DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Status of Claims
The amendment, filed on 19 November 2025, is acknowledged.
Claims 1, 16-18, and 21-22 have been amended.
Claims 4 and 15 have been cancelled.
Claims 23-24 were previously withdrawn from consideration in the non-final Office Action mailed on 26 August 2025.
Claims 1-3, 5, 9-14, and 16-22 are pending and under consideration in the instant Office Action, to the extent of the following previously elected species:
the specific biocompatible material is nanofibrillar cellulose;
the specific source of the nanofibrillar cellulose is tunicates; and
the specific condition treated is diabetes.
Objections Withdrawn
Objections to Claims
Applicant’s amendments to claims 1 and 21, submitted on 19 November 2025, have overcome the objection to the claims set forth in the Office Action mailed on 26 August 2025. Accordingly, the relevant objections are withdrawn.
Rejections Withdrawn
Rejections pursuant to 35 U.S.C. § 112
The rejections of claims 1, 16-18, and 21-22 under 35 U.S.C. § 112 are withdrawn in view of Applicant’s amendments to the claims. The rejections of claims 4 and 15 under 35 U.S.C. § 112 are rendered moot in view of Applicant’s cancellation of the claims.
Maintained Rejections
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.
Claims 1-3, 11-14, 17-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Song et al. (Adv. Drug Deliv. Rev. 2014, 79-80, 19., hereafter referred to as Song) and Miali et al. (ACS App. Mater. Interfaces 2019, 11, 31627., published on 14 August 2019, hereafter referred to as Miali).
Song teaches a review of the current use of hydrogels in tissue engineering, design parameters that impact vasculogenesis and angiogenesis, and the combination of hydrogels and 3D printing to create models of microfluidic channels (Abstract). The development of viable cancer treatments is a subject of great interest, but is often hindered by a “lack of competent preclinical models” (pg. 20, left column, para. 2). Hydrogels are taught to be useful in creating 3D in vitro models of tissue due to their tunable mechanical strength and chemical structures (pg. 20, right column, para. 2). In particular, modification of the crosslinking densities of hydrogels has been shown to impact the “proliferation, survival, and migration of the embedded cells” while chemical modification can impact tumor angiogenesis and technologies such as microfabrication and microfluidics have allowed for the development of “complex blood vessels, which show promise for more advanced and clinically relevant tumor angiogenesis models” (pg. 20, right column, para. 2).
Tumor growth is taught to involve not only angiogenesis, but also vasculogenesis, wherein endothelial progenitor cells (EPCs) are recruited to the vasculature site to promote further growth (pg. 21, left column, para. 2-3). Hydrogels are taught to be viable models for tumor growth because of their tunable microenvironments that can “be adequate 3D cellular microenvironments for supporting cell adhesion and growth of various cell types including cancer cells” (pg. 21, right column, final para.). One example of a 3D model is taught to be a hydrogel matrix that was formed around a cylindrical needle – following crosslinking of the hydrogel matrix, the needle was removed to create a cylindrical microfluidic channel that mimics microvessels and allows for perfusion studies (pg. 25, left column, para. 2 and Fig. 3). In one experiment, researchers coated the interior of the channel with human umbilical vein endothelial cells (HUVECs) to create perfusable microvessels that were models for angiogenesis (pg. 25, left column, para. 3).
In addition to molding, Song teaches that hydrogel models can be created via 3D printing (pg. 25, right column, para. 2-3). One 3D printed hydrogel was formed around a “sacrificial mold”, which was subsequently dissolved in water and removed to leave a network of hollow microfluidic channel, made of crosslinked hydrogel, which could be used to construct vasculature (pg. 25, left column, para. 3). Researchers embedded a variety of cells in the hydrogel matrix to serve as models, such as 10T1/2 mouse fibroblasts and tumorigenic cells (pg. 25, left column, para. 3). Finally, Song teaches that the hydrogels can be used to deliver cells, such as tumor cells (pg. 24, right column, para. 1) growth factors (pg. 25, right column, para. 1) to study angiogenesis, as well as drugs, including the anticancer drugs doxorubicin and paclitaxel (pg. 26, right column, para. 1).
Song does not teach the main central channel through the hydrogel to have connected branching channels. This deficiency is offset by the teachings of Miali.
Miali teaches the importance of vasculature in transporting molecules, cells, and nanoconstructs, its impact in the areas of tissue regeneration and therapy, and the benefits of vasculature mimicking a leaf over a single-channel microfluidic device (Abstract). Vascular transport of cells is described as vital to understand in order to design intravenously administered nanoconstructs, elucidate the mechanisms of cancer angiogenesis, and boosting immune response (pg. 31627, Introduction, para. 1). Fluidic assays are one method of gaining this knowledge, but current methods struggle to “replicate the complex branching and hierarchical organization of an authentic vascular network” (pg. 31627-31628, Introduction, para. 1-2).
An alternative approach that overcomes the limitations of prevalent methods is replicating the vein system of natural leaves, which obeys an energy minimization criterion known as Murray’s law – in short, energy is minimized and flow maximized when the cube of the radius of a parent channel is equal to the sum of the cubes of the radii of its daughter channels (pg. 31628, right column, para. 1). Miali developed a microfluidic device using soft lithography to mold polydimethylsiloxane (PDMS) into the shape of the vascular system in a Hedera helix leaf and, through curing, created a “leaf-microfluidic chip” from the cured PDMS polymer (pg. 31629, left column, para. 2 - right column, para. 1). The leaf chip was presented as both an open system (Fig. 2, Fig. S4) and a closed system (Fig. 3-5, Fig. S1-2). Using fluid dynamic studied, Miali found that the leaf-mimic network of channels followed Murray’s law and served as a viable model for the “complex natural networks for fluid transport in plants, insects, and mammals” (pg. 31635, Conclusions, para. 1). Further, Miali found the device to serve as a viable model for cancer cell migration through blood vessels, formation of blood clots, and the treatment of each with clinical and preclinical agents (pg. 31635, Conclusions, para. 2). Miali concluded that microvascular networks modeled on leaves can accurately replicate the complexity of human vasculature and be employed to strengthen the statistical relevance of studies of microvascular transport of cells, molecules, and fluids (pg. 31636, Conclusions, final para.).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to combine the teachings of Song and Miali to arrive at the invention of instant claims 1-3, 11-14, 17-18, and 20 because combining elements known in the prior art according to known methods yields predictable results. Song teaches a device, developed to model tumor vasculogenesis and angiogenesis, with one primary channel extending between two ends of a crosslinked hydrogel, created via 3D printing and removal of a sliding component, that delivered cells to developing vasculature inside the primary channel. The ordinary artisan would be motivated by the teachings of Miali to modify the hydrogel taught by Song to have branched channels connected to the main channel, modeled after the vasculature of a leaf, because Song teaches this vascular system to better mimic human vasculature, obey Murray’s law, and provide more reliable statistical data. One of ordinary skill would find these improvements desirable because Song teaches their hydrogel device to be a viable model for understanding vasculature, particularly in the area of cancer research, and the teachings of Miali would improve the viability and validity of the model.
Claims 11-14 and 20 are interpreted as reciting intended uses of the claimed device and the patentability of the claims relies upon the device itself, rather than its intended use. The uses recited in claims 11-14 and 20 do not further limit the claimed device and, because the claims each depend from claim 1, are prima facie obvious as a result of claim 1 being rendered obvious. See MPEP § 2111.02 and 2144.07. As a result, there is a reasonable expectation of success in arriving at the invention of instant claims 1-3, 11-14, 17-18, and 20 in view of the teachings of Song and Miali.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Song (Adv. Drug Deliv. Rev. 2014, 79-80, 19.) and Miali (ACS App. Mater. Interfaces 2019, 11, 31627., published on 14 August 2019) as applied to claims 1-3, 11-14, 17-18, and 20 above, and further in view of Zhang et al. (ACS Appl. Mater. Interfaces 2017, 9 (28), 24230., hereafter referred to as Zhang).
Song and Miali teach the above.
Song and Miali do not teach the crosslinked hydrogel device to comprise nanofibrillar cellulose derived from tunicates. This deficiency is offset by the teachings of Zhang.
Zhang teaches a method of improving the mechanical properties of hydrogels by reinforcing the polymer network with quaternized tunicate cellulose nanocrystals and Fe3+ ions (Abstract). Hydrogels, which are composed of cross-linked hydrophilic polymers, are taught to be widely used in the fields of sensing, tissue engineering, and drug delivery due to their biocompatibility and other properties (pg. 24230, Introduction, para. 1). However, practical application of hydrogels is taught to be limited by their poor mechanical properties (pg. 24230, Introduction, para. 1). Zhang teaches that the mechanical properties of hydrogels can be improved by reinforcing the polymer network with tunicate cellulose nanocrystals, creating a “dual cross-linked hydrogel network” (pg. 24230-24231, Introduction, para. 2-4). The tunicate cellulose fibers link the mono-cross-linked hydrogels to form the final dual cross-linked hydrogels (Fig. 1), resulting in hydrogels that are taught to possess “high tensile strength, high ductility, and high toughness”, expanding the “application potential of hydrogels in biomedical fields” (pg. 24236, Conclusions).
It would have been prima facie obvious to one of ordinary skill in the art to modify the invention rendered obvious by the teachings of Song and Miali with the teachings of Zhang to arrive at the invention of instant claims 9-10 because using a technique known in the art to improve a similar device yields predictable results. The ordinary artisan would be motivated to use nanocellulose derived from tunicates in the hydrogel device rendered obvious by Song and Miali because Zhang teaches ordinary hydrogels to possess poor mechanical properties, which would limit their practical application. By reinforcing the hydrogel with tunicate cellulose, Zhang teaches the mechanical properties would be improved, which one of ordinary skill would desire because it would improve the application of their device. As a result, there is a reasonable expectation of success in arriving at the invention of claims 9-10 in view of the teachings of Song and Miali and further in view of the teachings of Zhang.
Claims 5, 16, 19, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Song (Adv. Drug Deliv. Rev. 2014, 79-80, 19.) and Miali (ACS App. Mater. Interfaces 2019, 11, 31627., published on 14 August 2019) as applied to claims 1-3, 11-14, 17-18, and 20 above, and further in view of March et al. (U.S. Patent Application Publication No. US 2013/0095081 A1, published on 18 April 2013, hereafter referred to as March).
Song and Miali teach the above.
Song and Miali do not teach the device to be implanted in a human or animal, delivery of stem cells of stem cells and parenchymal cells, nor the treatment of diabetes. These deficiencies are offset by the teachings of March.
March teaches compositions and methods of treating disorders, in one embodiment an insulin related disorder, comprising administration of at least one mammalian stem cell and optionally at least one islet cell (Abstract). Administration of the treatment is taught via multiple routes, in one embodiment being surgical implantation (para. [0010] and claim 5). The insulin related disorder is taught to be Type 1, Type 2, or gestational diabetes, pre-diabetes, or impaired glucose tolerance (para. [0011] and claim 6). The islet cells are taught to originate from the pancreas, as some forms of diabetes are related to the “destruction of the insulin-producing b cells of the islets of Langerhans” (para. [0004-0005]).
In one embodiment, the composition comprising at least one mammalian stem cell and optionally at least one islet cell is administered in matrix form, said matrix being formed of collagen with embedded islets, adipose stem cells, and endothelial cells (para. [0019] and Example 15). The administration of the treatment is taught to effectuate “vascularization of a tissue of the patient at or near the site of administration” (para. [0022-0023], Examples 4-7 and claim 75). Finally, March teaches that their invention, in the form of a 3D collagen gel, acted as an in vivo and in vitro model for “vessel network assembly” following implantation into mice (Example 5).
It would have been prima facie obvious to a person of ordinary skill in the art, prior to the filing of the instant application, to modify the invention rendered obvious by the teachings of Song and Miali with the teachings of March to arrive at the invention of instant claims 5, 16, 19, and 21-22 because combining elements known in the prior art and applying the resulting product using a known technique yields predictable results. The teachings of Song and Miali render obvious a crosslinked hydrogel device that may be embedded with cells and/or molecules which are subsequently delivered as vasculature grows through predefined channels. An ordinary artisan would be motivated to select pancreatic islets and stem cells as the embedded cells in the hydrogel device rendered obvious above because March teaches these cells to be useful in treating insulin-related diseases, including diabetes, and their delivery would be improved by the advanced vasculature of the device rendered obvious by Song and Miali. One of ordinary skill would be motivated to use the hydrogel device embedded with stem cells and pancreatic islets to treat diabetes because, in addition to March teaching said cells to be capable of treatment, the ordinary artisan would desire practical applications of their device.
The person of ordinary skill would further be motivated to implant the device in a human or animal because, while the device rendered obvious by Song and Miali is biocompatible and a model for human tissue, neither reference taught implantation, and March teaches a biocompatible gel matrix to be successfully implanted, enabling vascularization and cell delivery. The advanced vascular system of the hydrogel device rendered obvious above would reasonably be expected improve the results following implantation as compared to the 3D matrix taught by March. As a result, there is a reasonable expectation of success in arriving at the invention of claims 5, 16, 19, and 21-22 in view of the teachings of Song and Miali and further in view of the teachings of March.
Response to Arguments
The Applicant’s arguments, filed on 19 November 2025, have been fully considered but are not persuasive.
In response to Applicant's allegation in the penultimate para. of pg. 6 and para. 1 of pg. 8 that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant does not provide an explicit argument explaining why the combination of the references above would require improper hindsight to arrive at the claimed invention. The Examiner argues that knowledge possessed by an ordinary artisan would be sufficient to combine the prior art teachings above and would be motivated to do so for the reasons detailed in the rejections above.
In response to applicant's arguments against the references individually from the penultimate para. of pg. 6 to para. 3 of pg. 7, and restated in the para. spanning the bottom of pg. 7 and top of pg. 8, 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 the penultimate para. of pg. 6, Applicant argues that the Song reference is directed toward engineering vasculature and studying vasculogenesis and angiogenesis, not implantable vascularized tissue. However, Song teaches that hydrogel devices can be used to deliver cells, which is recited in instant claim 1 and the Song reference is still considered relevant to the instant application (vide supra). In addition, Applicant argues that Song teaches a simple cylindrical channel rather than a main central channel with interconnected branching channels. In the rejection above, Song was not stated to teach interconnected branching channels from the main channel, and this argument is therefore not found persuasive.
In the para. spanning the bottom of pg. 6 and the top of pg. 7, Applicant argues that the technique taught by Miali to form interconnected channels in external microfluidic devices cannot be used to form a hydrogel matrix. The teachings of Miali were used to motivate branching channels modeled after the vasculature of a leaf because the structure obeys Murray’s law and provides a better model of human vasculature (vide supra). The manufacturing technique employed by Miali was not used to support the obviousness rejection and the argument is therefore found unpersuasive.
In para. 2 of pg. 7, Applicant argues that the Zhang reference teaches tunicate nanocrystals in nanocomposites rather than nanofibrillar tunicate hydrogels and that the two are chemically, structurally, and functionally distinct. The instant specification does not provide a definition of nanofibrillar cellulose and only discusses characteristics in the context of prior art, disclosing in para. [0006] that the nanofibrils can be 8-30 nm in diameter and “up to a micrometer long (by way of example only)”. The teachings of Peng et al. (Can. J. Chem. Eng. 2011, 9999, 1.) teach nanocrystalline cellulose to be rod-like, with diameters from 10-20 nm and lengths in the hundreds of nanometers (pg. 2, General Aspect of Nanocrystalline Cellulose). The Zhang reference does not teach the specific length or diameter of the tunicate nanocrystals used, but in view of the teachings of Peng et al., which define nanocrystalline cellulose as having characteristics that fall within those disclosed in the instant specification, and in absence of a definition in the instant application, the cellulose taught by Zhang is considered equivalent to the cellulose recited in the instant claims.
Finally, Applicant argues in para. 3 of pg. 7 that the March reference does not teach pre-formed interconnected vascular channels, sliding-mold fabrication, or nanofibrillar tunicate hydrogels. The rejection presented in the non-final Office Action mailed on 26 August 2025, did not make the above assertions regarding the teachings of March. Instead, the March reference was used for its teachings on implantation of devices in humans to deliver cells, in particular islet cells, which are commonly used in the treatment of diabetes mellitus, and/or stem cells (vide supra). Therefore, the argument is found unpersuasive.
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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/S.J.S./
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619