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 .
Information Disclosure Statement
The information disclosure statement (IDS) filed 06/18/2026 has been considered and the references therein are of record.
Response to Amendment
Applicant’s amendment filed 07/27/2026 is acknowledged. Claims 1, 7, 9, and 17 are amended. Claim 1 is amended to incorporate the limitations of original claims 7, 9, and 10. Claim 7 is amended to a subset of its original Markush group to distinguish it from amended claim 1. Claim 9 is amended to an alternative range. Claim 17 is amended (i) to incorporate a modified version of the limitation of canceled claim 20; and (ii) to specify that the degree of functionalization refers to the hydrogel. Claim 10 and 20 are canceled. Claims 1-9, 11-17, 21, and 22 are under examination.
Objections Withdrawn
The objection to claim 20 for minor informalities is withdrawn in response to Applicant’s cancellation of the claim.
Rejections Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claim 20 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in response to Applicant’s cancelation of the claim, and Applicant’s amendment to claim 17 that specifies that the degree of functionalization refers to the hydrogel.
Claim Rejections - 35 USC § 101
The rejection of claims 4, 6, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental process/abstract idea judicial exception without significantly more is withdrawn in response to Applicant’s arguments and upon further consideration. Applicant’s argument that the judicial exceptions are integrated into the practical application of assessing the effects of specific hydrogel composition as one part of the claimed method of treatment itself (for claims 4 and 6) or to specifying a spectral correlation that allows the skilled artisan to identify an important physical feature of a claimed composition is found to be persuasive.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 11-12, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al., 2016 is withdrawn in response to Applicant’s amendment to the claims which incorporates limitations into claim 1 that were not taught by Zhu. Therefore, the rejection of claims 2- 10, 13, 14, and 16 because of their dependence on these claims is also withdrawn.
Double Patenting
The provisional rejection of claims 1-9, 11-17, 21, and 22 on the ground of nonstatutory double patenting as being unpatentable over claims 30, 36, 46, 48, and 51-57 of co-pending Application No. 17/429540 is withdrawn in response to Applicant’s amendment to independent claims 1 and 17, which now require the treatment of specific disorders and degree of functionalization, neither of which are anticipated by the co-pending claims.
Rejections Maintained
This is a modified rejection necessitated by Applicant’s amendment to the claims.
Claim Rejections - 35 USC § 103
The rejection of claims 1-9, 11-17, 21, and 22 under 35 U.S.C. 103 as being unpatentable over Zhu et al., 2016 and in further view of Lee et al., 2014 (WO2014042463A1), Natesan et al., 2019, Carnahan et al., 2010 (EP2247645B1), and ThermoFisher, 2019 is maintained in response to Applicant’s amendment, which incorporated limitations of the cancelled claims.
The instant claims are drawn to a method of promoting arteriogenesis for treating a disorder in a subject by administering a crosslinked hydrogel that has a chemically-attached extracellular epitope of an N-cadherin peptide with SEQ ID NOs: 1 or 2, where the hydrogel comprises 1-20% or 3-15% of gelatin by weight, has pores with diameters of about 20-80 um, and stiffness of about 800 Pa to 5 kPa. The method provides arteriogenesis such that artery growth, arteriole growth, or a combination thereof occurs in 1-14 days, corresponds to a vessel with a diameter of about 0.1-1 mm, increases blood flow to an area having impaired blood flow, and repairs damage caused by ischemia. The instant claims are drawn to the disorder being ischemic heart disease, coronary artery disease, ischemic heart failure, peripheral artery disease, critical limb ischemia, diabetic foot ulcer, organ transplant, skin wound, and bone fracture. The method can use a crosslinker comprising an acrylate group, a phenol group, a multivalent polyethylene glycol (PEG), or a combination thereof, or via non-covalent interactions. The method uses a biomaterial that can be administered with cells, a growth factor, or a combination thereof. The method can use a biomaterial that is administered without cells. The instant claims are also drawn to a composition comprising a hydrogel crosslinked by a multivalent polyethylene glycol succinimidyl glutarate crosslinker with an average molecular weight of about 1-40 kDa and has an extracellular epitope of a cadherin protein chemically attached to the hydrogel, which has a degree of functionalization of about 10% to about 70% as measured by the amount of valine of the peptide relative to the amount of phenylalanine of the hydrogel per nuclear magnetic resonance.
Zhu teaches a method of promoting angiogenesis (page 46, 2nd column, Section 2.5 of Results, first paragraph; Fig. 4A; Fig. S7) by administering a crosslinked hydrogel that has a chemically-attached extracellular epitope of an N-cadherin peptide with sequence HAVDIGGGC that has 100% sequence identity to SEQ ID NO: 1 and 91.4% sequence identity to SEQ ID NO: 2, where the hydrogel is crosslinked via a crosslinker comprising an acrylate group (page 50, 2nd column, Section 4.1 of Materials and Methods, first paragraph) as required by instant claims 1 and 11. The method uses a biomaterial that is administered with cells (Fig. 1) as required by instant claims 15. Alignment data between the peptide taught by Zhu and instant SEQ ID NOs: 1 and 2, respectively, are shown below.
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126
589
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118
586
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Zhu does not explicitly teach a method of promoting arteriogenesis by administering a crosslinked hydrogel that has a chemically-attached extracellular epitope of an N-cadherin peptide with 100% sequence identity to SEQ ID NO: 2, where the hydrogel comprises 1-20% of gelatin by weight, has pores with diameters of about 20-80 um, and stiffness of about 800 Pa to 5 kPa. Zhu does not teach a method that provides arteriogenesis such that artery growth, arteriole growth, or a combination thereof occurs in 1-14 days, corresponds to a vessel with a diameter of about 0.1-1 mm, increases blood flow to an area having impaired blood flow, and repairs damage caused by ischemia. Zhu does not teach a method that uses a biomaterial that can be administered without cells. Zhu does not teach a composition comprising a hydrogel crosslinked by a multivalent polyethylene glycol succinimidyl glutarate crosslinker with an average molecular weight of about 1-40 kDa and has an extracellular epitope of a cadherin protein chemically attached to the hydrogel, where the hydrogel has a degree of functionalization of about 10% to about 70% as measured by the amount of valine of the peptide relative to the amount of phenylalanine of the hydrogel per nuclear magnetic resonance. To summarize, Zhu does not explicitly teach all of the limitations of claims 2-11, 13-14, and 16-22.
Lee teaches a method of promoting angiogenesis (para [75, 220-224, 243, & 291-311]; Fig. 7-15) by administering a multivalent polyethylene glycol succinimidyl glutarate-crosslinked hydrogel (para [71, 106, 110, 141,223, & 235]; Fig 14) that has been functionalized (para[30-32]; claims) with a chemically-attached angiogenic peptide (para [75]; Fig. 11; claims), where the peptide can be a cadherin protein (claims 4, 6, & 10), the hydrogel can comprise gelatin (para [102]), have pores of about 10-100 μm (claim 20) in diameter that can be optimized to a desired size (para [159-161]), stiffness of 0.2k- 2kPa (claim 19) that can be optimized (para [264]), can be administered with/without cells (claims), and can be used in medical treatment and wound healing (para [12, 41, & 128-130]). Lee teaches that gelatin can be used to offer controlled elasticity of the hydrogel (para [98-102]). Lee teaches that there is an optimal pore size for cell infiltration and host tissue ingrowth of endothelial cells (table 2). Lee teaches that porosity and pore architecture plays a significant role in cell survival, proliferation, and migration and are key to the hydrogel microenvironment and that the porosity of a hydrogel depends on PEG molecular weight and concentration (para [157-163]).
Lee does not explicitly teach the specific days within which artery/arteriole growth would occur. Lee does not explicitly teach that the artery/arteriole growth would be functional and would deliver blood to a wound. Lee does not explicitly teach the method of using the hydrogel would be useful for vascular and cardiovascular repair in human patients. Lee does not teach an extracellular epitope of an N-cadherin peptide with 100% sequence identity to SEQ ID NO: 2.
Natesan teaches a method of promoting arteriogenesis by administering to a wound a PEGylated fibrinogen hydrogel comprising multivalent PEG succinimidyl glutarate (page 325, 1st column, 3rd paragraph), where the artery/arteriole growth occurs within 8 days and were functional (Figure 7). Natesan teaches these hydrogels would be useful for treating patients, especially skin wounds (Innovations). Natesan teaches that the method promotes formation of mature, functional blood vessels with express smooth muscle cell markers (Figure 1-9).
Carnahan teaches a method of promoting angiogenesis for treating a disorder comprising administering a multivalent PEG succinimidyl glutarate crosslinked hydrogel, where the hydrogel can comprise gelatin and be used for vascular and cardiovascular repair (para [0027]).
Neither Natesan or Carnahan teach an extracellular epitope of an N-cadherin peptide with 100% sequence identity to instant SEQ ID NO: 2 (HAVDIGGGCE), which differs from instant SEQ ID NO: 1 by only an additional glutamic acid at the C-terminal of the peptide.
ThermoFisher teaches that carbodiimide compounds provide the most popular method for crosslinking to carboxylic acids (–COOH), such as occur in proteins (Introduction, Carboxyl-reactive crosslinker reactive groups, para 1-2). Thermofisher teaches that carbodiimide conjugation works by activating carboxyl groups for direct reaction with primary amines via amide bond formation (Introduction, Carboxyl-reactive crosslinker reactive groups, para 3). ThermoFisher teaches that EDC, which is a type of carbodiimide conjugation, provides the only method for crosslinking amines to carboxyl groups of peptides, using the C-terminus and/or side chain of glutamic acid (Applications for EDC crosslinking, 2. Label carboxyl groups using amine-containing compounds, para 1).
It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhu, Lee, Natesan, Carnahan, and ThermoFisher. One with ordinary skill in the art would be motivated to make and use the claimed invention because Zhu teaches a peptide that promotes angiogenesis and Lee teaches an adjustable hydrogel composition that can be tuned to a specific porosity and stiffness for optimal angiogenesis; in other words, an ordinary artisan would be motivated to combine the teaching of Zhu and Lee to make an optimizable hydrogel for promoting angiogenesis. An ordinary artisan would be motivated to use gelatin in the hydrogel composition since Lee teaches that gelatin can be used to offer controlled elasticity of the hydrogel. Furthermore, an ordinary artisan would have found it obvious that the method of using the hydrogel taught by Zhu and Lee would promote functional, blood-delivering artery/arteriole growth within 1-14 days to patient’s wounds and could be used for vascular and cardiovascular repair in view of Natesan’s and Carnahan’s teachings. An ordinary artisan would be motivated to add a glutamic acid to the C-terminus of the peptide taught by Zhu in view of the ThermoFisher’s teaching that crosslinking with EDC uses the C-terminus and/or side chains of glutamic acid. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
The prior art only differs from the claimed invention with respect to the claimed amounts and/or ranges of the pore size, diameter of vessels, percentage of gelatin, stiffness, multivariant PEG molecular weight, and degree of functionalization. The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. It would have been prima facie obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to arrive at the claimed invention because an ordinary artisan would have found it obvious to optimize the hydrogel through routine experimentation. Since Lee teaches that the hydrogel composition can be optimized, an ordinary artisan would have been motivated to optimize the composition to make the most angiogenic composition. MPEP 2144 sets forth Applicant’s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification teaches effective embodiments of the claimed invention that have various amounts or ranges recited for the pore size, diameter of vessels, percentage of gelatin, stiffness, multivariant PEG molecular weight, and degree of peptide functionalization, which is evidence of non-criticality to the claimed invention.
Therefore, claims 1-9, 11-17, 21, and 22 are obvious in view of the disclosures of Zhu, Lee, Natesan, Carnahan, and ThermoFisher.
Response to Arguments
Applicant argues that the claimed methods and compositions have surprising effects. Applicant argues that the inventors have surprisingly found that these biomaterials are potent inducers of arteriole and artery growth both in vitro and in vivo, not merely angiogenesis. Applicant argues that Zhu fails to disclose a biomaterial that comprises a crosslinked hydrogel comprising gelatin and a peptide chemically attached to the scaffold comprising an extracellular epitope of N-cadherin. Applicant argues that, in the examples of the application as filed, biomaterials as required by claim 1 (e.g., GelMA-Cad, also referred to as "Bioactive Cad" & "GelCad") are potent inducers of arteriole and artery growth both in vitro and in vivo. Applicant argues that, with reference to Example 2, biomaterials according to the invention 'Bioactive Cad' were shown to increase arteriole structure and density in a murine model. Applicant argues that, with reference to Example 3, biomaterials according to the invention were shown to promote arteriole growth in experiments with murine brain tissue both in vivo and ex vivo. Applicant argues that examples 5 and 6 demonstrate the claimed biomaterials promote smooth muscle cell growth contributing to the formation of arteriole structures and promote arterial growth in brain tissue. Applicant argues that further results pertaining to promotion of new vasculature was also observed with human brain tissue. Applicant argues that collectively these data demonstrate that upon embedding primary mouse and human tissues in the claimed biomaterials, said tissues rapidly sprout large blood vessels, where these vessels are millimeters in length and exhibit biomimetic organization of smooth muscle cell rings lining an inner endothelial cell core. Applicant argues that perfusable arteries rapidly grow into the biomaterials when implanted in vivo. Applicant argues that the claimed biomaterials provide a beneficial technology for promoting arteriogenesis. Applicant argues that neither Zhu nor its supporting references have been shown to provide guidance on biomaterials as claimed being potent inducers of arteriole and artery growth both in vitro and in vivo rather than capillary growth. Applicant argues that the Office cites Natesan as teaching arteriogenesis, but without providing evidence of where this feature is taught. Applicant argues that the cited references fail to provide any teaching which would motivate the skilled person to arrive at a biomaterial having the combination of features required by claim 1 with any reasonable expectation that such a biomaterial would exhibit the surprising results outlined above. Applicant argues that one of skill in the art would have no expectation of arriving at the advantageous uses of the claimed biomaterials from their disclosure.
This has been fully considered, but is not found to be persuasive. In regard to Applicant’s argument against Zhu individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In regards to Applicant’s arguments of results that would not have been expected in view of Zhu, it is the combination of the prior art references and the ability to optimize the composition as taught by Lee that makes it obvious to make the composition and reasonably expect the composition to induce arteriogenesis. In regards to Applicant’s argument that Natesan doesn’t teach arteriogenesis, Figures 5-6 specifically show that the vessels express smooth muscle actin, which is the same marker used by Applicant to identify arterioles, such as in Figure 8 of the Specification. As such, it would be obvious in view of the combined references that the composition would facilitate the growth of arteries/arterioles and could be optimized to make the most effective composition.
Conclusion
No claims are allowed.
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.
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/JOSEPH D. CESARE/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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