CTNF 18/289,777 CTNF 88187 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined pursuant to the first inventor to file provisions of the AIA. DETAILED ACTION Status of the Claims The Examiner acknowledges receipt of Applicants’ Response to Restriction Requirement, filed 19 November 2025 ( see below). Upon finalization and entry of the Restriction Requirement, claims 1 – 6, 8 – 11, 13 – 15, and 23 will be available for substantive examination. Response to Restriction/Election The Examiner acknowledges Applicants’ election, without traverse, of the invention of Group I, claims 1 – 6, 8 – 11, 13 – 15, and 23, in the Response filed on 19 November 2025. The Examiner further acknowledges Applicants’ election of the species alginate from the genus defined as hydrogel matrix, and aluminum hydroxide from the genus defined as adjuvant, for further examination, as clarified in a telephone interview with Dr. Mindy N. Rittner on 26 May 2026. Upon further consideration, the Examiner has withdrawn the species election with respect to the genera of biologic and stabilizing excipient. Claims 16 – 21 are hereby withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1 – 6, 8 – 11, 13 – 15, and 23 are under consideration to the extent that human surfactants are the stabilizing excipient, human cells are the biologic, and aluminum hydroxide is the adjuvant. Information Disclosure Statements The Examiner has considered the Information Disclosure Statements (IDS’s) filed 7 November 2023, 29 January 2024, and 3 July 2025, which are now of record in the file. Rejections Pursuant to 35 U.S.C. § 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. Claim 1 and 23, and claims 2 – 6, 8 – 11, and 13 – 15, dependent therefrom, are rejected pursuant to 35 U.S.C. § 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. For example, claim 1 is directed to a “printed composition ” comprising a formulation with liquid droplets that include a hydrogel precursor and a biologic. The formulation is subject to cross-linking to create “a gelled particle comprising a cross-linked hydrogel matrix with the biologic dispersed therein.” The claim also recites a limitation directed to the viscosity of the formulation being in the range of about 100 to about 500,00 mPa·sec. Claim 23 also recites a limitation directed to a formulation with a viscosity in the range of about 100 to about 500,00 mPa·sec. It is the Examiner’s position that one of ordinary skill in the art would be uncertain as to whether the recited viscosity range applies to the liquid formulation before cross-linking, or to the gelled particle after cross-linking, particularly given the broad range of viscosities recited in the limitation that are more likely to be characteristic of the gelled particle. Appropriate correction or cancelation is necessary. In the interests of compact prosecution, the Examiner shall interpret the viscosity limitation as being applicable to either the formulation or the gelled particle. Further with respect to claims 5 and 11, the claims recite limitations directed to ratios between hydrogel precursor and biologic (claim 5), and the concentration of the biologic in the formulation. Both claims also recite dependencies from claim 1. In looking to claim 3, which claim recites limitations directed to the species of biologic, the claim clearly recites both “mammalian cells,” and other sub-genera of biologics, such as, for example, proteins, hormones, and drugs. As disclosed in the cited references, quantification of the loading of a biologic in a hydrogel microsphere is expressed as an absolute count of cells, usually per unit volume. In contrast, other recited biologics are amendable to quantifying the loading (or concentration) of the biologic in the microspheres by typical mass/volume units. Consequently, when the biologic is in a form that does not lend itself to quantification in the form of typical mass/volume units, one of ordinary skill in the art would be uncertain as to how to determine if a given disclosure reads on these claims with incompatible “concentration” units. Appropriate correction or cancelation is necessary. Rejections Pursuant to 35 U.S.C. § 103 07-20-aia AIA The following is a quotation of 35 U.S.C. § 103 that 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 of this title, 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. 07-20-02-aia AIA 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 absent any evidence to the contrary. Applicants are advised of the obligation pursuant to 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 – 6, 8 – 11, 13, 15, and 23 are rejected pursuant to 35 U.S.C. § 103, as being obvious over US 2004/0071780 A1 to Lillard, J., et al ., published 15 April 2004, identified on the Information Disclosure Statement (IDS) submitted 7 November 2023, cite no. A9 (USPAT) (“Lillard “780”), in view of US 2021/0002433 A1 to Barney, L., et al ., published 7 January 2021 (“barney ‘433”). The Invention As Claimed Applicants claim a composition comprising a liquid droplet that comprises a formulation including an alginate precursor and a biologic, wherein, after cross-linking, the liquid droplet becomes a gelled particle that comprises a cross-linked hydrogel matrix with the biologic dispersed therein, wherein the formulation has a viscosity in a range from about 100 to about 500,000 mPa·sec, wherein the biologic comprises a cell, wherein the biologic is uniformly dispersed within the hydrogel matrix, wherein the gelled particle comprises a hydrogel-to-biologic ratio in a range from about 1:1 to about 1:1000, wherein the gelled particle comprises a shell of a biocompatible polymer, wherein the gelled particle comprises an encapsulation efficiency of at least about 55%, wherein the gelled particle has a diameter in a range from about 10 microns to about 2 mm, wherein the formulation includes the hydrogel precursor at a concentration of at least about 20 mg/mL to about 1000 mg/mL, wherein the formulation includes the biologic at a concentration of at least about 20 mg/mL to about 1000 mg/mL, and wherein the formulation further comprises a surfactant as an excipient. Applicants further claim a printed composition comprising a gelled particle comprising a cross-linked alginate matrix with a biologic dispersed therein, wherein the gelled particle is obtained by crosslinking a liquid droplet comprising a formulation including an alginate precursor and the biologic, the formulation having a viscosity in a range from about 100 to about 500,000 mPa·sec. The Teachings of the Cited References Lillard ‘780 discloses cross-linked alginate microspheres with diameters averaging 8.2 µ m, and coated with chitosan ( see Abstract), wherein the microspheres entrapped bovine serum albumin (BSA) with an entrapment efficiency of > 80%, and a loading of 18% wgt, with sizes in the range of 4 – 12 µ m, and coated with chitosan and polycaprolactone (PCL) to increase the mechanical strength and to provide control over the release of BSA ( see ¶[0011]), wherein an optimal size for a particle to be internalized by cells is 1 - 10 µ m in diameter ( see ¶[0014]), wherein, because presently available alginate microspheres are only effective for delivery of peptides and proteins over 8 - 10 days, there is a need to modify the surface and internal characteristics of microspheres for extended release, so that the microspheres were prepared by a technique in which chitosan was used to prevent the interaction of the protein (BSA) with the internal matrix, keeping separate the macromolecules and smaller molecules carried by the particles from the alginate matrix, and polycaprolactone (PCL) was used to coat the microparticles for extended time release for a programmed release rate, as determined by the number of PCL coating layers ( see ¶[0016]), wherein the microspheres are cross-linked with epichlorohydrin, which yields a more stable physical structure, as well as precise control for optimal size than typical CaCl 2 -cross-linked hydrogels ( see ¶[0017]), wherein the hydrogel precursor was sodium alginate ( see ¶[0021]), wherein the BSA was added at 0° C to the alginate solution prior to the addition of the cross-linking agent ( see ¶[0025]), wherein circular dichroism analysis was performed to evaluate the conformational integrity of BSA during microsphere formation, revealing that the unencapsulated BSA and the BSA released from the microspheres were virtually identical, indicating that the helical peak and alpha helical structures of BSA remained intact when compared to control BSA, and in contrast to alginate microspheres of the prior art, and that the protein did not interact chemically with the matrix material ( see ¶[0064]), wherein the microspheres may be particularly useful for administration of vaccines against diseases such as cholera, hepatitis, influenza, pneumonia and other diseases where the initial site of infection and immune response are mucosal membranes, and may also be used for administration of therapeutic agents such as peptides, steroids, proteins and other agents wherein the preservation of conformational properties is desirable ( see ¶[0073]), and wherein the method of administration, whether systemic (parenteral administration, oral administration) or by application to specific tissues (inhalation, instillation) will depend on the particular agent administered and the target tissue ( see ¶[0074]). The reference does not disclose a formulation with viscosities in the range of about 100 to about 500,000 mPa·sec, or the formulation concentrations of hydrogel precursor and biologic, nor their relative concentration ratios, or compositions further comprising excipients and/or adjuvants. The teachings of ### remedy those deficiencies. Barney ‘433 discloses compositions and methods for preparing hydrogel capsules using a cross-linking solution comprising a process additive ( see Abstract), wherein the hydrogel capsules are prepared by a process that uses an electrostatic droplet generator to form multiple droplets of a desired volume from a solution comprising a mixture of an afibrotic alginate and an unmodified alginate and then contacting the droplets with a cross-linking solution comprising multivalent cations to cross-link each droplet into a capsule ( see ¶[0002]), wherein the number of defect-free spherical hydrogel capsules is significantly increased when a process additive ( e.g ., a surfactant) is added to the cross-linking solution, and the process additive allows the preparation of alginates with viscosities in the range of 21.3 cP to at least 925.5 cP [21.3 mPa·sec – 925.5 mPa·sec] with a significantly higher cell loading capacity for multiple cell types than when the same process is performed without the additive ( see ¶[0003]), wherein a spherical capsule with a smooth surface may induce a lower amount of foreign body response (FBR) after implant than a spherical capsule of the same composition and size but with a rough surface, e.g ., a surface with one or more ridges ( id .), wherein the process comprises contacting a plurality of droplets of the alginate solution with an aqueous cross-linking solution which comprises a cross-linking agent, a buffer, an osmolarity-adjusting agent and a process additive ( see ¶[0004]), wherein the process additive is a surfactant, such as a polysorbate-type surfactant (TWEEN® 80) ( see ¶[0006]), wherein the cross-linking agent comprises divalent cations of a single type or a mixture of different types, e.g., one or more of Ba 2+ , Ca 2+ , Sr 2+ ( see ¶[0008]), wherein the type and concentration of buffer in the aqueous cross-linking solution is selected to maintain the solution pH at an approximately neutral level, e.g ., from about 6.5 to about 7.5 ( see ¶[0010]), wherein the polymer solution further comprises a suspension of cells, which may be provided as single cells, cell clusters ( e.g ., as spheroids), or cells attached to microcarriers, with a concentration of single cells in the polymer solution of at least 5 - 100 million cells/mL ( see ¶[0014]), wherein the capsules have diameters between about 1.2 and 1.8 mm ( see ¶[0018]), wherein the capsule compositions are prepared by loading a volume of hydrogel-forming polymer solution into a syringe that may then be placed into a syringe pump oriented vertically above a vessel containing an aqueous cross-linking solution which comprises a cross-linking agent, a buffer, an osmolarity-adjusting agent, and a process additive ( e.g ., a hydrophilic, non-ionic surfactant), and the syringe pump is then used to extrude the polymer solution, optionally containing a suspension of cells, into the vessel ( see ¶[0099]), wherein a wide variety of different human cell types can be used in the afibrotic hydrogel capsules, including epithelial cells, endothelial cells, fibroblast cells, mesenchymal stem cells, keratinocyte cells, cells derived from epithelial cells, endothelial cells, fibroblast cells, mesenchymal stem cells or keratinocyte cells, cells derived from induced pluripotent stem cells (iPSC)), and islet cells ( see ¶[0171]), wherein the encapsulated cells can be engineered to produce a single therapeutic agent, or a plurality of therapeutic agents ( see ¶[0190]), wherein microcapsule compositions were prepared by extruding droplets of a 70:30 mixture of afibrotic alginate:unmodified alginate into cross-linking solutions ( see ¶[0232]), and wherein, in an exemplified embodiment, an afibrotic alginate (modified with Compound 101 from Table 2) was dissolved at 5% weight to volume in 0.9% saline and then blended with 3% weight to volume of unmodified alginate [PRONOVA™ SLGl00 (FMC)] (also dissolved in 0.9% saline) at a volume ratio of 70% afibrotic alginate to 30% unmodified alginate, or 90% afibrotic alginate to 10% unmodified alginate ( see Example 3, ¶[0224]). Application of the Cited Art to the Claims It would have been prima facie obvious before the filing date of the claimed invention to prepare cross-linked alginate microspheres with diameters averaging 8.2 µ m, and coated with chitosan, wherein the microspheres entrapped bovine serum albumin (BSA) with an entrapment efficiency of > 80%, and a loading of 18% wgt, with sizes in the range of 4 – 12 µ m, and coated with chitosan and polycaprolactone (PCL) to increase the mechanical strength and to provide control over the release of BSA, wherein the microspheres are cross-linked with epichlorohydrin, which yields a more stable physical structure, as well as precise control for optimal size than typical CaCl 2 -cross-linked hydrogels, wherein the hydrogel precursor is sodium alginate wherein the BSA was added at 0° C to the alginate solution prior to the addition of the cross-linking agent, wherein the microspheres may be particularly useful for administration of vaccines against diseases such as cholera, hepatitis, influenza, pneumonia and other diseases where the initial site of infection and immune response are mucosal membranes, and may also be used for administration of therapeutic agents such as peptides, steroids, proteins and other agents wherein the preservation of conformational properties is desirable, and wherein the method of administration, whether systemic (parenteral administration, oral administration) or by application to specific tissues (inhalation, instillation) will depend on the particular agent administered and the target tissue, as taught by Lillard ‘780, and wherein the hydrogel capsules are prepared by a process that uses an electrostatic droplet generator to form multiple droplets of a desired volume from a solution comprising a mixture of an afibrotic alginate and an unmodified alginate and then contacting the droplets with a cross-linking solution comprising multivalent cations to cross-link each droplet into a capsule, wherein the number of defect-free spherical hydrogel capsules is significantly increased when a process additive ( e.g ., a surfactant) is added to the cross-linking solution, and the process additive allows the preparation of alginates with viscosities in the range of 21.3 cP to at least 925.5 cP [21.3 mPa·sec – 925.5 mPa·sec] with a significantly higher cell loading capacity for multiple cell types than when the same process is performed without the additive, wherein the process comprises contacting a plurality of droplets of the alginate solution with an aqueous cross-linking solution which comprises a cross-linking agent, a buffer, an osmolarity-adjusting agent, and a process additive, wherein the process additive is a surfactant, such as a polysorbate-type surfactant (TWEEN® 80), wherein the cross-linking agent comprises divalent cations of a single type or a mixture of different types, e.g. , one or more of Ba 2+ , Ca 2+ , Sr 2+ , wherein the polymer solution further comprises a suspension of cells, which may be provided as single cells, cell clusters ( e.g ., as spheroids), or cells attached to microcarriers, with a concentration of single cells in the polymer solution of at least 5 - 100 million cells/mL, wherein the capsule compositions are prepared by loading a volume of hydrogel-forming polymer solution into a syringe that may then be placed into a syringe pump oriented vertically above a vessel containing an aqueous cross-linking solution which comprises a cross-linking agent, a buffer, an osmolarity-adjusting agent, and a process additive ( e.g ., a hydrophilic, non-ionic surfactant), and the syringe pump is then used to extrude the polymer solution, optionally containing a suspension of cells, into the vessel, wherein a wide variety of different human cell types can be used in the hydrogel capsules, wherein the encapsulated cells can be engineered to produce a single therapeutic agent, or a plurality of therapeutic agents, wherein microcapsule compositions were prepared by extruding droplets of a 70:30 mixture of afibrotic alginate:unmodified alginate into cross-linking solutions ( see ¶[0232]), and wherein, in an exemplified embodiment, an afibrotic alginate (modified with Compound 101 from Table 2) was dissolved at 5% weight to volume in 0.9% saline and then blended with 3% weight to volume of unmodified alginate [PRONOVA™ SLGl00 (FMC)] (also dissolved in 0.9% saline) at a volume ratio of 70% afibrotic alginate to 30% unmodified alginate, or 90% afibrotic alginate to 10% unmodified alginate, as taught by Barney ‘433. One of skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the express teachings of Barney ‘433 to the effect that inclusion of a surfactant in the cross-linking solution for the formation of hydrogel microspheres with smooth surfaces that significantly lessen the likelihood of foreign body responses than spherical capsules with rough surfaces ( see ¶[0003]). With respect to claim 4, which claim recites a limitation directed to the biologic being “homogenously dispersed” in the hydrogel matrix, the Examiner notes that the cited references do not expressly address distribution of the biologic in the hydrogel microparticles. However, it is the Examiner’s position that the processes for preparing the cross-linked hydrogel particles as disclosed in the cited art start with homogeneous solutions of biologic and hydrogel precursors, the resulting microparticles, after cross-linking, would necessarily result in the biologic being homogeneously distributed in the microcapsules. With respect to claims 5 and 11, which claims recite limitations directed to the ratios between hydrogel precursor and biologic (claim 5), and concentration of the biologic in the formulation, the Examiner notes that the cited references disclose cells as the biologic, the cells being quantified by an absolute count rather than a mass/volume concentration, it is impossible to directly apply the art to those limitations. In light of the forgoing discussion, the Examiner concludes that the subject matter defined by claims 1 – 6, 8 – 11, 13, 15, and 23 would have been obvious within the meaning of 35 USC § 103. Claim 14 is rejected pursuant to 35 U.S.C. § 103, as being obvious over Lillard ‘780, in view of Barney ‘433, as applied in the above rejection of claims 1 – 6, 8 – 11, 13, 15, and 23, and further in view of US 2011/0027376 A1 to Boey, Y., et al ., published 3 February 2011 (“Boey ‘376”). The Invention As Claimed Claims 1 – 6, 8 – 11, 13, 15, and 23 are described above. In addition, Applicants claim a composition comprising a cross-linked hydrogel matrix with a biologic encapsulated within, wherein the composition further comprises aluminum hydroxide as an adjuvant. The Teachings of the Cited Art The teachings of Lillard ‘780 and Barney ‘433 are relied upon as applied in the above rection of claims 1 – 6, 8 – 11, 13, 15, and 23. The references do not disclose a composition comprising a cross-linked hydrogel matrix with a biologic encapsulated within, wherein the composition further comprises aluminum hydroxide as an adjuvant. The teachings of Boey ‘376 remedy that deficiency. Boey ‘376 discloses methods of synthesizing multi-walled microspheres comprising at least one hydrophilic active compound as well as the multi-walled microsphere obtained by the method, and pharmaceutical compositions comprising the microspheres ( see Abstract), wherein the microspheres are characterized in that they comprises a first, inner polymer layer and a second, outer polymer layer, wherein the polymer of the second polymer layer has a higher hydrophobicity and a higher intrinsic viscosity than the polymer of the inner polymer layer ( see ¶[0013]), wherein dissolving the hydrophilic active compound in a polar solvent before mixing it with a first solution comprising a first polymer allows the process to load microspheres with hydrophilic substances, such as active substances, including proteins, in a solution comprising not only the protein but also other substances, such as substances or compounds for stabilizing the protein to be encapsulated ( see ¶[0032]), wherein, besides proteins, other active compounds can also be encapsulated in the microspheres, such as drugs or vaccines ( see ¶[0086]), and wherein, when loaded with a vaccine or an immunologic adjuvant, the microspheres can further contain aluminum hydroxide ( see ¶[0087]). Application of the Cited Art to the Claims It would have been prima facie obvious before the filing date of the claimed invention to prepare cross-linked alginate microspheres coated with chitosan, wherein the microspheres entrap bovine serum albumin (BSA) with an entrapment efficiency of > 80%, as taught by Lillard ‘780 and Barney ‘433, wherein the alginate microspheres further comprise aluminum hydroxide, as taught by Boey ‘376. One of ordinary skill in the art would be motivated to do so, with a reasonable expectation of success in so doing, by the teachings of Boey ‘376 to the effect that the inclusion of an adjuvant, such as aluminum hydroxide, can increase the activity of the vaccine. In light of the forgoing discussion, the Examiner concludes that the subject matter defined by claim 14 would have been obvious within the meaning of 35 USC § 103. NO CLAIM IS ALLOWED. CONCLUSION Any inquiry concerning this communication or any other communications from the examiner should be directed to Daniel F. Coughlin whose telephone number is (571)270-3748. The examiner can normally be reached on M-F 8:30 am - 5:30 pm. If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, David J Blanchard, can be reached on (571)272-0827. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/-interviewpractice. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /DANIEL F COUGHLIN/ Examiner, Art Unit 1619 /DAVID J BLANCHARD/ Supervisory Patent Examiner, Art Unit 1619 Application/Control Number: 18/289,777 Page 2 Art Unit: 1619 Application/Control Number: 18/289,777 Page 3 Art Unit: 1619 Application/Control Number: 18/289,777 Page 4 Art Unit: 1619 Application/Control Number: 18/289,777 Page 5 Art Unit: 1619 Application/Control Number: 18/289,777 Page 6 Art Unit: 1619 Application/Control Number: 18/289,777 Page 7 Art Unit: 1619 Application/Control Number: 18/289,777 Page 8 Art Unit: 1619 Application/Control Number: 18/289,777 Page 9 Art Unit: 1619 Application/Control Number: 18/289,777 Page 10 Art Unit: 1619 Application/Control Number: 18/289,777 Page 11 Art Unit: 1619 Application/Control Number: 18/289,777 Page 12 Art Unit: 1619 Application/Control Number: 18/289,777 Page 13 Art Unit: 1619 Application/Control Number: 18/289,777 Page 14 Art Unit: 1619 Application/Control Number: 18/289,777 Page 15 Art Unit: 1619 Application/Control Number: 18/289,777 Page 16 Art Unit: 1619
Prosecution Insights