calcium channel blockers) in the nerve graft conduit.
George et al calcium channel blockers cobalt and manganese are effective to prevent axonal degeneration in axotomized axons (See Pg 6447, “Calcium channel blockers….”).
Given that Lee et al and George et al are both directed to therapies to restore peripheral nerves following dissection injury, it would have been prima facie obvious to have combined the treatments in order to provide additive therapeutic outcome. Specifically, it would have been prima facie obvious to have included calcium channel blocker cobalt and/or manganese to the nerve graft conduit of Lee et al. The nerve conduit of Lee et al would provide physical scaffolding, and the calcium channel blocker therapy would reduce axonal degeneration. Both promote nerve repair. There would have been reasonable basis to expect the combination would yield additive effects. This conclusion of obviousness is based on the ‘combining prior art elements according to known methods to yield predictable results’. MPEP 2143(I)(A).
Claims 28-31 and 33-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (J Bone Joint Surg Am, 2012), evidenced by Yannas et al (PNAS, 1989), and in view of Tomita et al (Glia, 2007).
The teachings of Lee et al are set forth above.
Regarding claims 31 and 34: Lee et al does not teach inclusion of a one or more glycoproteins, wherein the glycoprotein is myelin-associated glycoprotein (MAG) in the nerve graft conduit.
Tomita et al teach that application of MAG enhances functional recovery of transected sciatic nerves (See abstract).
Given that Lee et al and Tomita et al are both directed to therapies to restore sciatic nerves following dissection injury, it would have been prima facie obvious to have combined the treatments in order to provide additive therapeutic outcome. Specifically, it would have been prima facie obvious to have included glycoprotein MAG to the nerve graft conduit of Lee et al. The nerve conduit of Lee et al would provide physical scaffolding, and the MAG therapy improves quality of axonal regeneration and enhances functional recovery. Both result in nerve repair. There would have been reasonable basis to expect the combination would yield additive effects. This conclusion of obviousness is based on the ‘combining prior art elements according to known methods to yield predictable results’. MPEP 2143(I)(A).
Conclusion
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/ALLISON M FOX/Primary Examiner, Art Unit 1633
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