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 filed 2/3/2023 has been received and entered into the application file. Claims 1, 12, 13, 16-22 and 37-41 are pending, all of which have been considered on the merits.
Priority
Acknowledgement is made of the instant application being a continuation of prior-filed application 14/890251 (filed 11/10/2015, now US Patent 11446331), which is a national stage entry under 35 USC 371 of PCT/US2014/037435 (Filed 5/9/2014), which claims benefit of US Provisional application 61/822134 (filed 5/10/2013).
Claim Interpretation
Claim 1 is to a wound healing biological scaffold. The adjective wound healing is being treated as an intended use limitation. The only specific physical or chemical structure or property that is required to be considered appropriate as wound healing biological scaffold is that the scaffold is physically sized to be applied to a wound. The biological tissue scaffold of claim 1 is interpreted as being a scaffold seeded with ABCB5+ stem cells, wherein the scaffold is a porous matrix of cross-linked collagen and glycosaminoglycans, and wherein the scaffold includes a separate semi-permeable layer (i.e. in addition to the cross-linked collagen and glycosaminoglycans). At least 90% of the cells present in the scaffold must be ABCB5+ stem cells. It is noted that there are multiple types of ABCB5+ stem cells, for example, ABCB5+ mesenchymal stem cells, ABCB5+ ocular stem cells, etc. Not all stem cells are ABCB5+, not all ABCB5+ cells are stem cells.
Claim Objection
Claim 1 is objected to for a minor informality: In lines 2-3, it should read “cross-linked collagen and glycosaminoglycan”. Correction is required.
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 22 and 40 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 22: The recitation of the area in centimeters in parenthesis render the claim indefinite. The area in cm2 in parenthesis do not exactly correlate with the area in in2 presented within the claim. Thus it is unclear if the claim is to be limited to the area in in2 or the area in cm2. Correction is required.
Regarding claim 40: There is insufficient antecedent basis for the limitation “the population of stem cells” in line 1. Claim 1, as currently amended requires that at least 90% of the total cells present in the scaffold are ABCB5+ stem cells. It is unclear if claim 40 is attempting to further limit this percentage to at least 95%, or if it is attempting to limit an overall stem cell population within the tissue scaffold.
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 1, 12, 13, 16-22, 37 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Bartholomew et al (US 2013/0017175), in view of Frank et al (US 2008/0003206), evidenced by Taupin et al (Cureus, 2023) and Integra Product Sheet, 2025).
Bartholomew et al disclose use of bone marrow-derived mesenchymal stem cells in wound healing (See abstract). Bartholomew et al teach that activated mesenchymal stem cells and Integra scaffold synergize to ameliorate early perfusion and angiogenesis of diabetic wounds (See ¶0055-0026). Integra™ is described as a bilayered membrane system consisting of a silicone top and a layer made of collagen type I and choroitin-6-sulphate (See ¶0149).
Bartholomew et al disclose a diabetic wound healing model wherein wounds were treated with, inter alia, Integra scaffold with non-activated BM-MSCs or Integra scaffold with interferon gamma-activated BM-MSCs. The cells were seeded onto the scaffold in culture medium (See ¶0144-0157). Bartholomew et al report the wounds were successfully covered with the MSC-seeded Integra scaffolds (See Fig. 16 & 17, ¶0053-0054), and both cell-seeded varieties resulted in increased perfusion over the control (See Fig. 18C, ¶0055). Bartholomew et al also report that VEGF was present within the cell-seeded scaffolds (See Fig. 19, ¶0056).
The scaffold of Bartholomew et al is comparable to the instant claims as follows:
Regarding claims 1, 39 and 40: The Integra scaffold used by Bartholomew et al is the same scaffold used in the instant application. Taupin et al provide evidence Integra® is a bi-layer meshed scaffold that contains a silicon top layer (that reads on a separate semi-permeable layer) and a layer of crosslinked collagen type I from bovine tendon and chondroitin-6-sulfate (See Taupin et al, abstract). Thus, Integra scaffold meets the limitations of a porous matrix of cross-linked collagen and glycosaminoglycan scaffold, and wherein the scaffold includes a separate semi-permeable layer. The bone marrow derived MSCs (both activated and non-activated) read on stem cells. The cell-seeded scaffold is applicable to wounds, thus it reads on a wound healing biological tissue scaffold.
The method of Bartholomew et al differs from the instant claims in that Bartholomew et al disclose use of bone marrow-derived MSCs, not ABCB5+ dermal MSCs. Bartholomew et al teach that MSCs from different sources can be used in their method (See Bartholomew et al, ¶0031).
Frank et al disclose ABCB5+ dermal MSCs, which reads on ABCB5+ dermal MSCs. Frank et al specifically teaches that the ABCB5+ dermal MSCs show similar differentiation capacity and nearly identical profile with respect to surface markers as BM-MSCs (See Frank et al, ¶0032). Frank et al says “The [ABCB5+ dermal mesenchymal] stem cells may be used for any purpose that mesenchymal stem cells from other sources [sic: courses] are used.” (Frank et al, abstract). Frank et al disclose the skin-derived ABCB5+ MSCs may be more desirable for therapeutic use due to their accessibility (skin being easier to harvest than bone marrow) and greater immunomodulatory properties (See Frank et al, ¶0003 and 0032).
Given that both Bartholomew et al and Frank et al teach MSCs, it would have been prima facie obvious to have modified the method of Bartholomew et al to substitute the ABCB5+ dermal MSCs of Frank et al for the bone marrow-derived MSCs in the scaffold. There would have been reasonable expectation that substitution of the ABCB5+ dermal MSCs for the bone marrow MSCs of Bartholomew et al would have yielded predictable results because Frank et al teach that ABCB5+ dermal MSCs can be used in place of MSCs of other origins and because Bartholomew et al state that MSCs from other origins can be used in place of the bone marrow-MSCs. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Bartholomew et al teach use of homogeneous populations of bone marrow-derived MSCs, thus it would have been prima facie obvious to have used a pure, or substantially pure, population of ABCB5+ dermal MSCs (from Frank et al) as well. Frank et al teach means to obtain 99% pure ABCB5+ dermal mesenchymal stem cell populations (See Frank et al ¶0041).
Therefore, the scaffold of claims 1, 39 and 40 are considered prima facie obvious over Bartholomew et al in view of Frank et al.
Regarding claims 12, 13, 15, 17, 18, 19 and 41: The Integra® matrix meets the limitations of these claims. Taupin et al provide evidence that Integra® matrix has pore sizes from 70-200 µm (See Taupin et al, Pg 2 “Porosity:…”).
Regarding claim 22: Bartholomew et al does not disclose the size of the Integra® matrix they use. However, selection of a matrix within the claimed sizes would have been prima facie obvious. Differences in size, where the size does not affect the operation of the device, do not support patentability. “[W]here the only difference between the prior art and the claims was a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device, the claimed device was not patentably distinct from the prior art device.” See MPEP 2144.04(IV)(A). Furthermore, it is noted that the recited sizes are the commercially available sizes of Integra® matrix (See Integra Product Sheet at Pg 4).
Regarding claims 20 and 21: The culture medium in which the cells are provided and/or the VEGF reported to be present in the matrix of Bartholomew et al both read on one or more bioactive molecules effective to enhance wound healing, specifically growth factors, in the scaffold.
Regarding claims 37: Following the discussion of claim 1 above, it has been established that it would have been prima facie obvious to have used a pure, or substantially pure, population of ABCB5+ dermal MSCs from Frank et al in the scaffold of Bartholomew et al. Using 99% ABCB5+ dermal stem cells would mean there are less than 5% of any other cell type present in the scaffold.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 12, 13, 16-22 and 37-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11446331.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render the instant claims obvious.
The patented method involves making, and then implanting a cell-seeded scaffold. The cell-seeded scaffold produced by and then implanted via the patented methods anticipates the wound healing biological tissue scaffold of the instant claims. Thus, the patented method is considered to at least render obvious the currently claimed product because the patented claim method yields and uses the currently claimed product.
Regarding claims 1, 37 and 40: Patented claim 1 produces a biological tissue scaffold comprising ABCB5+ stem cells seeded on a scaffold comprising a porous matrix of cross-linked collagen and glycosaminoglycan, and wherein the scaffold includes a separate semi-permeable layer. Patented claim 1 states at least 99% of the total cells present in the scaffold are ABCB5+ stem cells.
Regarding claim 12: Patented claim 6 states the semi-permeable membrane is silicone.
Regarding claim 13: Patented claim 7 states the scaffold is meshed.
Regarding claims 16-18: Patented claims 8-10 disclose the pore sizes of the instant claims.
Regarding claim 19: Patented claim 4 discloses the same glycosaminoglycans claimed.
Regarding claims 20-21: The patented claims do not specifically teach inclusion of additional active ingredients, however inclusion of additional active ingredients effective to promote tissue regeneration would have been prima facie obvious to one having ordinary skill in the art. The various active agents disclosed in current claim 21 are well-known examples of bioactive agents that would have been expected to provide additive regenerative effects.
Regarding claim 22: Differences in size, where the size does not affect the operation of the device, do not support patentability. “[W]here the only difference between the prior art and the claims was a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device, the claimed device was not patentably distinct from the prior art device.” See MPEP 2144.04(IV)(A).
Regarding claim 38: Patented claim 3 states the ABCB5+ stem cells are ocular stem cells.
Regarding claim 39: Patented claim 4 states the ABCB5+ stem cells are dermal MSCs.
Regarding claim 41: Patented claim 5 states the collagen is bovine tendon collagen.
Claims 1, 12, 13, 16-22, 37 and 39-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-6 of U.S. Patent No. 11624051 in view of Bartholomew et al (US 2013/0017175), evidenced by Taupin et al (Cureus, 2023) and Integra Product Sheet, 2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims render obvious the instant claims as follows: Regarding claims 1, 12, 13, 16-19, 39, and 41: Patented claim 2 recites a method for promoting tissue regeneration, specifically regeneration of skin tissue, comprising…administering to a subject ABCB5+ dermal MSCs seeded onto a matrix or scaffold.
The patented claims are comparable to the instant claims in that they disclose use of an ABCB5+ dermal MSC-seeded scaffold which is similar to that currently claimed. Patented claims disclosing use of a product at least render obvious said product. The patented claims differ in that they do not specifically recite a collagen and glycosaminoglycan scaffold that includes a separate semi-permeable layer.
However, Bartholomew et al teach that Integra™ wound dressing is particularly well suited for seeding with MSCs for wound repair (See ¶0025-0026). Integra ™ wound dressing meets the limitations of the current claims regarding the scaffold composition and physical structure. (Taupin et al provide evidence that Integra® matrix has pore sizes from 70-200 µm (See Taupin et al, Pg 2 “Porosity:…”) and contains collagen from bovine tendon and chondroitin-6-sulfate (See Taupin et al, abstract); Integra Product sheet evidences that the Integra™ product was available in the sizes required by claim 22).
Because the patented claims are intending to treat skin defects, it would have been prima facie obvious to have selected the Integra scaffold of Bartholomew et al as the particular scaffold material for use in the patented method. One would have been motivated to make this selection based on the showing of success in Bartholomew et al using Integra. One would have had a reasonable expectation of successfully using the Integra™ matrix of Bartholomew et al in the method of the patented claims because Bartholomew et al show that Integra™ matrix supports MSCs and can be applied to skin defects.
Regarding claims 20-21: The patented claims do not specifically teach inclusion of additional active ingredients, however inclusion of additional active ingredients effective to promote tissue regeneration would have been prima facie obvious to one having ordinary skill in the art. The various active agents disclosed in current claim 21 are well-known examples of bioactive agents that would have been expected to provide additive regenerative effects.
Regarding claims 37 and 40: The patented claims state that at least 95% of the ABCB5+ dermal MSCs are ABCB5+ dermal MSCs. This appears to be a typographical error for “at least 95% of the cells are ABCB5+ dermal MSCs. However, even if not, it would have been prima facie obvious to use an ABCB5+ dermal MSC population that is at least 95% ABCB5+ dermal MSCs in order to optimize the active cell type. This would leave less than 5% of cells being any other cell type.
Claims 1, 12, 13, 16-22, 37 and 39-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9 and 11 of copending Application No. 18/120301 in view of Bartholomew et al (US 2013/0017175), evidenced by Taupin et al (Cureus, 2023) and Integra Product Sheet, 2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims render obvious the instant claims as follows: Regarding claims 1, 12, 13, 16-19, 37, 39, 40 and 41: Copending claim 9 recites a matrix seeded with a population of ABCB5+ dermal MSCs. Copending claim 11 states the matrix is a collagen matrix.
The copending claims are comparable to the instant claims in that they disclose an ABCB5+ dermal MSC-seeded scaffold which is similar to that currently claimed. The copending claims differ in that (1) they do not specifically recite a collagen and glycosaminoglycan scaffold that includes a separate semi-permeable layer, and (2) they do not teach the purity of the ABCB5+ dermal MSCs provided to the scaffold.
Regarding (1): Bartholomew et al teach that Integra™ wound dressing is a well-suited substrate for supporting growth of MSCs (See ¶0025-0026). Integra ™ wound dressing meets the limitations of the current claims regarding the scaffold composition and physical structure. (Taupin et al provide evidence that Integra® matrix has pore sizes from 70-200 µm (See Taupin et al, Pg 2 “Porosity:…”) and contains collagen from bovine tendon and chondroitin-6-sulfate (See Taupin et al, abstract); Integra Product sheet evidences that the Integra™ product was available in the sizes required by claim 22).
Given that the generic scaffold of the copending claims and the specific Integra™ scaffold are taught to support MSCs, it would have been prima facie obvious to have substituted one for the other with a reasonable expectation of success. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding (2): It would have been prima facie obvious to use an ABCB5+ dermal MSC population that is at least 95% ABCB5+ dermal MSCs in order to optimize the active cell type. This would leave less than 5% of cells being any other cell type.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/ALLISON M FOX/Primary Examiner, Art Unit 1633