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 9 September 2025, is acknowledged.
Claim 1 has been amended.
Claim 13 has been cancelled.
Claims 2, 10, 15-16, 18, 22-23 and 26-30 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Claims 1, 3-9, 12, 14, 19-21, and 24-25 are under consideration in the instant Office Action, to the extent of the following previous elected species:
The specific coumarin structure in the coumarin-polymer conjugate is 7-carboxymethoxy-4-methylcoumarin;
the specific polymer in the coumarin-polymer conjugate is hyaluronic acid;
the specific conjugation method of a covalent bond; and
the specific drug used in combination with the coumarin-polymer conjugate is a growth factor.
Objections Withdrawn
Objections to Drawings
Applicant’s newly submitted drawings, submitted on 9 September 2025, have overcome the objection to set forth in the Office Action mailed on 17 June 2025. Accordingly, the relevant objections are withdrawn.
Rejections Withdrawn
Rejections pursuant to 35 U.S.C. § 103
The rejections of claims 1, 3-9, 12, 14, 19-21, and 24-25 under 35 U.S.C. § 103 are withdrawn in view of the amendment to claim 1 and in favor of the new grounds of rejection below.
The rejection of claim 13 under 35 U.S.C. § 103 has been rendered moot by Applicant’s cancellation of the claim.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
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.
Claim 14 is 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.
Claim 14 depends from claim 13, which was cancelled by the Applicant in the response filed on 9 September 2025, rendering the claim indefinite. This rejection may be overcome by amending claim 14 to depend from a pending claim. For purposes of the instant Office action, claim 14 is being interpreted as depending from claim 1 in the interest of compact prosecution.
Claim 14 also recites the limitation "said wavelength l" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim because claim 13 has been cancelled.
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. 12, 20, and 24
Claims 1, 3-9, 14, 19, 21, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Azagarsamy (ACS Macro Lett. 2014, 3 (6), 515., published on 16 May 2014, provided by Applicant in IDS) in view of Ashammakhi et al. (Biomed. Microdevices 2019, 21 (42), 1-6., provided by Applicant in IDS, hereafter referred to as Ashammakhi), Haupt et al. (Anal. Chem. 1998, 70 (18), 3936., hereafter referred to as Haupt), and Kabb et al. (ACS Appl. Mater. Interfaces 2018, 10, 16793., provided by Applicant in IDS, hereafter referred to as Kabb).
Azagarsamy teaches the design, synthesis, and characterization of photodegradable hydrogels made from a coumarin molecule linked to a polymer (Abstract and pg. 515, para. 3). The coumarin complex 7-amino-4-methylcoumarin was modified to be covalently linked to a 4-armed poly(ethylene glycol) (PEG) polymer, creating coumarin-polymer conjugates which were subsequently formed into hydrogels in the presence of a Cu(I) catalyst (pg. 515, para. 3 - pg. 516, para. 1, Fig. 1, and Scheme 1). The coumarin-polymer conjugate is taught to have a single-photon absorption maximum of ~330 nm (Fig. S1) and a two-photon absorption maximum in the range of 720-860 nm (pg. 518, para. 2).
Azagarsamy further teaches hydrogels, “water-swollen cross-linked polymeric networks”, to be useful in the areas of tissues engineering and regenerative medicine because of properties including delivering therapeutics in a controlled manner, delivering cells, and allowing cell culturing in vitro (pg. 515, para. 1). Hydrogels that can degrade in response to an external stimulus are also taught to be useful scaffolds for releasing and delivering therapeutic cells and proteins (pg. 515, para. 1). The coumarin-polymer hydrogel taught by Azagarsamy photodegrades following irradiation at 365 nm, 405nm, and 860 nm (pg. 517, para. 2 - pg. 518, para. 2 and Fig. 3).
Azagarsamy does not teach the specific coumarin molecule 7-carboxymethoxy-4-methylcoumarin (CMMC), the polymer to be hyaluronic acid, nor crosslinking to occur via [2+2] cycloaddition initiated by IR irradiation. These deficiencies are offset by the teachings of Ashammakhi, Haupt, and Kabb.
Ashammakhi teaches the utility of 3D bioprinting in reparative and regenerative therapeutics, the drawbacks associated with 3D bioprinting in vitro and subsequent implantation, and the approaches to perform 3D bioprinting in situ (Abstract). Examples of drawbacks associated with 3D bioprinting outside of a patient and then implanting the printed constructs include logistics, sterility, and imperfect shapes and sizes (pg. 1, left column, para. 1 - pg. 2, left column, para. 1). 3D bioprinting of implants directly into the targeted tissue (i.e., in situ bioprinting) is taught to produce “more accurate reconstruction of tissue defects and result in faster and more efficient healing of tissue defects” (pg. 2, left column, para. 1). Ashammakhi teaches successful in situ bioprinting in sheep using mesenchymal stromal cells embedded in a hydrogel scaffold composed of gelatin and hyaluronic acid (HA) methacrylate polymers and in mice utilizing stem cells “embedded in photocrosslinkable heparin conjugated HA onto full-thickness skin wounds” (pg. 3, right column, para. 1-2). In the latter case, the mice models experienced “re-epithelialization, vascularization, ECM [extracellular matrix] production, and wound closure in treated wounds” (pg. 3, right column, para. 2).
Haupt teaches a fluorescent ligand displacement assay which utilizes a coumarin derivative as a fluorescent probe for immunoassays (Abstract). One of the fluorescent probes taught by Haupt is 7-carboxymethoxy-4-methylcoumarin (CMMC), chosen because of its small size and photophysical properties, including an absorption maximum at 323 nm and detectable emission at 385 nm (pg. 3937, right column, para. 4). Haupt teaches that the assay can be used in solvents including aqueous buffers and “organic solvents such as acetonitrile” (pg. 3939, Conclusion).
Kabb teaches hydrogels formed from crosslinked polymers comprising coumarin derivatives which can reversibly revert back to non-linked, free coumarin-polymer conjugates (Abstract). Coumarin compounds are taught to undergo a [2+2] cycloaddition following UV irradiation to yield crosslinked dimers and therefore have utility in crosslinking polymers (pg. 16793, right column, para. 1). The coumarin derivatives 7-(2-acryloyloxyethoxy)-4-methylcoumarin and 7-(2-acrylamidoethoxy)-4-methylcoumarin were taught to form hydrogels made of crosslinked polyacrylamide polymers following 365 nm irradiation and to undergo cycloreversion to re-form free coumarin-polymer conjugates following 254 nm irradiation (pg. 16795, Materials and Experimental Methods and Fig. 3).
The photoreversible coumarin comprising hydrogels were further taught to be capable of undergoing iterative solubilization-gelation cycles, forming hydrogels, followed by cycloreversion and subsequent crosslinking again to form hydrogels a second time (pg. 16797, right column, para. 2). These results inspired the use of the hydrogels to form cylinders which were selectively irradiated with 254 nm radiation to create patterned, hollow cylinders (pg. 16797, right column, final para. - pg. 16798, left, column, para. 3). Kabb concludes that the “reversible nature of the cross-links also allow[s] the hydrogels to be photopatterned” and that the method of patterned, selective irradiation can be “further extended to the formation of branched networks reminiscent of vasculature” (pg. 16799, Conclusions). Kabb also teaches that long exposure to UV irradiation is hazardous to cells, noting that the development of a system that “cures upon exposure to a more benign stimulus” would be desirable for biological applications.
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 Azagarsamy with the teachings of Ashammakhi, Haupt, and Kabb to arrive at the invention of claims 1, 3-9, 19, 21, and 25 because combining prior art elements according to known methods yields predictable results. An artisan would be motivated to modify the hydrogel scaffold taught by Azagarsamy to use hyaluronic acid as a polymer in place of PEG because Ashammakhi teaches its successful use in 3D bioprinting in situ for delivering therapeutic agents, which an artisan would recognize as being useful in the invention of Azagarsamy because it is directed to tissue engineering and regenerative medicine. One would further be motivated to use CMMC in the place of 7-azido-4-methylcoumarin in view of the teachings of Haupt because the latter teaches the ability of CMMC to be used as a fluorescent probe. An artisan would recognize the usefulness of a fluorescent probe, either while part of a hydrogel scaffold or as a free coumarin-polymer conjugate following photodegradation of the hydrogel, in a biomedical setting as an imaging agent. Kabb teaches coumarin compounds to be capable of undergoing [2+2] cycloaddition to form crosslinks and it would have been obvious to an artisan to try this method of forming crosslinked polymer hydrogels because the coumarin moiety is present in the invention rendered obvious by Azagarsamy, Ashammakhi, and Haupt.
Kabb further teaches the cycloaddition to occur following irradiation at 365 nm, but notes that sustained UV irradiation is harmful to cells and a “more benign stimulus” is desirable for biological applications. Azagarsamy taught that the coumarin-polymer conjugates of their invention undergo the same photochemical process following two-photon absorption in the range of 720-860 nm and one photon absorption at 365 and 405 nm. An artisan would be motivated to try irradiating the coumarin-polymer conjugate with light in the IR region because those wavelengths are less harmful to cells and the conjugate is known to undergo two-photon absorption to perform the same photochemistry as when absorbing a single photon of higher energy, therefore the artisan would reasonably expect crosslinking to occur. The absorption spectrum of the coumarin-polymer conjugate is inherent to the molecular structure and in the invention rendered obvious by the teachings of Azagarsamy, Ashammakhi, and Haupt, with a CMMC and hyaluronic acid conjugate, two-photon absorption in the range of wavelengths recited in instant claim 1 would be reasonably expected to occur. As a result, there is a reasonable expectation of success in arriving at the invention of instant claims 1, 3-9, 14, 19, 21, and 25 in view of the teachings of Azagarsamy, Ashammakhi, Haupt, and Kabb.
Claims 12, 20, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Azagarsamy (ACS Macro Lett. 2014, 3 (6), 515., published on 16 May 2014, provided by Applicant in IDS) in view of Ashammakhi (Biomed. Microdevices 2019, 21 (42), 1-6., provided by Applicant in IDS), Haupt (Anal. Chem. 1998, 70 (18), 3936.), and Kabb (ACS Appl. Mater. Interfaces 2018, 10, 16793., provided by Applicant in IDS) as applied to claims 1, 3-9, 14, 19, 21, and 25 above, and further in view of Broguiere et al. (Adv. Mater. 2018, 30, 1801621., hereafter referred to as Broguiere).
Azagarsamy, Ashammakhi, Haupt, and Kabb teach the above, and particularly relevant to claims 12, 20, and 24, Azagarsamy teaches that the coumarin-polymer conjugate hydrogels of their invention are useful in tissue engineering studies (Azagarsamy, pg. 518, final para.) and Ashammakhi teaches the importance of structural integrity and precise fit of 3D bioprinted structures for reparative and regenerative therapy (Ashammakhi, Abstract).
Azagarsamy, Ashammakhi, Haupt, and Kabb do not teach the hydrogel of their invention to comprise an organoid nor the inclusion of growth factors in the invention. These deficiencies are offset by the teachings of Broguiere.
Broguiere teaches that epithelial organoids, which are simplified models of organs that are traditionally grown in animal- and tumor-derived basement membrane extract (BME), can also successfully be grown in hydrogels (Abstract). Organoids, which are self-organizing cellular structures, are taught to “mimic various aspects and functions of the respective tissue, and therefore are valuable to study organ development and human diseases”, as well as being useful for drug screening and toxicology studies (pg. 1, para. 1). BME, the typical medium used to grow organoids, is taught to have associated drawbacks including batch-to-batch variations and limitations on the modulation of physical and biochemical properties of the growing organoids, resulting in a strong interest in BME alternatives (pg. 1, para. 2 - pg. 2, left column, para. 2). Broguiere teaches that fibrin-based hydrogels supported long-term growth of epithelial organoids and “could be used as a universal alternative to BME for culturing organoids derived from different types of tissues” (pg. 6, right column, para. 1). Finally, Broguiere teaches each of the organoids grown within hydrogels to have been cultured with the required growth factors R-spondin-1, noggin, and human epidermal growth factor (EGF) (pg. 1, para. 2 and pg. 8-9, Experimental Section).
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 Azagarsamy, Ashammakhi, Haupt, and Kabb with the teachings of Broguiere to arrive at the invention of instant claims 12, 20, and 24 because combining prior art elements according to known methods yields predictable results. Azagarsamy and Ashammakhi both teach the use of hydrogel scaffolds in the field of tissue engineering and its importance to advancing the field. An ordinary artisan would be motivated to use the coumarin-polymer conjugate hydrogels rendered obvious by Azagarsamy, Ashammakhi, Haupt, and Kabb to grow organoids in view of the teachings of Broguiere because the latter reference teaches the utility of organoids, the need for alternatives to BME in the growth of organoids, and the success of fibrin-based hydrogels in growing organoids, which would provide the artisan with a reasonable expectation that the coumarin-containing hydrogels would successfully support organoid growth. The artisan would further be motivated to incorporate growth factors in the hydrogel-organoid product because Broguiere teaches that they are necessary for proper organoid growth. As a result, there is a reasonable expectation of success in arriving at the invention of claims 12, 20, and 24 in view of the teachings of Azagarsamy, Ashammakhi, Haupt, and Kabb and further in view of the teachings of Broguiere.
Response to Arguments
The Applicant’s arguments, filed on 9 September 2025, have been fully considered but are not persuasive.
In the sections titled “Rejection of Claims 1, 3-9…” and “Rejections of Claims 12, 20…” on pg. 7 of the remarks, Applicant argues that the relevant rejections set forth in the Office Action mailed on 17 June 2025, should be withdrawn in view of the amendment to base claim 1. The rejections were withdrawn in favor of the new grounds of rejection set forth above.
From para. 1 of pg. 8 to para. 2 of pg. 9 of the remarks, Applicant argues that the crosslinked coumarin-polymer conjugates taught by the Azagarsamy reference are created via a click-chemistry reaction, rather than a photoinitiated [2+2] cycloaddition reaction as recited by the instant application. The Examiner does not dispute this difference, but the differences are rendered obvious in view of the teachings of Kabb as described above. In para. 4 and 6 of pg. 9, Applicant argued that Ashammakhi and Kabb do not remedy the deficiencies of Azargarsamy regarding photoinitiated [2+2] cycloaddition with wavelengths in the IR region because both references teach the use of shorter wavelength lasers. As argued above, Kabb teaches that sustained UV irradiation is harmful to cells and a “more benign stimulus” is desirable for biological applications, and Azagarsamy teaches that the coumarin-polymer conjugates of their invention undergo the same photochemical process following two-photon absorption in the range of 720-860 nm and one photon absorption at 365 and 405 nm. An artisan would be motivated to try irradiating the coumarin-polymer conjugate with light in the IR region because those wavelengths are less harmful to cells and the conjugate is known to undergo two-photon absorption to perform the same photochemistry as when absorbing a single photon of higher energy, therefore the artisan would reasonably expect crosslinking to occur. As cited from the KSR decision in MEEP § 2143.II.C., "[a] person of ordinary skill in the art is also a person of ordinary creativity, not an automato "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968) n." KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. at 421, 82 USPQ2d at 1397.
In response to applicant's argument in para. 4 of pg. 8 of the remarks that the references fail to show certain features of the invention, in particular that an advantage of the instant invention is “the ability to control the shape and design of the hydrogel in situ and in vivo at tissue-penetrating wavelengths”, it is noted that the features upon which applicant relies are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the Kabb and Azagarsamy references in the final para. of pg. 9, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as stated above, Kabb teaches coumarin compounds to be capable of undergoing [2+2] cycloaddition to form crosslinks and it would have been obvious to an artisan to try this method of forming crosslinked polymer hydrogels because the coumarin moiety is present in the invention of Azagarsamy, and utilizing [2+2] cycloaddition in the place of click-chemistry could produce a crosslinked hydrogel with different advantageous properties, which an ordinary artisan would be motivated to investigate. Therefore, the argument that there is no motivation to combine the references is considered unpersuasive.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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