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 .
Claims 1-14, of record 7/25/2023 are pending. Prosecution on the merits commences for claims 1-14.
PRIORITY
The instant application, filed 7/25/2023, claims priority to US Provisional Application No. 63/369,388, filed 7/25/2022. Thus, the earliest possible priority for the instant application is 7/25/2022.
Information Disclosure Statement
The Information Disclosures Statements of record 7/25/2023, 3/14/2024 (x3), 4/08/2024, 6/06/2024, and 2/20/2025 have been considered by the Examiner. Initialed copies have been included with the mailing of this action.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See paragraph [0089] of the published specification.
Drawings
The electronic files providing the Drawings of record 7/25/203 and 10/23/2023 are objected to because they provide the drawings in color.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
If Applicant does not intend for the drawings to be in color, Applicant should resubmit the electronic files with drawings in black and white.
CLAIMS
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Independent claims 1, 13 and 14 are drawn to a “dual remuscularization-revascularization system” comprising vascularized engineered human myocardial tissues comprising mid-diameter vessels, wherein the vessels are coated with endothelial cells (claim 1), and methods of making such systems. Claims 1, 13 and 14 are presented below:
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Claim Interpretation
The claims comprise recite limitations of “dual remuscularization-revascularization system,” “vascularized engineered human myocardial tissues (vEHMs),” “biomaterial matrix,” “mid-diameter vessels” and “arteriole-scale channels.”
Under a broadest reasonable interpretation (BRI), words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the relevant time. The ordinary and customary meaning of a term may be evidenced by a variety of sources, including the words of the claims themselves, the specification, drawings, and prior art. However, the best source for determining the meaning of a claim term is the specification - the greatest clarity is obtained when the specification serves as a glossary for the claim terms. MPEP 2111.01.
The specification does not define the minimal structural requirements of a “dual remuscularization-revascularization system.” Nor is the Examiner able to identify a specific art-recognized meaning. Thus, such systems comprise only the structures recited in the claims.
The specification does not define the minimal structural requirements of “vascularized engineered human myocardial tissues” or “vEHMs.” Paragraph [0071] of the published specification discloses, “Vascularized engineered human myocardial tissues (vEHMs) have the biomedical art-recognized meaning.” However, the specification provides no prior art reference, nor is the Examiner able to identify a specific biomedical art-recognized meaning. Thus, such tissues comprise only the structures recited in the claims.
Paragraph [0070] of the published specification teaches, “Vascularization has the biomedical art-recognized meaning of the process of growing blood vessels into a tissue to improve oxygen and nutrient supply.” Presumably, once a “vascularized” tissue is a tissue comprising blood vessels.
The broadest reasonable interpretation of vascularized engineered human myocardial tissue (vEHM) is an engineered tissue comprising 1) human cardiomyocytes derived from human pluripotent stem cells and 2) blood vessels.
Paragraph [0064] of the published specification teaches, “Mid-diameter vessels and mid-scale vessels have the biomedical art-recognized meaning. Mid-diameter vessels are smaller than large arteries and larger than capillaries. Arterioles have the biomedical art-recognized meaning of small bloods vessels that branch off from an artery and carry blood away from the heart to the tissues and organs. Arteriole-scale vessels are known in the biomedical art to be 7 μm to 500 μm in diameter. Mesa-diameter arterioles have the biomedical art-recognized meaning.”
Paragraph [0051] of the published specification teaches, “Biomaterial has the biomedical art-recognized meaning. A biocompatible matrix can be a biomaterial selected from biopolymers such as a proteins or polysaccharides, for example a biomaterial such as collagen, gelatin, fibrin, a polysaccharide, e.g., hyaluronic acids, chitosan, and derivatives thereof, collagen, chitosan, etc. Vessel structures can be patterned using a sacrificial biomaterial such as alginate, sugars, etc.”
At paragraph [0063] the published specification teaches, “Matrix has the biomedical art-recognized meaning. A biocompatible matrix can be made of a biomaterial selected from biopolymers such as a proteins or polysaccharides, for example a biomaterial such as collagen, gelatin, fibrin, a polysaccharide, e.g., hyaluronic acids, chitosan, and derivatives thereof, collagen, chitosan, etc.”
Thus, for the purposes of prosecution, the broadest reasonable interpretation of claim 1 is a system comprising, at least, human cardiomyocytes derived from pluripotent stem cells and vessels embedded in a matrix, wherein the vessels comprise diameters of 7 μm to 500 μm, and the vessels are lined with endothelial cells.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 10-12 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 10 recites, “The system of claim 1, wherein the vessels have been self-connected to a subject's vasculature.”
Claim 11 recites, “The system of claim 1, wherein the patterned, arteriole-scale vasculature successfully is inosculated with the vasculature of a subject.”
Claim 12 recites, “The system of claim 1, wherein such implanted tissues are used in surgical settings to restore cardiac vascular or contractile function for patients with ischemic heart disease.”
Paragraph [0067] of the published specification teaches “Subject, Patient, or Host has the biomedical art-recognized meaning of an animal, e.g., a human, to whom a treatment can be administered.”
Thus, claims 10-12 encompass embodiments wherein the “dual remuscularization-revascularization system” have been implanted in a subject, which includes human subjects.
Claim Objections
Claims 1 and 6 are objected to because of the following informalities:
Claim 1 comprises a typographical error. Line 5 recites, “wherein the embedded vEHMs mid-diameter vessels” and should recite “wherein the embedded vEHMs comprise mid-diameter vessels” or similar language.
Claim 6 recites, “wherein the embedded vEHMs comprise both mid-diameter vessels and large diameter vessels.” It would be remedial to amend claim 8 to recite, “wherein the embedded vEHMs further comprise .
Appropriate correction is required.
Claim Rejections - 35 USC § 112 - indefinite
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 1-14 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.
Section (a) of Claim 1 requires wherein the dual remuscularization-revascularization system comprises vascularized engineered human myocardial tissues (vEHMs) “embedded in a biomaterial matrix, wherein the embedded vEHMs are in a pattern” which is unclear.
It is unclear whether the claimed limitation is referring to
a) the localization of the (embedded) vEHMs within the matrix, perhaps in a repeated way (i.e. patterned)? Such as:
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b) the vEHMs directly, and is referring to the cardiomyocytes and/or vessels of the vEHMs, and their orientation/structural relationship. As noted above, vEHM is interpreted as human cardiomyocytes derived from human pluripotent stem cells and blood vessels. The specification discloses “patterned vessels have the biomedical art-recognized meaning” at paragraph [0067]. The Examiner notes in this interpretation, the claim requires “the embedded vEHMs” are in a pattern, not simply any vessels within the vEHMs. Thus paragraph [0067] provides no aid in clarifying the claim regarding “vEHMs”. In addition, the specification provides no definition of patterned vEHMs, nor is the Examiner able to identify a specific biomedical art-recognized meaning for vEHMs in a pattern, or patterned vEHMs. Thus, a skilled artisan would not know the metes and bounds of the claimed invention.
Claim 1 recites the limitation "the vessel structure" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claim 2 recites the limitation "the components of the system" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 recites the limitation "the components of the system" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 6 requires wherein the vEHMs comprise both “mid-diameter” vessels and “large diameter” vessels. The claim is indefinite because the specification teaches the diameter of “large vessels” is encompassed by the diameter of “mid-diameter”/ “arteriole-scale” vessel range (7 μm to 500 μm), with no way to determine the difference between a “mid-diameter” vessel from a “large diameter” vessel.
Paragraph [0064] of the specification teaches,
“Mid-diameter vessels and mid-scale vessels have the biomedical art-recognized meaning. Mid-diameter vessels are smaller than large arteries and larger than capillaries. Arterioles have the biomedical art-recognized meaning of small bloods vessels that branch off from an artery and carry blood away from the heart to the tissues and organs. Arteriole-scale vessels are known in the biomedical art to be 7 μm to 500 μm in diameter. Meso-diameter arterioles have the biomedical art-recognized meaning. In one example, microCT-based 3D vascular reconstructions showed the presence of mid-diameter vessels and the improved presence of large vessels (>50 μm) in vEHMs perfused in vitro. In another example, large vessels (400 μm diameter) were produced as well as mid-diameter vessels.”
This section teaches “mid-diameter vessels” comprise arteriole- scale vessels, which are 7 μm to 500 μm in diameter. However, this section does not define the diameter of “large diameter” vessels, but rather teaches embodiments wherein “large vessels” have diameters greater than 50 μm “(>50 μm)”, or 400 μm diameter “(400 μm diameter)” which are encompassed by the diameter of “mid-diameter” vessels.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “mid-diameter” vessel, and the claim also recites "large diameter" vessel which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 8 recites, wherein “the vessels perfuse the whole of the embedded vEHMs” which is unclear.
Initially, the claim recites the limitation "the whole of the embedded vEHMs" in line 1. There is insufficient antecedent basis for this limitation in the claim.
As noted above, the vEHMs of claim 1 minimally comprise 1) human cardiomyocytes and 2) vessels. As currently worded, the claim requires vEHMs are embedded within a matrix. Neither the claim, nor specification, require a vEHM comprises 1) human cardiomyocytes, 2) vessels and 3) matrix.
The use of the word “perfuse” in the context of a composition claim is confusing. It is unclear whether the claim is attempting to encompass embodiments wherein vessels from one or more vEHMs interconnects to another one or more vEHMs through the matrix, such that all of the embedded vEHMs are interconnected vEHMs via vessels? Or is the claim attempting to encompass embodiments relating to intended use, wherein the vessels are capable of transporting a perfusate (liquid/nutrient) to all vEHMs within the matrix? Clarification of the structure encompassed by the claim is required.
Claim 9 recites, “wherein the vessels are patterned for the largest inlet vessel to be micro-surgically anastomosed to a host vessel” which is indefinite.
Initially, the claim recites the limitation "the largest inlet vessel" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Further, it is unclear how a vessel is “patterned” for the largest inlet vessel to be micro-surgically anastomosed to a host vessel? Paragraph [0062] of the published specification discloses vessels which are surgically attached to host vessels are anastomosed. But this does not clarify the structural requirements of the claim. There is no other recitation of “inlet vessel” in the specification. Clarification of the structure encompassed by the claim is required.
Claim 11 recites the limitation "the patterned, arteriole-scale vasculature " in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 recites the limitation "such implanted tissues" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 13, directed to the method of making a dual remuscularization-revascularization system comprising vascularized engineered human myocardial tissues (vEHMs) is indefinite.
Claim 13 recites:
A method of making a dual remuscularization-revascularization system comprising vascularized engineered human myocardial tissues (vEHMs), comprising the steps of:
(a) mixing hiPSC-cardiomyocytes and human primary cardiac fibroblasts into a biomaterial matrix;
(b) embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels; and
(c) culturing the vascularized engineered human myocardial tissues under dynamic perfusion conditions.
Section (b) recites, “embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels” which is unclear. The specification does not define “a pattern with arteriole-scale channels” nor does the claim articulate how this step relates to either the production of a vEHMs or the dual remuscularization-revascularization system produced.
Sections (a)-(c) encompass the active steps required by the claimed method, but the claim does not identify where within the methodology 1) the engineered human myocardial tissues are formed; or 2) where the dual remuscularization-revascularization system (comprising the vEHMs) is formed. For example, step (c) requires culturing “the vascularized engineered human myocardial tissues” which would mean such vEHMs are already formed. Are the vEHMs formed at the end of section (a)? at the end of section (b)?
Is the dual remuscularization-revascularization system (comprising the vEHMs) produced after section (c)? Or is the dual remuscularization-revascularization system (comprising the vEHMs) produced after section (b) and section (c) represents a further manipulation of the already produced system?
Clarification of the methodology and how the claimed steps result in the production of the structures encompassed with in the claims is required.
Claim 14, also directed to the method of making a dual remuscularization-revascularization system comprising vascularized engineered human myocardial tissues (vEHMs) is also indefinite.
Claim 14 recites:
A method of making a dual remuscularization-revascularization system comprising vascularized engineered human myocardial tissues (vEHMs), comprising the steps of:
(a) embedding fibers coated with endothelial cells in a biomaterial matrix to form a pattern with arteriole-scale channels;
(b) perfusing hiPSC-cardiomyocytes into the biomaterial matrix in vitro;
(c) culturing the vascularized engineered human myocardial tissues under dynamic perfusion conditions.
Section (a) recites, “embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels” which is unclear. The specification does not define “a pattern with arteriole-scale channels” nor does the claim articulate how this step relates to either the production of a vEHMs or the dual remuscularization-revascularization system produced.
Sections (a)-(c) encompass the active steps required by the claimed method, but the claim does not identify where within the methodology 1) the engineered human myocardial tissues are formed; or 2) where the dual remuscularization-revascularization system (comprising the vEHMs) is formed. For example, step (c) requires culturing “the vascularized engineered human myocardial tissues” which would mean such vEHMs are already formed. Are the vEHMs formed at the end of section (b)? at the end of section (c)?
Is the dual remuscularization-revascularization system (comprising the vEHMs) produced after section (c)? Or is the dual remuscularization-revascularization system (comprising the vEHMs) produced after section (b) and section (c) represents a further manipulation of the already produced system?
Clarification of the methodology and how the claimed steps result in the production of the structures encompassed with in the claims is required.
Claims 4-5, 7 and 10 are included in the rejection because they depend from a rejected claim.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-9 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Noor et al. 3D Printing of Personalized Thick and Perfusable Cardiac Patches and Hearts. Advanced Science, 2019. 6, 1900344; 10 pages.
Noor discloses methods of generating vascularized engineered cardiac tissue constructs. Noor generates a vascularized engineered human myocardial tissue comprising human ipsc-cardiomyocytes (CM) embedded in a hydrogel bioink, and endothelial cells (EC) embedded in a hydrogel bioink, wherein the hydrogel bioink is a biomaterial matrix (pages 2, 5, FIGs 1, 4, 5). Noor generates one construct wherein the cardiomyocytes and endothelial cells are printed as a personalized 3D patch, wherein the cells are printed according to a patient’s individual-specific 3D structure and orientation of the major blood vessels of the left ventricle (pages 3-4, FIGs 3-4). Noor generates a second construct, wherein the cells are printed as layers in a crisscross geometry, with two bottom layers of CMs, a layer of ECs, and two top layers of CMs (page 4, page 8, “Cardiac Patches Printing Process”, FIG 4, FIG 5 b, c, e, and supplemental FIG. 7). Thus both the personalized 3D patch as well as the construct printed with crisscross geometry read on embedded “in a pattern” in the engineered myocardial tissue construct, absent evidence to the contrary. Noor shows the constructs comprises mid-diameter vessels (FIGs 3c, 3d, 4f, 4g; 5f), wherein the endothelial cells are localized to the vessel wall (FIG 4f, 4g). Thus, Noor anticipates claim 1.
With regard to claim 2, Noor discloses the vascularized engineered human myocardial tissue construct comprising autologous matrix and cells is biocompatible and can be transplanted into a subject (page 1-2; FIG. 1).
With regard to claim 3, Noor discloses components of the vascularized engineered human myocardial tissue construct comprises gelatin or alginate, which are degradable (page 5, page 9, “Printing in a Support Bath”).
With regard to claim 5, the claim requires wherein the vEHMs have high cardiomyocyte density. Paragraph [0059] the published specification teaches, “High cardiomyocyte density has the biomedical art recognized meaning. High cardiomyocyte density can be from 106-108 cells/mL.” Noor discloses the vascularized engineered human myocardial tissue constructs are printed with cardiomyocyte-laden bioink comprising 1 x 108 cells/mL (page 8, “Bioinks Preparation”), and shows that the printed vascularized myocardial tissue constructs had high cellular viability (Page 5, FIG. 4D). Thus, the vascularized myocardial tissue constructs of Noor have high cardiomyocyte density.
With regard to claim 6, Noor discloses the vascularized engineered human myocardial tissue constructs comprise vessels of at least 300 μm down to capillary sized vessels (pages 3-5, FIGs 3c, 3d, 4a, 4f, 4g; 5f). Thus, Noor discloses the vascularized engineered human myocardial tissue constructs comprise both mid-diameter vessels and large diameter vessels.
With regard to claim 7, Noor discloses the vascularized engineered human myocardial tissue constructs comprise branched vessels (FIGs 4f, 6b).
With regard to claim 8, Noor discloses the vascularized engineered human myocardial tissue constructs comprise vessels of at least 300 μm down to capillary sized vessels in order to ensure the entire construct to adequate oxygenation (page 3-4, FIGs 3c, 3d). Thus, the vessels perfuse the whole construct.
With regard to claims 9 and 12, Noor discloses the design of the construct is based on the individual-specific 3D structure and orientation of the major blood vessels of the left ventricle, wherein constructs can be constructed with autologous biomatrix and cells, and transplanted back into the patient to repair or replace injured heart tissues (abstract, pages 2-3; FIG 1, 3). Noor perfuses the construct via the largest inlet (supplemental FIG 3b). Noor discloses the constructs can be used to treat end-stage heart failure, wherein following transplantation onto defected heart tissue aids in heart regeneration.
Claims 1-3, 6-9 and 12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US Patent Application Publication No. 2020/0316254 to Cui.
Cui discloses methods of generating vascularized engineered cardiac tissue constructs. Cui generates a vascularized engineered human myocardial tissue comprising human ipsc-cardiomyocytes (CM) embedded in a hydrogel bioink, and endothelial cells (EC) embedded in a hydrogel bioink, wherein the hydrogel bioink is a biomaterial matrix (paragraphs [0083]-[0088], [0090], [0093]-[0096]). Cui discloses the cardiomyocytes and endothelial cells are printed as layers, wherein the CMs are printed as layers of anistropic fibers, which mimic the natural tissue of the cardiac fibers, and the ECs are printed as layers of perfusable vascular structures between the one or more layers of anistropic fibers (paragraphs [0091]-[0097], FIG 2A, 2B). The printed layers of anistropic fibers comprising the CMs and the vascular layers comprising the ECs read on wherein the cells are embedded “in a pattern” in the engineered myocardial tissue construct, absent evidence to the contrary. The vascularized engineered cardiac tissue construct height (i.e., thickness), which necessarily comprise multiple layers of anistropic fibers and vascular layers, ranges from 200 μm to 1 cm, and exemplifies a construct of 500 μm in height (paragraphs [0100], [0104]-[0105]). Cui shows the construct comprises vessels of large to small (including capillary) diameter vessels (paragraphs [0094]-[0095]), including mid-diameter vessels of less than 250 μm (FIG 7A). Cui discloses the endothelial cells are localized to the vessel wall (paragraphs [0088], [0096], claim 7; FIG 7C; 12D, 13F-H, 14I-J). Thus, Cui anticipates claim 1.
With regard to claim 2, Cui discloses the vascularized engineered human myocardial tissue is biocompatible (paragraph [0095]).
With regard to claim 3, Cui discloses components of the vascularized engineered human myocardial tissue comprise degradable (i.e., fugitive) bioinks (paragraphs [0088], [0096]).
With regard to claim 6, Cui discloses the vascularized engineered human myocardial tissue constructs comprise vessels of at least 250 μm up to 2 mm sized vessels (FIG 7A, paragraphs [0094]-[0095]). Thus, Cui discloses the vascularized engineered human myocardial tissue constructs comprise both mid-diameter vessels and large diameter vessels.
With regard to claim 7, Cui discloses the vascularized engineered human myocardial tissue constructs comprise branched vessels (paragraph [0088]).
With regard to claim 8, Cui discloses the vascularized engineered human myocardial tissue constructs comprise vessels throughout the entire construct in order to provide adequate nutrients and oxygenation (paragraphs [0089], [0092], [0097]). Thus, the vessels perfuse the whole construct.
With regard to claims 9-13, Cui discloses the design of the construct is based on the individual-specific heart 3D structure and is transplanted into a patient to repair or replace injured heart tissues and promote angiogenesis. Cui shows the constructs implanted in vivo successfully integrated, exhibited vessel formation, and anastomose, improving injured or infarcted hearts (paragraphs [0084], [0089]-[0091], [0102], [0104], [0118]-[0120]; FIG 2A).
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.
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 4 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2020/0316254 to Cui, as applied to claims 1-3, 6-9 and 12 above, further in view of US Patent Application No. 2016/0115457 to Kim. Claim 4 is directed to an embodiment wherein the vascularized engineered human myocardial tissue construct is within a packaging.
The disclosure of Cui is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Cui teaches the vascularized engineered human myocardial tissue construct system of claim 1. Cui discloses the constructs are formulated as cardiac tissue patches.
However, Cui does not disclose wherein the vascularized engineered human myocardial tissue construct system is within a packaging, as required by instant claim 4.
Kim discloses engineered myocardial tissue constructs suitable for implant may be formulated as a patch, and within packaging, enabling easy transport to destinations for therapeutic use, such as hospitals or battlefields (paragraph [0262]).
It would have been obvious to combine the vascularized engineered human myocardial tissue construct of Cui with the disclosure of Kim. A skilled artisan would have been motivated to include a vascularized engineered human myocardial tissue construct patch in packaging in order to enable transport for therapeutic use. A skilled artisan would have had a reasonable expectation of success because placing engineered myocardial tissue constructs in packaging was known at the time of the invention.
Claims 1-3, and 5-12 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application No. 2015/0125507 to Chen, further in view of Noor et al. 3D Printing of Personalized Thick and Perfusable Cardiac Patches and Hearts. Advanced Science, 2019. 6, 1900344; 10 pages.
With regard to claim 1, Chen discloses patterned biomaterial vascularized tissue-specific constructs comprising patterned cellular cords (vessels) and extracellular matrix embedded within a 3D scaffold (abstract, paragraphs [0007]-[0019], [0042]-[0046], [0051]-[0059], [0062]-[0064], [0081], [0119]-[0121], FIG 19, FIG 20A-C). The cellular cords (vessels) comprise different diameters, and are formed by seeding templates (channels, grooves, trenches, or 3D bioprinted filaments) within the tissue-specific construct with human endothelial cells (paragraphs [0015]-[0017], [0054], [0060]-[0064]). The cords (vessels) are seeded by embedding endothelial cells in a biomaterial matrix which line the side walls of the cords (paragraphs [0014]-[0016], [0026], [0040]-[0041], [0064], [0072], [0082], [0144], [0173], Example 1; Example 2). The diameter of the cords (vessels) can be from 7 um to 500 um, which reads on a mid-diameter vessel (paragraphs [0040]).
Chen discloses the vascularized tissue constructs are further seeded with tissue-specific human cells embedded within the 3D scaffold in defined regions or patterns (paragraphs [0046], [0059], [0081]-[0082], [0100], [0114]-[0121], [0173], Example 1). The tissue-specific cells include ips-derived tissue specific cells, including cardiomyocytes (paragraphs [0074], [0076], [0120], [0135]). Chen discloses the tissue constructs comprise cardiac tissue constructs (paragraphs [0127]-[0129]).
Thus, Chen discloses vascularized engineered myocardial tissue constructs comprising cardiomyocytes and endothelial cells in a biomatrix, wherein the constructs comprise patterned mid-sized vessels lined with endothelial cells, and wherein the constructs comprise cardiomyocytes in defined regions or patterns. Chen discloses strict control of both the vascular geometry and tissue-specific cells within the vascularized constructs enhances the construct’s viability and therapeutic use for treating ischemia (paragraphs [0043], [0046]-[0049]).
Specifically, Chen discloses a vascularized engineered myocardial tissue comprising all of the presently claimed structures, including, (a) vascularized engineered human myocardial tissues embedded in a biomaterial matrix, wherein the embedded vEHMs are in a pattern, wherein the embedded vEHMs mid-diameter vessels; and (b) endothelial cells coated on the vessel structure, wherein the endothelial cells are localized to a vessel wall.
However, Chen does not exemplify a vascularized engineered myocardial construct as claimed.
Noor generates vascularized engineered cardiac tissue constructs wherein cardiomyocytes and endothelial cells are embedded in defined regions or patterns in the scaffold of the engineered myocardial tissue construct (Abstract, pages 2-3, 5; FIGs. 1, 3-5). Noor shows the constructs comprises mid-diameter vessels (FIGs 3c, 3d, 4f, 4g; 5f) wherein the endothelial cells are localized to the vessel wall (FIG 4f, 4g).
It would have been obvious to generate the vascularized myocardial construct as claimed from the disclosure of Chen in view of Noor. A skilled artisan would have been motivated to generate the construct because Chen discloses all of the claimed features, and discloses constructs that control both the vascular geometry and tissue-specific cells within the vascularized constructs enhances the construct’s viability and therapeutic use. A skilled artisan would have had a reasonable expectation of success at the time of the invention because vascularized engineered myocardial constructs that control both the vascular geometry and tissue-specific cells within the vascularized constructs were known at the time of the invention, as shown by Noor.
With regards to claims 2-3, Chen discloses the system is biocompatible and degradable (paragraphs [0016], [0063]-[0068], [0107]-[0111]).
With regard to claim 5, Chen does not disclose wherein the construct has high density cardiomyocytes. However, Noor discloses the vascularized engineered human myocardial tissue constructs are printed with cardiomyocyte-laden bioink comprising 1 x 108 cells/mL (page 8, “Bioinks Preparation”), and shows that the printed vascularized myocardial tissue constructs had high cellular viability (Page 5, FIG. 4D). As such, the vascularized myocardial tissue constructs of Noor have high cardiomyocyte density. Claim 5 is obvious for the same reasons as stated above for claim 1.
With regard to claims 6, Chen discloses the vessels can be mid-diameter and large diameter as needed ranging from 8 um to 20 mm (paragraphs [0017], [0085], [0091]) .
With regard to claims 7-8, Chen discloses the vessels are branched, and perfuse the whole construct (paragraphs [0083]-[0084], [0168], [0175], [0181]).
With regard to claims 9-12, Chen discloses the construct is implanted into a subject with sutures (anastomose) or host cells invade the construct (inosculate) to connect the vascularized tissue construct to the subject’s vasculature, and can be used to restore cardiac vascular function (paragraphs [0047], [0048], [0127]-[0130], [0137], [0170]-[0181]). Thus Chen renders obvious claims 9-12.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application No. 2015/0125507 to Chen, further in view of US Patent Application Publication No. 2016/0201034 to Zimmerman and US Patent Application Publication No. 2020/0316254 to Cui.
Claim 13 is directed to a method of making a dual remuscularization-revascularization system comprising vascularized engineered human myocardial tissues (vEHMs), comprising the steps of:
(a) mixing hiPSC-cardiomyocytes and human primary cardiac fibroblasts into a biomaterial matrix;
(b) embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels; and
(c) culturing the vascularized engineered human myocardial tissues under dynamic perfusion conditions.
Chen discloses methods of making vascularized engineered myocardial tissue constructs comprising cardiomyocytes and endothelial cells in a biomatrix 3D scaffold, wherein the constructs comprise patterned mid-sized vessels lined with endothelial cells, and cardiomyocytes in defined regions or patterns (abstract, paragraphs [0007]-[0019], [0042]-[0046], [0051]-[0059], [0062]-[0064], [0081], [0119]-[0121], [0127]-[0129], FIG 19, FIG 20A-C).
Chen discloses the method comprises seeding defined regions or patterns of a 3D scaffold with tissue-specific human cells, such as iPSC-derived tissue specific cells, including cardiomyocytes (paragraphs [0046], [0059], [0074], [0076], [0081]-[0082], [0100], [0114]-[0121], [0127]-[0129], [0135], [0173], Example 1). Chen discloses tissue-specific cells are introduced into the construct as a suspension of one or more cell types with a biomatrix (paragraph [0066], [0070]-[0071], [0074]), including fibroblasts, wherein the cells are human, autologous, and utilized without any additional derivation, which reads on primary cells (paragraphs [0076], [0080], [0126]).
Chen discloses the vessels (cords) are formed by seeding templates (channels, grooves, trenches, filaments or fibers) within the 3D scaffold with human endothelial cells (paragraphs [0015]-[0017], [0054], [0060]-[0064]). The diameter of the channel or filament template for the cords (vessels) can be from 50 um to 500 um, which reads on arteriole-scale channels (paragraph [0040]). Chen discloses an embodiment wherein the cords are formed by seeding cells onto fibers in order to control the pattern or location of cords within the construct (paragraph [0054]). Thus, Chen suggests the methods comprises embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels.
When generating constructs with two or more cell types, Chen discloses the cells are introduced sequentially, to the same or different positions within the construct (paragraph [0059]). Chen discloses the culture of seeded constructs allows for the formation of vessels (prevascularization) within the construct (paragraph [0161], [0174]).
With regard to claim 13, Chen discloses a method of making vascularized engineered human myocardial tissue, comprising the steps of:
(a) mixing hiPSC-cardiomyocytes into a biomaterial matrix;
(b) embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels; and
(c) culturing the vascularized engineered human myocardial tissues.
However, Chen does not disclose wherein the method requires mixing human primary cardiac fibroblasts with the cardiomyocytes into the biomatrix, or wherein the tissue construct is cultured under dynamic perfusion conditions, as required by claim 13.
Zimmerman teaches including cardiac fibroblasts in engineered cardiac tissue constructs comprising iPSC-cardiomyocytes increases the contractile force of the construct (paragraphs [0039], [0041], [0053]-[0055], [0138], [0138]; FIG. 3).
Cui discloses methods of generating vascularized engineered cardiac tissue constructs (paragraphs [0083]-[0088], [0090], [0093]-[0096]). Cui generates a vascularized engineered human myocardial tissue comprising mixing human iPSC-cardiomyocytes (CM), and optionally cardiac fibroblasts, in a hydrogel bioink (paragraphs [0087], [0095]), and mixing endothelial cells (EC) in a hydrogel bioink (paragraph [0088]). Cui discloses the method comprises printing layers of anistropic fibers comprising CM and layers of perfusable vascular structures comprising the ECs [0091]-[0097], FIG 2A, 2B). The vascular layers comprise mid-diameter (arteriole-scale) vessels (paragraphs [0094]-[0095], [0100], [0104]-[0105]; FIG 7A). Thus, the printed vascularized engineered cardiac tissue construct comprises a pattern with arteriole-scale vessels.
Cui discloses the printed vascularized engineered cardiac tissue construct is cultured in vitro under dynamic perfusion conditions (paragraphs [0095], [0109]-[0110], [0126]-[0130]). Cui shows vascularized engineered cardiac tissue constructs subjected to dynamic perfusion conditions demonstrate increases in functional markers for cardiomyogenesis and angiogenesis (paragraphs [0110], [0130]; FIGs 8A-8D, 9A-9F; 10A-10D; 36A-36D; 37A-37D).
It would have been obvious to combine the method of making a vascularized engineered cardiac tissue construct of Chen, comprising mixing hiPSC-cardiomyocytes into a biomaterial matrix; embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels; and culturing the vascularized engineered human myocardial tissues, further with the methods of Zimmerman and Cui. A skilled artisan would have been motivated to include primary cardiac fibroblasts in the biomatrix with the cardiomyocytes in order to increase the contractility of the construct, as taught by Zimmerman. A skilled artisan would have been motivated to culture the vascularized engineered cardiac tissue under dynamic perfusion conditions because Cui discloses subjecting such constructs to dynamic perfusion conditions increases the cardiomyogenesis and angiogenesis markers/function of the construct. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as all of the portions of the claim was known in the art of making engineered myocardial constructs at the time of the invention.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application No. 2015/0125507 to Chen, further in view of US Patent Application Publication No. 2020/0316254 to Cui.
Claim 14 is directed to a method comprising the steps of:
(a) embedding fibers coated with endothelial cells in a biomaterial matrix to form a pattern with arteriole-scale channels;
(b) perfusing hiPSC-cardiomyocytes into the biomaterial matrix in vitro;
(c) culturing the vascularized engineered human myocardial tissues under dynamic perfusion conditions.
Chen discloses methods of making vascularized engineered myocardial tissue constructs comprising cardiomyocytes and endothelial cells in a biomatrix 3D scaffold, wherein the constructs comprise patterned mid-sized vessels lined with endothelial cells, and cardiomyocytes in defined regions or patterns (abstract, paragraphs [0007]-[0019], [0042]-[0046], [0051]-[0059], [0062]-[0064], [0081], [0119]-[0121], [0127]-[0129], FIG 19, FIG 20A-C).
Chen discloses the method comprises generating the vessels (cords) in the construct by seeding templates (channels, grooves, trenches, filaments or fibers) within the 3D scaffold with human endothelial cells (paragraphs [0015]-[0017], [0054], [0060]-[0064]). The diameter of the channel or filament template for the cords (vessels) can be from 50 um to 500 um, which reads on arteriole-scale channels (paragraph [0040]). Chen discloses an embodiment wherein the cords are formed by seeding cells onto fibers in order to control the pattern or location of cords within the construct (paragraph [0054]). Thus, Chen suggests the method comprises embedding fibers coated with endothelial cells in the biomaterial matrix to form a pattern with arteriole-scale channels.
Chen further discloses seeding defined regions or patterns of a 3D scaffold with tissue-specific human cells, such as hiPSC-derived tissue specific cells, including cardiomyocytes (paragraphs [0046], [0059], [0074], [0076], [0081]-[0082], [0100], [0114]-[0121], [0127]-[0129], [0135], [0173], Example 1). Chen discloses tissue-specific cells are introduced into the construct as a suspension of one or more cell types with a biomatrix (paragraph [0066], [0070]-[0071], [0074]), including fibroblasts, wherein the cells are human, autologous, and utilized without any additional derivation, which reads on primary cells (paragraphs [0076], [0080], [0126]). Seeding the tissue-specific cells via suspension reads on “perfusing hiPSC-cardiomyocytes into the biomaterial matrix.”
When generating constructs with two or more cell types, Chen discloses the cells are introduced sequentially, to the same or different positions within the construct (paragraph [0059]). Chen discloses the culture of seeded constructs allows for the formation of vessels (prevascularization) within the construct (paragraph [0161], [0174]).
However, Chen does not disclose wherein the tissue construct is cultured under dynamic perfusion conditions, as required by claim 14.
Cui discloses methods of generating vascularized engineered cardiac tissue constructs (paragraphs [0083]-[0088], [0090], [0093]-[0096]). Cui generates a vascularized engineered human myocardial tissue comprising mixing human iPSC-cardiomyocytes (CM), and optionally cardiac fibroblasts, in a hydrogel bioink (paragraphs [0087], [0095]), and mixing endothelial cells (EC) in a hydrogel bioink (paragraph [0088]). Cui discloses the method comprises printing layers of anistropic fibers comprising CM and layers of perfusable vascular structures comprising the ECs [0091]-[0097], FIG 2A, 2B). The vascular layers comprise mid-diameter (arteriole-scale) vessels (paragraphs [0094]-[0095], [0100], [0104]-[0105]; FIG 7A). Thus, the printed vascularized engineered cardiac tissue construct comprises a pattern with arteriole-scale vessels.
Cui discloses the printed vascularized engineered cardiac tissue construct is cultured in vitro under dynamic perfusion conditions (paragraphs [0095], [0109]-[0110], [0126]-[0130]). Cui shows vascularized engineered cardiac tissue constructs subjected to dynamic perfusion conditions demonstrate increases in functional markers for cardiomyogenesis and angiogenesis (paragraphs [0110], [0130]; FIGs 8A-8D, 9A-9F; 10A-10D; 36A-36D; 37A-37D).
It would have been obvious to combine the method of making a vascularized engineered cardiac tissue construct of Chen, comprising embedding fibers coated with endothelial cells in a biomaterial matrix to form a pattern with arteriole-scale channels; perfusing IPS-cardiomyocytes into the biomaterial matrix, and culturing the vascularized engineered human myocardial tissues, further with the method Cui. A skilled artisan would have been motivated to culture the vascularized engineered cardiac tissue under dynamic perfusion conditions because Cui discloses subjecting such constructs to dynamic perfusion conditions increases the cardiomyogenesis and angiogenesis markers/function of the construct. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as culturing engineered myocardial constructs via dynamic perfusion conditions was known in the art at the time of the invention.
Conclusion
No claims are allowed.
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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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