DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response to restriction requirement filed on March 31, 2026 have been received and entered. Claims 1-15 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-13, and 15 in the reply filed on March 31, 2026 is acknowledged.
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 31, 2026.
Priority
This application is a 371 of PCT/EP2021/072240 filed on 08/10/2021, which claims priority from foreign application DE 10 2020 004 900.1 filed on 08/12/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/04/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 1-13 and 15 are under consideration.
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, 3-7, 9 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over King et al (WO2015152954, dated 08/10/2015, IDS) as evidenced by Sorrell et al (Tissue Engineering Part A, 2009, 15(7), 1751-1761), Melero-Martin et al (WO2012040408, dated 03/29/2012) and Hur ( Arterioscler Thromb Vasc Biol. 2004; 24: 288-293).
Claims are directed for 3D printing autologous pre-vascularized breast tissue constructs comprising the steps of:
Providing a triculture consisting of adipose mesenchymal stem cells, fibroblasts, and endothelial progenitor cells,
Mixing the triculture cells with a bioink composed of biopolymers,
Printing three-dimensional structures of the breast tissue construct using the triculture-added bioink from step (ii),
wherein the cells of the triculture are pretreated with growth media prior to printing so that the endothelial progenitor cells differentiate into endothelial cells and the adipose mesenchymal stem cells differentiate into adipocytes, and wherein the development of vessel-like structures is induced after 3D printing.
Claim interpretation: Regarding Claim 9, recitation of endothelial progenitor cell is obtainable by a process is interpreted as product by process and therefore process to obtain the product is not given any patentable weight (see MPEP2113).
With respect to claims 1, 4-6, 15, King teaches a method for 3D printing breast tissue, said method comprising
providing a stromal tissue comprising of mesenchymal stem cells, mammary fibroblast and endothelial cells, wherein adipose mesenchymal stem cells differentiate into adipocytes prior to bio-printing (example 4), wherein the cell culture media comprises soluble components that support the growth, maintenance, or differentiation of human fibroblasts, human endothelial cells, adipocyte (see para. 108, claim 12, 25 of ‘954);
printing the bio-ink comprising an extrusion compound or a polymer and plurality of the cells of step (i) in cell culture media to allow the cells to cohere to form the three-dimensional, engineered, biological breast tissue (see para. 108), wherein the extrusion compound comprises a bio-polymer such as an alginate or collagen (see para. 79-82, claim 12, 14 of ‘954). It is further disclosed that during the bioprinting process, robust microvascular networks is created using endothelial cells as a component of the three-dimensional breast tissue design (see para. 7). The tri culturing of MSC, endothelial cells and fibroblast is known to result in a tube-like structure as evident from the teaching of Sorrell (see fig. 3A, page 1755 col. 2, para. 2).
Regarding claim 3, King teaches that 3D printing could be accomplished by a continuous bioprinting method is to dispense bio-ink from a bioprinter via capillary tube, connected to a reservoir of bio-ink (see para. 68).
King differs from claimed invention by not disclosing providing EPC as part of triculture in presence of growth medium that differentiate into a differentiated endothelial cell prior to bioprinting (claims 1, 5) or EPCs are late endothelial progenitor cells from the patient's blood (claim 8).
Before the effective filing date of instant application, Melero-Martin teaches a composition comprising an enriched population of isolated EPCs and an enriched population of isolated mesenchymal progenitor cells, wherein the EPCs and MPCs induce the formation of new blood vessels with functional connections to the subject's vasculature and the formation of new adipose tissue (see para. 215). It is further disclosed that other cell type may include fibroblast cells (see para. 215). Melero-Martin teaches autologous human blood-derived endothelial progenitor cells (EPCs) and bone marrow derived mesenchymal progenitor cells (bmMPCs) or adipose tissue derived mesenchymal progenitor cells (watMPCs) (see para. 5).
EPC are subcultured on 1 % gelatin-coated tissue culture plates using ECFC-medium: EGM-2
supplemented with 20% PBS (see para. 271). It is further disclosed that EPC have the ability to expand and differentiate into ECs, the cells that make up the inner lining of blood vessels, and are known to participate in both vasculogenesis and vascular homeostasis (para. 168) (limitation of claims 7-9). The combination of references differs from claimed invention by not disclosing EPCs are late EPCs.
Hur cures the deficiency by isolating early and late EPC from human peripheral blood
from the same donors (abstract). It is further disclosed that late EPC produced more nitric oxide, incorporated more readily into human umbilical vein endothelial cells monolayer, and formed capillary tube better than early EPC (see abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of King by substituting the endothelial cells in triculture with EPC as disclosed in Melero-Martin, prior to printing triculture-added bioink in the method for 3D printing of autologous pre vascularized breast tissue construct, as instantly claimed, with a reasonable expectation of success, before the effective filing date instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use late EPC because prior explicitly reported these produced more nitric oxide, incorporated more readily into human umbilical vein endothelial cells monolayer, and formed capillary tube better than early EPC . One of skill in the art would have been expected to have a reasonable expectation of success because prior art teaches EPC along with MSC are capable of differentiating into EC, adipocytes that are known to participate in both vasculogenesis and vascular homeostasis within breast tissue. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 1, 7 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over King et al (WO2015152954, dated 08/10/2015), Sorrell et al (Tissue Engineering Part A, 2009, 15(7), 1751-1761), Melero-Martin et al (WO2012040408, dated 03/29/2012), Hur ( Arterioscler Thromb Vasc Biol. 2004; 24: 288-293) as applied above and further in view of Miranville (Circulation. 2004;110:349-355).
The teaching of King, Sorrell, Melero-Martin and Hur have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing MSC characterized in that the adipose mesenchymal stem cells are selected from a present adipose tissue sample of the patient by anti-CD34 coupled magnetic beads.
However, before the effective filing date of instant invention, Miranville teaches isolating adipose mesenchymal stem cells from an adipose tissue from a subject undergoing plastic surgery. Miranville teaches isolation of CD34-positive cells (CD34+) from the SVF by use of CD34-coupled magnetic microbeads (see page 350, col. 1, para. 2 and 3).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of providing adipose MSC in triculture as disclosed in King by isolating said cells from adipose tissue of the patient by using anti-CD34 coupled magnetic beads as disclosed in Miranville, prior to printing triculture-added bioink in the method for 3D printing of autologous pre vascularized breast tissue construct, as instantly claimed, with a reasonable expectation of success, before the effective filing date instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because method results in isolation of cell population from adipose tissue that could be used for therapeutic purpose to improve neovascularization. One of skill in the art would have been expected to have a reasonable expectation of success because prior art reported successful isolation of adipose MSC using anti-CD34 coupled magnetic beads as evident from the teaching of Miranville . It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 1, 10 are rejected under 35 U.S.C. 103 as being unpatentable over King et al (WO2015152954, dated 08/10/2015), Sorrell et al (Tissue Engineering Part A, 2009, 15(7), 1751-1761), Melero-Martin et al (WO2012040408, dated 03/29/2012), Hur (Arterioscler Thromb Vasc Biol. 2004; 24: 288-293) as applied above and further in view of Chun et al (Tissue Eng Regen Med 2019;16(4):385–393).
The teaching of King, Sorrell, Melero-Martin and Hur have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing that the bioink is contained in a composition comprising self-extracted extracellular matrix from adipose tissue (adECM).
Chun cures the deficiency by disclosing isolating extracellular matrix (ECM) from adipose tissue (see abstract). It is disclosed that human adipose-derived ECM is superior in terms of bio compatibility, biodegradability, and/or bioinductivity because it has lower immunogenicity and is less likely to transmit pathogens during clinical application (see page 388, col. 1, last para.). Chun further teaches that the adipose ECM graft could maintain volume, structure, strength, and/or stiffness, which pro moted mechanical support, cell shape/function stability, the transport of chemical signals, angiogenesis, and vascularization of the graft (see page 388, col. 2, para. 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method as disclosed in King by substituting the bioink comprising alginate/collagen with another self-extracted ECM from adipose tissue as disclosed in Chun, prior to printing triculture-added bioink in the method for 3D printing of autologous pre vascularized breast tissue construct, as instantly claimed, with a reasonable expectation of success, before the effective filing date instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because human adipose-derived ECM is superior in terms of bio compatibility, biodegradability, and/or bioinductivity because it has lower immunogenicity (see above). One of skill in the art would have been expected to have a reasonable expectation of success because prior art reported successful isolation ECM from adipose tissue to improve vessel development as evident from the teaching of Chun. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 1, 7 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over King et al (WO2015152954, dated 08/10/2015), Sorrell et al (Tissue Engineering Part A, 2009, 15(7), 1751-1761), Melero-Martin et al (WO2012040408, dated 03/29/2012), Hur (Arterioscler Thromb Vasc Biol. 2004; 24: 288-293) as applied above and further in view of Patil (Journal of Oral and Maxillofacial Pathology, 2020, 68-75).
The teaching of King, Sorrell, Melero-Martin and Hur have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing fibroblasts are from an oral mucosa sample of the patient.
However, before the effective filing date of instant invention, Patil teaches isolating human buccal mucosal fibroblasts from an oral mucosal sample of a subject (see page 69, col. 2, last para).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of providing fibroblast cells in triculture as disclosed in King by isolating said fibroblast cells from an oral mucosa sample as disclosed in Patil, prior to printing triculture-added bioink in the method for 3D printing of autologous pre vascularized breast tissue construct, as instantly claimed, with a reasonable expectation of success, before the effective filing date instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because method would allow use of established protocol to isolate fibroblast cells from autologous patient in need thereof. One of skill in the art would have been expected to have a reasonable expectation of success because prior art reported successful isolation of fibroblast from an oral mucosa sample of the patient as evident from the teaching of Patil . It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 1, 2, 6 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over King et al (WO2015152954, dated 08/10/2015), Sorrell et al (Tissue Engineering Part A, 2009, 15(7), 1751-1761), Melero-Martin et al (WO2012040408, dated 03/29/2012), Hur ( Arterioscler Thromb Vasc Biol. 2004; 24: 288-293) as applied above and further in view of Gettler,(Tissue Engineering, Part C, 2017, 23, 516-524)/Barrs (Chem. Rev. 2020, 120, 10887−10949).
The teaching of King, Sorrell, Melero-Martin and Hur have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing that the development of vessel-like structures after 3D printing is induced with collagen I.
Gettler teaches development of vessel-like structures after 3D printing that is induced with collagen I. reported using three-dimensional bioprinting technology to evaluate the ability to form SVF cell-laden spheroids comprising endothelial cells with collagen I as a gel-forming biomatrix that maintained viability of the cells that undergo a time-dependent contraction with the retention of angiogenic sprout phenotype (see abstract, fig. 6D,E). Likewise, Barrs teaches printing the aggregates EC they were placed in a glass capillary so that spheroids are densely packed at the tip and could be deposited sequentially into a collagen I substrate (see page 10902, col. 1, para. 2, fig. 12A-C).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of King by substituting the endothelial cells in triculture with endothelial cells that are cultured as spheroids prior to printing and activated by collagen I as suggested in Gettler/ Barrs, prior to printing triculture-added bioink in the method for 3D printing of autologous pre vascularized breast tissue construct, as instantly claimed, with a reasonable expectation of success, before the effective filing date instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art reported collagen I may stimulate angiogenesis by binding endothelial cell-surface integrins α1β1 and α2β2 via the GFPGER sequence of the collagen fibril and collagen I activates Src and Rho to initiate capillary morphogenesis in ECs (see page 10904, col. 1, para. 3). One of skill in the art would have been expected to have a reasonable expectation of success because prior art teaches use of collagen 1 to activate capillary morphogenesis in ECs as evident from the teaching of Barrs/ Gettler. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
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 2-13 and 15 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 pre-AIA the applicant regards as the invention.
Claims 2-13 and 15 are vague and unclear. Each claim recites that the method is “characterized in….” when further limiting the method steps set forth in claim 1. However, it is not clear if each of the limitation in claims 2-13 and 15 require the specific components collagen 1, channel system, differentiated cells, specific bioink parent cell, origin or cells source of cells in the claims. The term “characterized in” is broad and does not make clear that the method steps are limited to the specific limitations in claim 2-13 and 15. Appropriate correction is required.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
Prosecution Insights