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 .
Status of Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 27, 2026 has been entered.
Receipt of Applicants’ Remarks, amended claims and Declaration on 03/27/2026 are acknowledged.
Claims 1, 2, 5, 6, 9, 14,16, 25-26, 50, 53, 56, 58-60, 63, and 78-79 are pending.
Claims 3, 4, 7, 8, 10-13, 15, 17-24, 27-49, 51-52, 54-55, 57, 61-62, 64-65, 67, 69, 71, 73-74 and 77 are cancelled.
Claims 36, 66, 68, 70, 72, 75, 76 are withdrawn per the restriction requirement.
Claim 1, 2, 5, 6, 9, 14, 16, 25-26, 50, 53, 56 and withdrawn claims 66, 68, 70,72,75 and 76 are all amended.
Claims 78-79 are new.
Claims 1, 2, 5, 6, 9, 14, 16, 25-26, 50, 53, 56, 58-60, 63, and 78-79 are under examination in this application.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 2, 5, 6, 9, 14, 16, 25-26, 50, 53, 56, 58-60, 63, and 78-79 are rejected under 35 U.S.C. 103 as being unpatentable over Paluck et al. (Heparin-Mimicking Polymers: Synthesis and Biological Applications, Biomacromolecules 2016, 17, 3417-3440; hereinafter “Paluck”) in view of Powis et al. (Inhibition of Growth Factor Binding and Intracellular Ca²⁺ Signalling by Dextran Sulfates of Different Sizes and Degrees of Sulfation, Cancer Chemotherapy and Pharmacology 30, 483–486 (1992); hereinafter “Powis”), Sun C. et al. (Sun C, Liu M, Sun P, Yang M, Yates EA, Guo Z, Fernig DG. Sulfated Polysaccharides Interact with Fibroblast Growth Factors and Protect from Denaturation, FEBS Open Bio 9(8):1477–1487 (2019); hereinafter “Sun 2019.”), Sun G. et al. (Functional Neovascularization of Biodegradable Dextran Hydrogels with Multiple Angiogenic Growth Factors, Biomaterials 32, 95–106 (2011); hereinafter “Sun 2011”), and Liu et al. (A Biomimetic Hydrogel Based on Methacrylated Dextran-graft-Lysine and Gelatin for 3D Smooth Muscle Cell Culture, Biomaterials 31, 1158–1170 (2010); hereinafter “Liu”), and further in view of Li et al. (Functional Hydrogels with Tunable Structures and Properties for Tissue Engineering Applications, Frontiers in Chemistry, Oct. 2018, Vol. 6, Art. 499; hereinafter “Li”). Chauvierre et al. (Artificial Oxygen Carrier Based on Polysaccharides-Poly(alkyl cyanoacrylates) Nanoparticle Templates, Biomaterials 31, 6069–6074 (2010); hereinafter “Chauvierre”) is additionally relied upon for claim 14.
Regarding claim 1, the claim now recites a hydrogel comprising a plurality of synthetic polymers cross-linked to each other by a cross-linker, wherein: (i) the synthetic polymers comprise a dextran modified to comprise one or more negatively charged functional groups, wherein the negatively charged functional groups comprise a sulfate group and the synthetic polymers comprise greater than 1 sulfate group per monosaccharide unit; (ii) the cross-linker is derived from an alkene containing moiety covalently attached to the synthetic polymers; (iii) the negatively charged functional groups provide negative charge sufficient to promote binding of a growth factor, growth factor activity, and vascularization; and (iv) the synthetic polymers do not impair blood coagulation.
Paluck teaches heparin-mimicking polymers based on dextran modified with negatively charged functional groups. Specifically, Paluck discloses carboxymethyl benzylamide sulfonate dextrans (CMDBS), in which the hydroxyl groups of the dextran backbone are chemically modified to carry carboxymethyl, benzyl, and sulfonate functional groups (p. 3419, para. 2.1, Fig. 3). Paluck establishes that negatively charged sulfonate groups on a dextran backbone confer heparin-mimicking properties including binding of fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), and platelet-derived growth factors (PDGFs) (Table 1, p. 3418), and promotion of cell proliferation and growth factor activity. Paluck further establishes that the amount and presentation of negative charge on the dextran polymer is a recognized result-effective variable that controls the extent of growth factor interaction and biological activity, and that this could be altered by exploiting co-monomers with different reactivity ratios (p. 3436, left col., last para.).
Powis establishes two independent propositions: first, the structural fact that dextran sulfates with degrees of sulfate substitution (DS) up to 1.9 O-sulfate groups per monosaccharide unit exist and interact with PDGF (Powis, abstract, p. 483); second, that the anticoagulant activity of dextran sulfate is MW-dependent rather than DS-dependent (id., pp. 483–484), meaning low-MW dextran sulfate variants within the range of claim 26 (5 kDa to 650 kDa) can be selected to minimize anticoagulant activity while retaining O-sulfate groups for growth factor binding.
Sun 2019 directly demonstrates that dextran sulfate (DXS) binds both FGF1 and FGF2 and protects them from thermal denaturation comparably to heparin, as demonstrated by differential scanning fluorimetry and cell proliferation assays (abstract; Figs. 3–5, pp. 1479–1482). Specifically, Sun 2019 show that DXS was more effective at stabilizing FGF1 than heparin (p. 1480, Fig. 3C) and that DXS stabilization of FGF2 reached a melting temperature of 77.2°C, with DXS remaining bound to FGF2 throughout thermal denaturation (p. 1480, Fig. 4C). Sun 2019 further demonstrates that polysaccharides with high degrees of sulfation — such as dextran sulfate and heparin — bind and stabilize FGFs, while chondroitin sulfate, which has a lower degree of sulfation, does not (pp. 1479–1480), directly establishing that sufficient sulfation of a dextran backbone is what drives FGF binding and activity. These data establish that dextran sulfate with direct O-sulfate groups promotes FGF growth factor binding and activity as recited in claim 1. Sun 2019 is relied upon for two teachings: (1) DXS binds FGF1 and FGF2 directly and maintains their conformation and biological activity, which satisfies the limitations “promotes binding of a growth factor” and “growth factor activity” as recited in claim 1; and (2) that sufficient sulfation of a dextran backbone — not any structural motif unique to heparin — is the determinative factor driving FGF binding. Notably, Sun 2019 specifies that dextran sulfate (DXS) contains six sulfate groups per disaccharide (Sun 2019, p. 1479), which corresponds to approximately 3 sulfate groups per monosaccharide unit — directly confirming that dextran sulfate with DS greater than 1 per monosaccharide unit, as recited in claim 1, is a well-characterized, commercially available material whose FGF-binding properties were established in the prior art before the effective filing date.
The vascularization component of claim 1 is taught by Sun 2011, which demonstrates that dextran-GMA hydrogels loaded with growth factors promote functional neovascularization in vivo (Sun 2011, p. 95, abstract; Figs. 3–5). The references work in combination: Paluck, Powis, and Sun 2019 collectively teach the sulfated dextran → growth factor binding nexus; Sun 2011 and Liu teach the dextran-methacrylate hydrogel platform that promotes vascularization when combined with the sulfated dextran of the other references.
A person of ordinary skill in the art (PHOSITA) combining the teachings of Paluck (negatively charged dextran derivatives promote growth factor binding and heparin-mimicking activity), Powis (dextran sulfates with DS up to 1.9 O-sulfate groups per monosaccharide unit are structurally achievable), and Sun 2019 (dextran sulfate specifically binds FGF1 and FGF2 with high affinity, more effectively than heparin for FGF1) would have been motivated and would have had a reasonable expectation of success in producing a dextran modified with greater than 1 direct O-sulfate group per monosaccharide unit to achieve the claimed growth factor binding and vascularization activity. Optimizing the degree of sulfation on the dextran backbone to achieve sufficient negative charge density for growth factor binding represents routine optimization of a recognized result-effective variable. See In re Aller, 220 F.2d 454, 456 (CCPA 1955); MPEP § 2144.05.
Regarding the limitation that the synthetic polymers do not impair blood coagulation:
Powis discloses that the growth factor-inhibiting activity of dextran sulfates correlates with molecular weight rather than degree of sulfate substitution (abstract, p. 483–484). This establishes that the degree of O-sulfation and the anticoagulant activity of dextran sulfate can be decoupled through MW selection. The art has consistently recognized that low-molecular-weight dextran sulfates (e.g., 5–10 kDa) are significantly less anticoagulant than high-MW forms, because dextran sulfate anticoagulation is predominantly MW-dependent. See Powis (MW 5–500 kDa tested; p. 484). Claim 26, which depends from claim 1, expressly encompasses synthetic polymers with mean weight-average molecular weights from 5 kDa to 650 kDa — the lower end of this range encompasses compositions where anticoagulant activity would be expected to be minimal or absent based on the MW-dependence established by Powis, even at DS > 1 per monosaccharide unit.
Paluck further teaches that the anticoagulant activity of CMDBS dextran derivatives is composition-dependent and that certain CMDBS variants exhibit much lower antithrombotic activity than heparin itself (p. 3419, right col., 2nd to last para.), establishing the general principle that negatively charged dextran derivatives can be formulated to minimize anticoagulant activity while retaining growth factor binding properties. Achieving a non-anticoagulant, growth factor-binding dextran sulfate composition by selecting appropriate MW and DS combinations represents routine optimization of recognized result-effective variables. See In re Aller, 220 F.2d 454, 456 (CCPA 1955); In re Applied Materials, 692 F.3d 1289, 1295–96 (Fed. Cir. 2012); MPEP § 2144.05.
However, neither Paluck, Powis, nor Sun 2019 specifically discloses a dextran hydrogel in which the sulfated dextran polymers are cross-linked via an alkene-containing moiety covalently attached to the polymer chains.
Sun 2011 discloses biodegradable dextran hydrogels formed by functionalizing dextran with glycidyl methacrylate (GMA) groups, wherein the epoxide ring of GMA is opened by the dextran hydroxyl groups, leaving a pendant methacrylate group covalently attached to the dextran backbone (Materials and Methods, p. 96). The resulting glycidyl-methacrylate-derivatized dextran (Dex-GMA) has methacrylate groups — alkene-containing moieties — covalently attached to the synthetic polymer chains as recited in claim 1. Sun 2011 teaches that these Dex-GMA polymers are cross-linked via thiol-Michael addition reaction between the pendant methacrylate groups and dithiothreitol (DTT) as the dithiol crosslinker, forming a stable three-dimensional hydrogel network (id., pp. 95–96). Sun 2011 further demonstrates that these Dex-GMA hydrogels promote functional neovascularization and VEGF-mediated tissue vascularization when loaded with angiogenic growth factors, and that the degree of GMA substitution controls hydrogel mechanical properties and growth factor release capability (pp. 96–100, Figs. 1–5).
Liu independently discloses a biomimetic hydrogel based on methacrylate-functionalized dextran (Dex-MA), wherein methacrylate groups are covalently attached to the dextran backbone via glycidyl methacrylate to provide pendant alkene-containing crosslinkable moieties (p. 1159, section 2.1). Liu teaches that photo-crosslinking through the pendant methacrylate double bonds forms stable dextran hydrogels for vascular tissue engineering (pp. 1159, 1163–1165), providing independent confirmation of the same dextran-methacrylate hydrogel platform.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Paluck, Powis, and Sun 2019 (sulfated dextran with direct O-sulfate groups at DS > 1 per monosaccharide, promoting FGF/VEGF/PDGF binding without anticoagulation) with the teachings of Sun 2011 and Liu (dextran functionalized with covalently attached methacrylate groups forming crosslinked hydrogels) to arrive at the claimed hydrogel. Therefore motivation for this combination is reasonably strong:
First, all five references operate within the same technical field of modified dextran polymers for biomedical and tissue engineering applications, and a PHOSITA would have been familiar with all of them.
Second, Sun 2011 and Liu establish that covalently attaching pendant methacrylate groups to dextran hydroxyl groups via glycidyl methacrylate is a well-known, routine synthetic transformation (Sun 2011, p. 96; Liu, p. 1159). Because dextran has three reactive hydroxyl groups per monosaccharide unit (C2, C3, and C4), a PHOSITA would have recognized that some hydroxyl groups can be modified with sulfate groups (as in Powis) while others are modified with methacrylate groups (as in Sun 2011 and Liu), yielding a bifunctionally modified dextran that retains negatively charged O-sulfate groups for growth factor binding while gaining crosslinkable methacrylate moieties for hydrogel formation.
Third, the explicit goal of producing a vascularizing hydrogel with heparin-mimicking growth factor binding properties but without anticoagulant activity was an expressly recognized objective in the art. Paluck identifies enhancing therapeutic efficacy and reducing side effects through fine-tuning of heparin-binding motifs as a motivating objective (p. 3417, abstract). Sun 2011 states an objective of promoting vascularization through growth-factor-loaded dextran hydrogels (p. 95, abstract). Sun 2019 establishes that dextran sulfate achieves the growth factor binding activity needed. Combining the sulfated dextran growth-factor-binding properties taught by Paluck, Powis, and Sun 2019 with the hydrogel-forming capability of crosslinked Dex-GMA taught by Sun 2011 and Liu would have represented a predictable combination of known elements yielding expected results. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416–421 (2007); MPEP § 2141(III)(A).
From the teachings of the references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. The invention as a whole would have been prima facie obvious before the effective filing date, especially in the absence of evidence to the contrary.
Regarding claim 2, the claim now requires the synthetic polymers to promote growth factor binding, growth factor activity, and vascularization to a greater extent than a corresponding polysaccharide bearing hydroxyl groups instead of negatively charged functional groups. Paluck expressly teaches that unmodified dextran lacking negatively charged groups does not interact with heparin-binding growth factors, whereas CMDBS dextran derivatives bind FGFs, VEGFs, and PDGFs (Table 1, p. 3418; p. 3419, right col., para. 2.1). Powis discloses that native dextran at DS = 0 has no growth factor interaction, while dextran sulfates at DS > 0 interact with growth factors (Powis, p. 484). Sun 2019 demonstrates that unmodified dextran does not bind or stabilize FGFs, while dextran sulfate (DXS) does so comparably to or better than heparin (Sun 2019, Figs. 3–5, pp. 1479–1482). Sun 2011 teaches that growth-factor-loaded dextran hydrogels promote vascularization significantly beyond baseline dextran scaffolds lacking growth factor binding activity (Sun 2011, pp. 98-100, Figs. 3–5).
Regarding claim 5, Paluck (Table 1, p. 3418) exemplifies growth factors involved in cell growth and migration including FGFs, VEGFs, and PDGFs. All growth factors recited in claim 5 — VEGF, FGF, BMP, EGF, PDGF, WNT, and combinations thereof — are known heparin-binding growth factors that interact with negatively charged sulfated polysaccharides as established by Paluck and Sun 2019.
Regarding claim 6, Paluck (Table 1, p. 3418) lists chemokines and cytokines that activate or are released from inflammatory cells as heparin-binding proteins. Claim 6 recites a cytokine that is optionally an interleukin, interferon, or chemokine, which falls within Paluck’s disclosed class of negatively-charged-dextran-binding proteins.
Regarding claim 9, Paluck discloses that poly(4-styrenesulfonic acid) (pSS), a sulfonated polymer, promotes FGF2 signaling in muscle progenitor cells to a level most comparable to heparin among the sulfonated polymers tested (p. 3432, left col., 1st para.). Sun 2019 demonstrates that DXS binds FGF1 directly and preserves its biological activity following incubation at physiological temperature, at a level comparable to heparin (Sun 2019, Fig. 6, p. 1481–1482). This establishes that dextran sulfate with direct O-sulfate groups promotes growth factor binding and maintains growth factor activity as recited in claim 9. Paluck further discloses that sulfonated polymers including pSS promote FGF2-dependent signaling in muscle progenitor cells to a level most comparable to heparin (p. 3432, left col., 1st para.). Together these references establish that sulfated dextran-based polymers can promote growth factor dependent cell signaling equivalent to heparin.
Regarding claim 14, the claim now requires the synthetic polymers to be characterized by a zeta potential of about −10 mV to about −60 mV. Chauvierre teaches the effect of negatively charged modifications on the zeta potential of polysaccharide-based materials, disclosing that the zeta potential of dextran-based nanoparticles varied from −10 mV for unmodified 70 kDa dextran-bearing particles to −47 mV for highly charged heparin-PIBCA nanoparticles, and that BTCA-modified dextran nanoparticles reached −31 mV (Chauvierre, p. 6071, para. 3.2.2, Zeta potential effect). The range of −10 mV to −47 mV disclosed in Chauvierre for increasingly charged dextran derivatives directly overlaps with the claimed range of about −10 mV to about −60 mV. It would have been obvious to one of ordinary skill in the art that increasing the degree of O-sulfation on the dextran backbone — as taught by Powis (DS 0.3 to 1.9) — would shift the zeta potential to more negative values within the claimed range, as more sulfate groups increase the negative charge density of the polymer. See In re Aller, 220 F.2d 454, 456 (CCPA 1955).
Regarding claim 16, Powis discloses dextran sulfates with DS up to 1.9 sulfate groups per monosaccharide unit (Powis, p. 483), which expressly encompasses at least about 1.5 sulfate groups per monosaccharide unit as recited in claim 16. Paluck discloses that the CMDBS synthesis achieves varying degrees of sulfonate substitution by repeating sulfonation reaction steps, with three hydroxyl positions per dextran monosaccharide available for modification (Paluck, p. 3419, right col., 1st para.), and that the degree of negative charge is a result-effective variable controlling biological activity (p. 3436, left col., last para.). It would have been prima facie obvious to optimize the degree of O-sulfation to at least about 1.5 sulfate groups per monosaccharide unit to achieve a sufficient degree of negative charge for growth factor binding activity, as this parameter is both routinely adjustable and within the DS range expressly disclosed by Powis. See In re Aller, 220 F.2d 454, 456 (CCPA 1955); MPEP § 2144.05.
Regarding claims 25 and 26, Paluck discloses CMDBS as a semisynthetic derivative of dextran (p. 3419, para. 2.1; claim 25) with molecular weights ranging from 5.5 to 190 kDa (p. 3419, right col., para. 2). Powis discloses dextran sulfates with molecular sizes from 5 to 500 kDa (Powis, p. 483). The claimed mean weight-average molecular weight range of about 5 kDa to about 650 kDa in claim 26 is fully encompassed by the molecular weight ranges collectively disclosed by Paluck and Powis.
Regarding claims 50, 53, and 56, Li discloses hydrogels further comprising cell-adhesive peptides (p. 4, right col., last 4 lines of “photopolymerization” section; claim 50), at least one growth factor loaded into the hydrogel (p. 10, right col., last para.; claim 53), and a population of cells including those derived from bone, cardiac, heart valve, skin, and muscle tissue (p. 3, Table 1; claim 56).
Regarding claims 58–60 and 63, Li discloses hydrogels supporting multiple cell type populations (p. 3, Table 1; claim 58), including parenchymal cells from heart, lung, liver, kidney, and muscle (id.; claims 58, 60), as well as stromal cells including endothelial cells and fibroblasts (id.; claim 63). Claim 59 recites parenchymal cells, stromal cells, or both, all of which are within Li’s tissue engineering cell type disclosures.
Regarding claim 78, Sun 2011 expressly teaches that the alkene-containing moiety covalently attached to the dextran backbone is a methacrylate group, introduced via glycidyl methacrylate to yield Dex-GMA (Sun 2011, Materials and Methods, p. 96). Methacrylate is one of the group consisting of methacrylate, acrylate, and maleimide recited in the Markush group of claim 78. Liu independently teaches the same methacrylate-functionalized dextran platform (Liu, p. 1159, section 2.1), providing further prior art support for the methacrylate moiety of claim 78.
Regarding claim 79, Sun 2011 expressly teaches that the alkene-containing moiety covalently attached to the dextran polymer backbone is methacrylate, introduced via glycidyl methacrylate (Sun 2011, p. 96). Liu independently teaches the same methacrylate group on dextran via glycidyl methacrylate for crosslinkable hydrogel formation (Liu, p. 1159, section 2.1). Both references directly meet the limitation of claim 79 that the alkene-containing moiety is specifically methacrylate.
Response to Remarks/Arguments
Applicants’ arguments filed 03/27/2026 have been fully considered but are not persuasive.
Applicants argue that the cited references fail to teach or suggest a hydrogel comprising synthetic dextran polymers that both promote growth factor binding and vascularization and do not impair blood coagulation.
This traversal is not persuasive. As set forth above, Sun 2019 directly demonstrates that dextran sulfate (DXS) with direct O-sulfate groups on the glucose monosaccharide backbone binds FGF1 and FGF2 with high affinity and potentiates their biological activity (Sun 2019, abstract; Figs. 3–5, pp. 1479-1482). Sun 2019 establishes that it is the degree of sulfation, not any specific structural motif unique to heparin, that drives FGF binding activity. Separately, Powis establishes that the growth factor interaction of dextran sulfates correlates with molecular weight, not degree of sulfation — meaning that low-molecular-weight dextran sulfates with DS > 1 per monosaccharide can achieve growth factor interaction without the high MW required for potent anticoagulation. Paluck further establishes the general principle that negatively charged dextran derivatives can be formulated across a range of compositions, and that compositions with low sulfonate/carboxymethyl content exhibit substantially reduced antithrombotic activity relative to heparin (Paluck, p. 3419, right col., 2nd to last para.). A PHOSITA selecting appropriate MW and DS combinations within the ranges expressly taught by Powis (DS 0.3–1.9, MW 5–500 kDa) would have had a reasonable expectation of achieving a non-anticoagulant, growth-factor-binding dextran sulfate composition through routine experimentation. See KSR, 550 U.S. at 421.
Applicants argue that the cited references fail to teach or suggest a cross-linker derived from an alkene-containing moiety covalently attached to the synthetic polymers.
This traversal is not persuasive. Sun 2011 expressly teaches that glycidyl methacrylate-derivatized dextran (Dex-GMA) contains pendant methacrylate groups covalently esterified to the dextran hydroxyl groups, and that cross-linking via Michael addition between these pendant methacrylate groups and a dithiol crosslinker forms a stable dextran hydrogel (Sun 2011, p. 96). Liu independently teaches pendant methacrylate groups covalently attached to dextran for photo-crosslinkable hydrogel formation (Liu, p. 1159). Both alkene-group installation reactions — GMA ring-opening onto dextran hydroxyls, or direct esterification — are well-established, routine dextran modification techniques that a PHOSITA would have been fully motivated to apply to a sulfated dextran backbone.
Response to Amendment
The declaration under 37 CFR 1.132 filed 03/27/2026 is insufficient to overcome the rejection of claim 1, 2, 5, 6, 9, 14, 16, 25-26, 50, 53, 56, 58-60, 63, and 78-79 based upon the combination of cited prior art of record applied under 35 U.S.C. 103 as set forth in the last Office action because: showing is not commensurate in scope with the claims.
Applicants have submitted a declaration asserting that preparation of the claimed dual-modified dextran hydrogel presented significant solubility and processability challenges. The examiner has considered this declaration but finds it insufficient to rebut the prima facie case of obviousness for the following reasons.
First, the declaration addresses process difficulty rather than unexpected results in the final product. Evidence of difficulty in synthesis does not establish non-obviousness where the combination of prior art elements and expected results has been demonstrated. See In re Merck & Co., 800 F.2d 1091, 1099 (Fed. Cir. 1986); MPEP § 716.02(a).
Second, to be probative of non-obviousness, evidence of unexpected results must be commensurate in scope with the claims. See MPEP § 716.02(a); In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). The pending claims broadly encompass dextran polymers modified with “greater than 1 sulfate group per monosaccharide unit” and “an alkene containing moiety” across a wide range of molecular weights (claim 26: 5 kDa to 650 kDa) and sulfation levels (claim 16: at least about 1.5 per monosaccharide unit). The declaration addresses specific experimental conditions used by the inventors and does not demonstrate that unexpected challenges or results extend across the entire claimed scope.
Third, as acknowledged in the declaration itself, the inventors overcame the solubility and processability challenges by controlling reaction conditions. The fact that a PHOSITA could identify and solve these challenges through routine experimentation — as the inventors themselves did — confirms that a reasonable expectation of success existed. See KSR, 550 U.S. at 421. The specification’s own disclosure that these challenges were overcome through process optimization further confirms that this represented expected synthetic engineering rather than an unpredictable result.
Fourth, the broader literature confirms that bifunctional modification of dextran with both sulfate groups and methacrylate groups on the same backbone is a structurally foreseeable modification. Dextran has three reactive hydroxyl groups per monosaccharide unit (C2, C3, C4), and both O-sulfation and GMA esterification proceed on these hydroxyl groups by well-characterized reactions. A PHOSITA would have predicted the need to balance the degree of each modification and would have adjusted reaction conditions accordingly as a matter of routine practice. See KSR, 550 U.S. at 418.
Regarding Applicants’ broader argument that the combination of references does not establish a prima facie case of obviousness:
The prior art itself explicitly identified the same problem and the relevant technical components to address it. Paluck identifies as a motivating goal producing dextran-based heparin mimetics that retain therapeutic activity while reducing side effects (p. 3417, abstract). Sun 2019 demonstrates that dextran sulfate is a direct, high-affinity ligand for FGF1 and FGF2, more effective than heparin for FGF1 stabilization (p. 1480). Sun 2011 demonstrates that dextran-GMA hydrogels promote vascularization (p. 95, abstract). When the prior art identifies the same objective and provides technically complementary components to achieve it, combining those components does not rise to the level of non-obvious invention. See KSR, 550 U.S. at 418–420; In re Fulton, 391 F.3d 1195, 1200–01 (Fed. Cir. 2004).
Therefore, a prima facie case of obviousness has been established and the rejection is maintained.
Conclusion
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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