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 .
Detailed Action
Previous Rejections
Applicants' arguments, filed 02/25/26, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112 (d)
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.
Claim 19 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.
Claim 19 recites the amount “approximately 10 percent weight by volume of the gelatin methacrylate, which can be interpreted as any amount close to 10 or less than 10 and claim 18 recites the amount to be 10-15 percent weight by volume. Thus, the amount is not further limiting. 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 § 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 1-2, 5-7 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bagley et al. (WO 2018/071639 A1, presented in IDS) in view of Gaharwar et al. (WO 2018/169965A1) and further in view of Shoseyov et al. (US PG Pub. 2020/0179562A).
Bagley et al. disclose an objective to overcome previous shortcomings with 3D printing of tissues by providing bioinks made entirely or predominantly of collagen. Bagley et al. discloses the crosslinking of collagen with LAP (lithium phenyl-2, 4,6-trimethyloenzoylphosphinate, [0080]), whereas in addition example 4 points to 3d printing of a mixture of collagen and gelatin methacrylate, see title, abstract, [0031-34]. The reference teaches that in the bioinks of the present invention, cells behave more like they do naturally in the body. The cells within the bioink can remodel the scaffold, and the scaffold can be subsequently resorbed in vivo. Cells can attach and migrate through the structures. The cells easily survive the rigors of being 3-D printed with conventional 3-D printing equipment when combined with these natural bioinks. The natural bioink has the mechanical properties to allow the printing of 3-D constructs that hold shape and structure, see [0065]. ECM (extra cellular matrix) molecule can be added from any tissue or organ such as heart, skin bladder etc., see [0083]. The bioink may comprise one or more type of cells, see [0083]. Human adipose derived stem cell printed in collagen is shown in [0028]. Fibrinogen can be used as a crosslinking agent, see [0080]. The reference teaches fibronectin in [0005] and [0051].
Bagley does not teach the claimed amount of gelatin methacrylate used in the bioink composition.
Bagley et al. does not disclose the exact combination of gelatin methacrylate and collagen methacrylate as claimed.
Gaharwar et al. while teaching a biodegradable and biocompatible construct teaches use of a bioink for tissue regeneration purposes, see abstract. The amount taught in the bioink is 10% w/v gelatin methacrylate and in some embodiments it ranges from about 5% to about 15% w/v gelatin methacrylate, see (page 12, lines 21-23 and page 9, lines 11-13).
It would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have utilized the known and useful amount of gelatin methacrylate as taught by Gaharwar et al. and use it into the bioink composition of Bagley et al. One of ordinary skill would have been motivated to do so because Bagley teaches use of gelatin methacrylate in a bioink composition and Gaharwar provides the generic amounts of gelatin methacrylate in a bioink for tissue regeneration purposes. The amount of gelatin methacrylate overlaps with he claimed amount and thus creates a case of obviousness because in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art”, a prima facie case of obviousness exists. MPEP 2144.05 A.
Bagley et al. does not disclose the exact combination of gelatin methacrylate and collagen methacrylate as claimed.
Shoseyov et al. discloses additive manufacturing, 3D printing (bioprinting or bio-ink) of 3D objects, see abstract and [0093] and [0148]-[0152]. Figure 5 teaches collagen methacrylate ink, see [0079]. The materials include gelatin methacrylate and collagen methacrylate in acetic acid solution, see [0463] and [0317]. The reference teaches an exemplary curable materials usable in the context of the present embodiments include, but are not limited to, Matrigel, Gelatin methacrylate (GelMA), see [0337] and [0336]. The reference teaches Collagen methacrylate can be used as a rapidly self-assembling type I collagen to form cross-linked hydrogels for tissue engineering [see, for example, Isaacson et al., Experimental Eye Research 173, 188-193 (2018)]. It has been used with mesenchymal stem cells [Kathryn E. Drzewiecki et al., A thermoreversible, photo-crosslinkable collagen bio-ink for free-form fabrication of scaffolds for regenerative medicine, TECHNOLOGY (2017)], fibroblasts, adipose derived stem cells, epithelial cells, and many more. Collagen methacrylate is useful for forming scaffolds with varying degree of stiffness, by altering collagen concentration or the curing conditions (e.g., intensity and duration of irradiation), see [0020]. The reference teaches that according to some of any of the embodiments of the present invention, a concentration of the recombinant human collagen in the modeling material formulation ranges from 0.5 mg/mL to 50 mg/mL, or from 0.5 mg/mL to 20 mg/mL, see [0033]. The reference teaches that according to some of any of the embodiments of the present invention, the formulation further comprises at least one curable material other than the recombinant human collagen featuring the curable group, see [0034] and the reference teaches that according to some of any of the embodiments of the present invention, a weight ratio of the recombinant human collagen featuring the curable group and the at least one curable material ranges from 10:1 to 1:2, or from 10:1 to 1:1, or from 5:1 to 2:1, see [0035]. The reference thus teaches the generic amounts of collagen methacrylate ranging from 0.5 mg/mL to 50 mg/mL, or from 0.5 mg/mL to 20 mg/mL, as discussed above (and 0.5mg/ml is equal to 0.05%) and this amount overlaps with the claimed amount and creates a case of obviousness.
It would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have utilized the combination of collagen methacrylate and gelatin methacrylate in bioink composition of Bagley as modified by Gaharwar et al. motivated by the teachings of Shoseyov et al., teaching use of both the methacrylates in 3D printing and bio-ink printing composition. The references thus teach a bio-ink composition comprising gelatin methacrylate and collagen methacrylate and their used amounts that overlaps with the claimed amount as discussed above. Additionally, it would be within skill of an artisan to optimize the amount of collagen methacrylate and additional component, gelatin methacrylate by performing experimental manipulations and come to the claimed invention for bioprinting/bioink composition.
Claims 8-12 are rejected under 35 U.S.C. 103 as being unpatentable over Bagley et al. (WO 2018/071639 A1, presented in IDS) in view of Gaharwar et al. (WO 2018/169965A1) and further in view of Shoseyov et al. (US PG Pub. 2020/0179562A) and Li et al. (RA. Li et al. ; Biomaterials 163 (2018) 116-127, presented in IDS ).
Bagley et al. as discussed above does not disclose human cardiac fibroblast-derived induced pluripotent stem cells or cardiomyocytes comprising stem cells.
Li et al. teaches that tissue engineers and stem cell biologists have made exciting progress toward creating simplified models of human heart muscles or aligned monolayers to help bridge a longstanding gap between experimental animals and clinical trials. However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump. Here, we developed a next-generation in vitro biomimetic model of pumping human heart chamber and demonstrated its capability for pharmaceutical testing. From human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen- based extracellular matrix hydrogel, we engineered a three-dimensional (2D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures, see abstract.
It would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have utilized into the bioink of human cardiac fibroblast-derived induced pluripotent stem cells or cardiomyocytes comprising stem cells. One of ordinary skill would have been motivated to do so because Bagley et al. teaches that the bioink may comprise one or more type of cells, see [0083] and Li teaches from human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen- based extracellular matrix hydrogel, engineered in a three-dimensional (2D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures. Thus, one of ordinary skill would utilize bioink comprising collagen and gelatin methacrylate of primary reference with the cells of Li with an expectation of obtaining stem cell differentiation of cardiomyocytes.
Claims 3-4 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Bagley et al. (WO 2018/071639 A1, presented in IDS) in view of Gaharwar et al. (WO 2018/169965A1) and further in view of Li et al. (RA. Li et al.; Biomaterials 163 (2018) 116-127, presented in IDS ) and Perlingeiro et al. (USP 9,850,497).
The references discussed above do not teach use of solvent or medium such as mTeSR, sodium hydroxide and pluripotent stem cells comprising chondrocytes precursors.
Perlingeiro et al. teaches gene targeting methods and tools, see title. The reference teaches a general method of correcting a gene, for example a gene with many known mutations, such as a gene with mutations in many different exons which could vary from subject to subject (e.g., patient), as well as a set of tools (TALENs and gene targeting vectors) to accomplish such method, see abstract. The cells can be cultured in culture medium that is established in the art and commercially available from the American Type Culture Collection (ATCC), Invitrogen and other companies. Such media include, but are not limited to, mTESR, see description. It is taught under materials and methods, that (91) Human DMD induced pluripotent stem cells (DMD-hiPSCs) were maintained in feeder free conditions using mTeSR medium (STEMCELL Technologies).
It would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have utilized pluripotent stem cells in feeder free conditions using mTeSR medium as taught by Perlingeiro et al. into the bioink composition of Bagley et al. which teaches use of cells and Perlingeiro provides medium for stem cells.
Applicant argues that Bagley describes that "[t]he present invention addresses previous shortcomings in the art by providing bioinks made entirely or predominantly of collagen and methods of using the same"⁶ and that "[p]redominantly' is defined as composing greater than 30%, e.g., greater than 30%, 40%, 50%, 60%, or 70%, of the mass of solids in a solution or gel." According to this description by Bagley, one of ordinary skill in the art would not have modified the Bagley bioink to have 0.1 to 1.0 percent weight by volume of collagen methacrylate, as recited by claim 1, because doing so would fundamentally change the principle of operation of Bagley…of solids in a solution. This is three times lower than the minimum amount of collagen required to be included in the bioink described by Bagley. Using such a relatively low amount of collagen methacrylate directly contradicts Bagley's principle of overcoming the shortcomings in the art of using a collagen-predominant bioink. Therefore, one of ordinary skill in the art would have consciously avoided modifying the Bagley bioink to have 0.1 to 1.0 percent weight by volume of collagen methacrylate, as required by claim 1. Even if another reference discloses the claimed amount of collagen methacrylate, one of ordinary skill in the art would have avoided modification to include such an amount of collagen methacrylate. As such, there is no rational reason to modify Bagley based on Gaharwar or Shoseyov to arrive at "[a] bioink composition comprising 10 to 15 percent weight by volume of gelatin methacrylate; and 0.1 to 1.0 percent weight by volume of collagen methacrylate," as recited by claim 1.
Applicant’s arguments are fully considered but is not persuasive. Bagley explicitly teaches that the bioink may be formed in a concentrated solution. In some embodiments, the undenatured collagen is present in the bioink at a concentration of greater than 1 mg/ml. In some embodiments, the undenatured collagen is at a concentration of greater than 3 mg/ml. In some embodiments, the undenatured collagen is at a concentration of greater than 5 mg/ml. In some embodiments, the undenatured collagen is at a concentration of greater than 10 mg/ml. In some embodiments, the undenatured collagen is at a concentration of greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mg/ml, see [0067] and claim 17. Therefore, the reference provides various amounts used in making a bioink formulation. Shoseyov teaches that according to some of any of the embodiments of the present invention, a concentration of the recombinant human collagen in the modeling material formulation ranges from 0.5 mg/mL to 50 mg/mL, or from 0.5 mg/mL to 20 mg/mL, see [0033]. And Gaharwar et al. while teaching a biodegradable and biocompatible construct teaches use of a bioink for tissue regeneration purposes, see abstract wherein the amount taught in the bioink is 10% w/v gelatin methacrylate and in some embodiments it ranges from about 5% to about 15% w/v gelatin methacrylate, see (page 12, lines 21-23 and page 9, lines 11-13). Therefore, the generic amounts are taught by the references which are all directed to a bioink formulation. It would therefore have been obvious to one of ordinary skill to utilize the combination of collagen methacrylate and gelatin methacrylate in bioink composition of Bagley as modified by Gaharwar et al. motivated by the teachings of Shoseyov et al., teaching use of both the methacrylates in 3D printing and bio-ink printing composition and optimize the amount of collagen methacrylate, and additional component, gelatin methacrylate by performing experimental manipulations and come to the claimed invention for bioprinting/bioink composition given the references teach the generic amounts known to be used for bioink printing formulations.
Applicant states that the claimed bioink formulations can provide various advantages. For example, "the bioink formulations described herein may facilitate proliferation and/or migration for any cell type. In this manner, "the bioinks described herein may be applied to any cell type, such as cell types that may be challenging to manipulate to make engineered structures outside of the body. A bioink composition that includes "10 to 15 percent weight by volume of gelatin methacrylate" and "0.1 to 1.0 percent weight by volume of collagen methacrylate," as recited by amended claim 1, can thus be used to facilitate cell proliferation and migration in order to create engineered structures. In one example, paragraph [0089] explains that "ECM engagement and stem cell differentiation can be improved using a ECM formulation that promotes cardiomyocyte differentiation and fold this formulation into a bioink that can be deposited with spatial fidelity." The Office has not cited any reason that would have caused one of ordinary skill in the art to modify the composition of Bagley to arrive at a bioink composition in which there is 10 to 15 percent weight by volume of gelatin methacrylate and 0.1 to 1.0 percent weight by volume of collagen methacrylate matter, as recited by independent claim 1.
Applicants arguments are not persuasive. The rationale to use the teachings of the references have been discussed above and no experimental comparative analysis/evidence have been provided by applicants with the closest prior art. Bagley explicitly teaches the natural bioink has the mechanical properties to allow the printing of 3-D constructs that hold shape and structure, see [0065]. ECM (extra cellular matrix) molecule can be added from any tissue or organ such as heart, skin bladder etc., see [0083]. The bioink may comprise one or more type of cells, see [0083]. Human adipose derived stem cell printed in collagen is shown in [0028]. Therefore, absent comparison with the prior art, it cannot be inferred that the claimed bioink composition shows advantages to an unexpected level. And the tests used in a comparison must be made under identical conditions except for the novel features of the invention. See MPEP 716.02(e).
Action is final
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SNIGDHA MAEWALL whose telephone number is (571)272-6197. The examiner can normally be reached Monday thru Friday; 8:30 AM to 5PM.
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/SNIGDHA MAEWALL/ Primary Examiner, Art Unit 1612
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