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 December 2025, is acknowledged.
Claims 143, 146, 149, 151-153, and 155-156 have been amended.
Claims 144-145 and 150 have been cancelled.
Claims 147 and 157-164 were previously withdrawn from consideration in the non-final Office Action, mailed on 22 September 2025.
Claims 143, 146, 148-149, 151-156 are pending and under consideration in the instant Office Action, to the extent of the following previously elected species:
the allogenic cells are islet cells;
the trophoblasts are cytotrophoblasts;
the microencapsulation device is a hydrogel matrix; and
the adhesive peptide is collagen IV and laminin.
Objections Withdrawn
Objections to Claims
Applicant’s cancellation of claims 144-145 has rendered moot the objection to claim 145 set forth in the Office Action mailed on 22 September 2025. Accordingly, the relevant objection is withdrawn.
Rejections Withdrawn
Rejections pursuant to 35 U.S.C. § 103
The rejection of claims 144-145 and 150 under 35 U.S.C. § 103 is withdrawn in view of Applicant’s cancellation of the claims.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.
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 143, 146, 148-149, 152, and 156 are rejected under 35 U.S.C. 103 as being unpatentable over Beck et al. (Tissue Eng. 2007, 13 (3), 589., provided by Applicant in IDS, hereafter referred to as Beck) in view of Talayev et al. (Clin. Exp. Immunol. 2010, 162, 91., hereafter referred to as Talayev) and Haider et al. (Stem Cell Rep. 2018, 11, 537., provided by Applicant in IDS, hereafter referred to as Haider).
Beck teaches the limitations in islet cell function following cell replacement treatment, as well as strategies to overcome these limitations and enhance cell function (Abstract). Diabetes mellitus is taught to be a destructive disease, affecting over 150 million worldwide and causing in excess of 200,000 deaths each year in the U.S. (pg. 589, Introduction, para. 1). Current therapies for treating diabetic patients include insulin injection, dietary restriction, and exercise for early stage disease and pancreas transplantation or purified islet cell transplantation for progressed disease accompanied by severe symptoms (pg. 589, Introduction, para. 3).
Islet transplantation, the transfer of healthy islet cells from a donor to a diabetic patient (allogeneic transplantation), has advantages over pancreas transplantation including “elimination of major surgery, the reduced mass at transplantation time (beta-cells are about 1% of the total pancreas weight), and the potential storage of donor cells by cryopreservation” (pg. 590, Islet Transplantation, para. 1). While this treatment has successfully controlled glucose levels in patients, it does have several associated drawbacks, including low islet cell availability, clumping of cells leading to core cell death, and host immune system rejection (pg. 590, Islet Transplantation, para. 1). “Even in autografts, immune protection is necessary, because in type I diabetes, the immune system is responsible for the destruction of the original b cells. Yet immune protection is more vital in allografts” (pg. 594, left column, Immuno-protection properties). For example, immune system macrophages activated by chemoattractants are taught to produce nitric oxide which can damage islet cells (pg. 594, left column, Immuno-protection properties).
One approach to overcoming these drawbacks is encapsulation of islet cells, using an “immune-protective biomaterial to create a permselective membrane around a group of islet cells”, creating a device often called a “bioartificial pancreas” (pg. 590, Islet Transplantation, para. 2). The device allows islet cells to regulate blood glucose levels via insulin release, while isolating the islet cells from portions of the host immune system, and is interpreted as being equivalent to the microencapsulation device of the instant application (pg. 590, Islet Transplantation, para. 2). Co-encapsulation of the islet cells with other biological structures, such as erythrocytes or Sertoli cells, is taught to be a method of protecting islet cells from destruction via nitric oxide as discussed above (pg. 594, left column, Immuno-protection properties). The material used to create hydrogels which encapsulate islet cells must be biocompatible and examples are taught to include alginate, polysulphone, poly(ethylene glycol) (PEG), and poly-L-lysine (pg. 590, Encapsulation Material, para. 1-2). Hydrogels made of the materials above is considered analogous to a “degradable hydrogel matrix comprising a 3D matrix” as recited in instant claim 149.
Beck further teaches methods for increasing the number of islet cells to be implanted, such as using stem cells (pg. 591, Cells Used for Encapsulation, para. 1). Islet cells are taught to be “terminally differentiated” cells, preventing their growth in vitro, resulting in transplantation patients relying solely on allograft donors for functioning islet cells (pg. 591, Cells Used for Encapsulation, para. 1). One method of mitigating this limitation is the use of stem or precursor cells, which are capable of differentiation, to produce more islet cells (pg. 591, right column, final para.). Beck teaches that a previous study has successfully used embryonic stem cells to assemble into a 3D cluster and produce insulin, mimicking pancreas function (pg. 591, right column, final para.). Beck notes that several factors must be present for successful differentiation of stem cells into islet cells, including vascular endothelial growth factor A (VEGF-A) and fetal soluble factors (pg. 591, right column, final para.). Further strategies are taught to include culturing islet cells on surfaces comprising collagen type I or IV, laminin, or RGD peptides (pg. 595, left column, para. 2).
Beck does not teach the islet cells to be co-encapsulated in a hydrogel with cytotrophoblasts nor organoids comprising cytotrophoblasts. These deficiencies are offset by the teachings of Talayev and Haider.
Talayev teaches the role of human placenta cytotrophoblast cells on the maturation of dendritic cells and their ability to stimulate immune response in vitro (Abstract). Human pregnancy is taught to depend upon regulatory mechanisms of maternal immune systems and the mechanisms are “mediated by the effect of fetal trophoblast cells” (Abstract). Trophoblasts have effects including limiting “the destructive alloimmune response”, modulating natural killer (NK) cell functions, inducing regulatory T cells, inhibiting effector T lymphocytes, and others (pg. 91, left column, para. 1). Further, Talayev teaches trophoblast cells to produce hormones and anti-inflammatory cytokines, express human leucocyte antigen (HLA) molecules, and produce other protective molecules and regulatory proteins (pg. 91, left column, para. 1 - pg. 91, right column, para. 1).
Maternal decidual leucocytes are taught to include dendritic cells (DCs), along with NK cells, macrophages, and T lymphocytes, and DCs are “known to be antigen-presenting cells with a unique ability to recruit naïve T lymphocytes into a primary immune response and to induce their maturation into effector and memory T cells” (pg. 91, right column, para. 2). Talayev investigated the impact of cytotrophoblast cells (CTCs) on the morphology, phenotype, and function of DCs in vitro by culturing the cells together (pg. 92, left column, para. 2 and pg. 93, MLC). The presence of CTCs during the maturation of DCs did not significantly impact their ability to express proteins CD14, CD80, CD83, or CD86 nor HLA molecules, but did significantly reduce their ability to stimulate IFN-g production (pg. 96, right column, para. 3). Talayev teaches that inhibition of the production of an interleukin is the likely cause for the reduction, which may result in a reduced immune response (pg. 96, right column, final para. - pg. 97, left column, para. 1). Further, CTCs are taught to reduce the ability of DCs to induce loss of CD62L from T lymphocytes, reducing T cell migration and subsequently reducing immune response, “thus prevent[ing] the participation of these cells in local immune reactions dangerous for the fetus” (pg. 97, left column, para. 2).
Haider teaches human cytotrophoblast (CTB) organoid cultures (CTB-ORGs) which are derived from purified first-trimester placental CTBs and used to model human placenta and related diseases (Abstract). CTBs are taught to be difficult to adequately model due to cell line divergence from primary tissue, cessation of cell proliferation, and other issues (pg. 537, Introduction, para. 1). To overcome issues with modeling placental CTB in organoids, Haider teaches culture conditions in which CTB-ORGs are capable of self-renewal and expansion, extravillous trophoblast (EVT) progenitor development, and cell differentiation, (pg. 537, right column, final para. - pg. 538, left column, para. 1).
The conditions under which the CTB-ORGs are capable of self-renewal, expansion, and differentiation are encapsulation within Matrigel hydrogels (pg. 538, Establishment of Long-Term Expanding Human Trophoblast Organoids, para. 1). Cytotrophoblasts embedded in a hydrogel is interpreted as being a “placenta-mimicking device” as recited in the instant application. The Matrigel used in the teachings of Haider is “Growth factor-reduced Matrigel” from Corning (pg. 548, right column, para. 1), which according to the Technical Data Sheet comprises laminin, collagen IV, and vascular endothelial growth factor (VEGF) (see Technical Data Sheet - Corning GFR Matrigel).
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 of Beck to encapsulate cytotrophoblast organoids alongside islet cells in hydrogel, in view of the teachings of Talayev and Haider, because combining prior art elements according to known methods to impart a known benefit yields predictable results. Beck teaches that diabetes mellitus is a damaging disease in need of effective treatment and that islet cell transplantation is an effective treatment method. Though transplantation comes with drawbacks, Beck teaches that encapsulation within a hydrogel can mitigate some of these drawbacks, in particular when the hydrogel comprises PEG and/or alginate to allow insulin passage but prevent destruction via host immune system and when co-encapsulated with a biostructure that can provide protection. Beck further teaches that islet cells can exhibit increased survival and function when cultured alongside collagen IV and laminin.
One of ordinary skill in the art would be motivated before the effective filing date of the claimed invention to use cytotrophoblasts as the biological structure co-encapsulated with islet cells in the hydrogel taught by Beck in view of the teachings of Talayev because Talayev teaches cytotrophoblasts to be capable of reducing immune responses when cultured alongside other cells. Beck teaches that both allogeneic and autologous islet cells need protection from immune systems when transplanted and in view of the teachings of Talayev, an ordinary artisan would be motivated to use cytotrophoblasts to provide such protection. Further, the ordinary artisan would be motivated to encapsulate CTB-ORGs alongside islet cells in view of the teachings of Haider because Haider teaches that CTB-ORGs encapsulated in hydrogel are capable of self-renewal, expansion, and differentiation. One of ordinary skill would recognize that the ability of cytotrophoblasts in organoids to self-renew and expand would be beneficial properties for cells providing protection to islet cells producing insulin to possess. As a result, there is a reasonable expectation of success in arriving at the invention of instant claims 143-146, 148-150, 152, and 156 in view of the teachings of Beck, Talayev, and Haider.
Claim 151 is rejected under 35 U.S.C. 103 as being unpatentable over Beck (Tissue Eng. 2007, 13 (3), 589., provided by Applicant in IDS) in view of Talayev (Clin. Exp. Immunol. 2010, 162, 91.) and Haider (Stem Cell Rep. 2018, 11, 537., provided by Applicant in IDS) as applied to claims 143, 146, 148-149, 152, and 156 above, and further in view of Reichmann et al. (U.S. Patent Application Publication No. US 2017/0258965 A1, published on 14 September 2017, hereafter referred to as Reichmann) and Mach (U.S. Patent No. 9,814,682 B2, published on 14 November 2017, provided by Applicant in IDS).
Beck, Talayev, and Haider teach the above.
Beck, Talayev, and Haider do not teach more than one hydrogel within the placenta-mimicking device nor the cells within the device to be operable to generate a vaccine. These deficiencies are offset by the teachings of Reichmann and Mach.
Reichmann teaches a tissue graft comprising two or more cell types encapsulated within a gel, which subsequently cultures the encapsulated cells to form at least one biostructure (Abstract). The goal of the invention of Reichmann is taught to be an improved, mechanically stable graft device containing cells and at least one biostructure in a biocompatible, biodegradable hydrogel matrix for clinical use in humans and/or testing (para. [0007]). Mechanical stability is taught to be imparted via the use of hydrogel matrices made from fibrin or collagen (para. [0050] and claim 17). The cells in the biostructure are taught to be of human or other mammalian origin, may be stem cells or cells of trophoblast origin, and are intended to be used in a treatment, which is interpreted as being “therapeutic” (para. [0017] and [0025] and claims 23 and 35).
Reichmann further teaches that vascularization is important to the biostructures because, when compared to non-vascularized tissue grafts, vascularized hydrogels have been “shown to faster and better regenerate in vivo” (para. [0053]). To aid vascularization, Reichmann teaches the inclusion of vascular endothelial growth factor (VEGF) in a culture medium with their hydrogels (Example 1). In some embodiments, the tissue graft may comprise two biostructures, each comprising cells that may be identical or different, and each capable of being an organ or tissue structure, such as vascular structure (claims 19-22).
Mach teaches a cell-based vaccine composition which comprises immune-protected, encapsulated cells which produce an immunomodulator and an antigenic component (Abstract). First generation vaccines, which comprised only antigens against which an immune response was desired, are taught to be weakly efficient and surpassed by second generation vaccines, which include one or more adjuvants as immunomodulators to enhance patient immune response (column 1, lines 34-43). Mach teaches that “a widely applicable technique used for providing the necessary adjuvant is simply to combine the antigen with the adjuvant in the vaccinating composition…thereby supplying the antigen and adjuvant in a simultaneous and co-localised manner” (column 1, lines 44-50). This technique is taught to be more complicated for cell-based vaccines, with some strategies including cell implantation, encapsulation in “pegylated, liposomal microspheres”, and implanting the immunomodulator and antigen cells in close proximity, “thereby providing an efficient local release of adjuvant at the vaccine site” (column 1, line 55 - column 2, line 14). Mach further teaches that the cells utilized in the cell-based vaccine must be “physically protected against the immune response of the host” to prevent premature destruction (column 5, lines 28-37). One strategy to achieve such protection is encapsulation in a device (column 5, lines 43-52).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing of the instant application, to design the placenta-mimicking device rendered obvious above by the teachings of Beck, Talayev, and Haider with two distinct hydrogels, each containing a different cell type, to generate a cell-based vaccine in view of the teachings of Reichmann and Mach because the use of a known technique to improve a similar device in the same manner yields predictable results. The device rendered obvious above comprises a hydrogel, inside of which are organoids containing cytotrophoblasts and islet cells, intended to treat patients with diabetes mellitus. Mach teaches that implantation and co-localization of immunomodulator and antigen cells can produce a vaccine to treat a patient, but must be protected from the immune system of the host. It would be obvious to an ordinary artisan that cytotrophoblasts and islet cells could be implanted and co-localized in the placenta-mimicking device rendered obvious above to produce a vaccine-like result for treatment of diabetes mellitus, and further that the hydrogel structure of the device would protect the encapsulated cells from the immune system of the host. Further, in view of the teachings of Reichmann, a person of ordinary skill would find it obvious to localize the cytotrophoblast-containing organoids and islet cells in two separate hydrogel structures. As a result, there is a reasonable expectation of success in arriving at the invention of claim 151 in view of the teachings of Beck, Talayev, and Haider and further in view of the teachings of Reichmann and Mach.
Claims 153-155 are rejected under 35 U.S.C. 103 as being unpatentable over Beck (Tissue Eng. 2007, 13 (3), 589., provided by Applicant in IDS) in view of Talayev (Clin. Exp. Immunol. 2010, 162, 91.) and Haider (Stem Cell Rep. 2018, 11, 537., provided by Applicant in IDS) as applied to claims 143, 146, 148-149, 152, and 156 above, and further in view of Garcia et al. (U.S. Patent No. 9,381,217 B2, published on 5 July 2016, provided by Applicant in IDS, hereafter referred to as Garcia).
Beck, Talayev, and Haider teach the above.
Beck, Talayev, and Haider do not teach the hydrogel matrix to comprise crosslinkers nor the hydrogel matrix to be nondegradable. These deficiencies are offset by the teachings of Garcia.
Garcia teaches methods of encapsulating cells and other biologic agents in micro hydrogels (Abstract and column 2, lines 63-65). Microencapsulation of cells is taught to be a promising strategy for immunoprotection following transplantation, with several successful cases utilizing alginate, natural and synthetic hydrogels, and microfluidic droplets (column 1, lines 27-66). In particular, Garcia teaches that encapsulation and minimizing the volume of the encapsulation is “important in many regenerative medicine scenarios, including pancreatic islet transplantation” (column 1, lines 51-53). In one embodiment, Garcia teaches a microgel encapsulation that utilizes a four arm maleimide-linked polyethylene glycol (PEG-4MAL) macromer crosslinked covalently with dithiothreitol (DTT) or a peptide with a cleavage site for one or more proteases or other enzymes (column 3, lines 19-26). Garcia teaches that such a microgel has variable permeability, achieved via variation of the size of PEG-4MAL from 10 kDa to 20 kDa, is “particularly well suited for preparing viable, microencapsulated monodispersed multi-cell islets”, and can be functionalized with adhesive peptides to “enhance cell adhesion and survival” (column 3, line 41 - column 4, line 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 placenta-mimicking device rendered obvious by the teachings of Beck, Talayev, and Haider to consist of a hydrogel comprising PEG-4MAL and the nondegradable linker DTT in view of the teachings of Garcia because combining prior art elements according to known methods to impart a known benefit yields predictable results. Haider and Beck rendered obvious a placenta-mimicking device comprising a hydrogel, inside of which are organoids containing cytotrophoblasts and islet cells, intended to treat patients with diabetes mellitus. Garcia teaches that PEG-4MAL and the nondegradable linker DTT can be used to create a micro hydrogel that is “particularly well suited” for encapsulating living, viable islet cells. Further, Garcia teaches the microgel to have the advantage of variable permeability, which the ordinary artisan would recognize as beneficial to protect the islet cells from the host immune system while allowing passage of insulin and other required biomolecules as a result of the teachings of Beck. It would be obvious to one of ordinary skill that use of DTT as a linker that will not degrade except in the presence of protease or other enzymes would lend structural integrity to the hydrogel and be beneficial in the device rendered obvious above. As a result, there is a reasonable expectation of success in arriving at the invention of claims 153-155 in view of the teachings of Beck, Talayev, and Haider and further in view of the teachings of Garcia.
Response to Arguments
The Applicant’s arguments, filed on 19 December 2024, have been fully considered but are not persuasive.
In the penultimate para. of pg. 7 of the Remarks, Applicant argues that the Beck reference does not teach trophoblast cells encapsulated in combination with islet cells nor a 3D hydrogel matrix comprising a material selected from PEG, alginate, and agarose. Regarding the combination of islet cells and trophoblast cells, Beck was not argued to teach this combination in the non-final Office Action mailed on 22 September 2025; the rejection was based upon the combination of the teachings of the Beck, Talayev, and Haider references (vide supra) and the argument is found to be unpersuasive. Regarding the teaching of a hydrogel matrix comprising a material selected from PEG, alginate, and agarose, the Examiner respectfully disagrees, as the Beck reference does teach encapsulation material comprising alginate and PEG (vide supra).
In response to applicant's arguments against the references individually in the para. that spans 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). Applicant argues that the Talayev reference “merely describes the effect of cytotrophoblast cells on dendritic cells” and that the Haider reference “discloses methods associated with long term expanding organoid cultures from cytotrophoblast cells”. In addition, Applicant argues in para. 2 of pg. 8 that none of the references “teach or suggest trophoblast cells in combination with islet cells in a placenta-mimicking device”. As stated above, the rejection above is based upon the combination of references, and Applicant has not provided an argument against the combination of references motivated by the argument provided in the rejection under 35 U.S.C. § 103 above. Therefore, the argument is not found to be persuasive.
Finally, in the section that spans the bottom of pg. 8 and top of pg. 9, Applicant references three research awards to support their argument that “the contribution of the disclosure of the application [is novel] over what was known at the time of filing”. The Examiner acknowledges the awards received by the Applicant, but reminds them that the patentability of an invention is dictated by title 35 of the United States Code, and in particular what would be obvious to a person of ordinary skill at the time of filing of the instant application is dictated by 35 U.S.C. § 103. See also MPEP § 2144.
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