DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Acknowledgement is made of applicant’s election without traverse of the species of
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In order to advance prosecution, compounds 100-121 of Table 4 will be examined at this time.
It is noted that claim 16 was canceled in the amendment filed 7/15/2024. Thus, its status as “amended” in the claim listing of 6/5/2026 is incorrect.
Claims 11, 12, 26, and 28 have been canceled. Claims 1, 4-6, 9, 13-15, 25, 27, 29-33, 40, and 41 have been amended. Claims 1-6, 9, 13-15, 17-25, 27, 29-41 and 43-46 are pending and examined on the merits to the extent that the FBR-mitigating compound comprises compounds 100-121 of Table 4.
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.
Claims 1-6, 9, 13-15, 17-24, 45 and 46 are 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.
(A1)Claim 1 is vague and indefinite in the recitation of “each immunomodulatory protein secreted by the first plurality of cells” in section (i).
(A2)Claim 17 is vague and indefinite in the recitation of “each plurality of genetically modified cells”.
Claim 1 requires that the first plurality of mammalian cells is genetically modified to express and secrete one or more immunomodulatory proteins selected from Il-10 and Il-22. Thus, the claim minimally requires only one of cells secreting Il-10 or Il-20, and only one plurality of cells. In this context, the meaning of “each” immunomodulatory protein secreted by the first plurality of cells and “each” plurality of genetically modified cells is unclear, as there would be only one immunomodulatory protein being secreted, and one plurality of cells.
(B)The recitation of “the barrier compartment” in claim 18 lacks specific antecedent basis in claim 1.
(C)The recitation of “hydrogel forming polymer” in claims 18 and 19 is unclear is vague and indefinite because it is unclear if the hydrogel is yet to form the polymer in the barrier compartment or if it has already formed the polymer prior to being part of the device. Amendment of claims 18 and 19 to delete the term “forming” would overcome this portion of the rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Barney et al (WO2019/169245) in view of Kalo et al (WO2019/165140), Alabbas et al (Clinical and Translational Immunology, 2018, e1017, 14 pages) abstract of Khaliq (Investigative Ophthalmology & visual Science, 1996, Vol. 37, pp. 436-443), Anderson et al (WO2012/112982), Dudley et al (U.S. 2016/0303133) and Chibout et al (U.S. 2003/0119797).
Claim 1 is drawn to an implantable device comprising an extended release formulation of a glucocorticoid and a plurality of mammalian cells genetically modified to express and excrete one or more immunomodulatory proteins selected from an Il-10 protein or an Il-22 protein, wherein the device, after implantation, (a) prevents the contact of the genetically modified cells with the immune cells of the subject; (b) prevents the genetically modified cells from migrating out of the device; and (c)allows for the delivery of immunomodulatory protein to the subject in an amount and for a time to induce an anti-inflammatory immune response in the subject, wherein the device comprises (iii) a compound disposed on the exterior surface that mitigates FBR; (iv) no alginate on the surface of the device; and (v) the first plurality of genetically modified cells are genetically modified ARPE-19 cells. Claim 2 specifies that the time in which the immunomodulatory protein is delivered is at least 30 days. Claim 4 specifies that the anti-inflammatory immune response comprises an increase in Il-22 in the plasma of the subject. Claim 6 requires that the device comprises features (iii), (iv) and (v). Claim 9 specifies that the plurality of genetically modified cells comprise an exogenous nucleotide sequence encoding Il-10 or Il-22. Claim 13 requires that the glucocorticoid of claim 1 is of formula (IV). Claim 17 specifies that the plurality of genetically modified cells is surrounded by a barrier compartment.
Claim 18 requires that the barrier compartment comprises a hydrogel. Claim 19 requires that the cell containing compartment comprises a hydrogel.
Claim 21 requires that the FBR-mitigating compound is a compound of Formula (I). Claim 22 specifies that the FBR compounds of claim 21 are selected, in part, from compounds 100-121. Compound 23 requires that the FBR-mitigating compound of claim 22 is compound 101. Claim 24 requires that the FBR-mitigating compound of claim 22 is compound 100.
Claim 25 is drawn to a hydrogel capsule comprising (a) a cell containing compartment comprising genetically modified cells which continuously express or secrete a first immunomodulatory protein which is Il-10 or Il-22; (b) a barrier compartment surrounding the cell-containing compartment which comprises an alginate covalently modified with compounds selected from a group including compounds 100, 101, 110 and 112-114; and (c) an extended-release formulation of a glucocorticoid, wherein the hydrogel capsule has a spherical shape and a diameter of 0.5mm to 5mm.
Claim 27 requires, in part, that the extended release formulation is present in the barrier compartment. Claim 29 specifies that the glucocorticoid is a compound of formula (IV). Claim 35 specifies that the barrier compartment comprises an alginate covalently modified with the FBR mitigating compound of compound 101. Claim 36 specifies that the barrier has an average thickness of about 10-300 microns, about 20 to 150 microns or about 40 to 75 microns. Claim 37 requires that the barrier further comprises an unmodified alginate, Claim 39 requires that the genetically modified cells are ARPE-19 cells.
Claim 43 is drawn to a composition comprising a preparation of hydrogel capsules of claim 25 and a pharmaceutically acceptable excipient. Claim 44 requires that the composition has a volume of less than 10 ml.
Claim 45 is drawn to a method of treating a subject in need of therapy with an immunomodulatory protein, comprising administering to said subject the device of claim 1. Claim 46 specifies that the administration of claim 45 is by implantation into the peritoneum.
Barney et al teach a composition comprising spherical hydrogel capsules encapsulating cells which have a diameter of between 1.35 and 1.65 mm (claim 15 of ‘245) which meets the same limitation of instant claim 25, part (c). Barney et al teach biocompatible hydrogel capsules which encapsulate cells producing Il-10 or Il-22 (page 52, line 6), which meets the immunomodulatory protein in claim 1 and 25(a). The delivery of the encapsulated cells when implanted meets the limitation of claim 4 requiring Il-10 or Il-20 in the plasma of the subject. Barney et al teach a process for preparing a hydrogel capsule from a polymer solution which comprises at least one afibrotic hydrogel-forming polymer , wherein the polymer solution further comprises a cell suspension comprising a plurality of cells (claim 11 of ‘245) and wherein the afibrotic hydrogel-forming polymer comprises a compound of Formula (i) (claim 12 of ’25) which meets the limitations in claim 21. Barney et al teach that the afibrotic polymer comprises an alginate modified with an afibrotic compound and an unmodified alginate (page 4, lines 12-13 and 15-16). Barney et al teach the afibrotic compounds 100-120 (Table 2, pages 43-46) which meet the limitations of instant claims 22, 23, 24 and the modified alginates in claim 25(b). Barney et al teach an embodiment wherein the polymer solution comprises a mixture of a n afibrotic alginate and an unmodified alginate (page 4, lines 15-16) which meet that limitation in claim 37. Barney et al teach that that the cells in the encapsulated suspension are RPE cells engineered to express the therapeutic protein (page 4, lines 29-30). Barney et al teach that “RPE” cells include cells derived from ARPE-19 (page 13, lines 4-6) which meets the limitations of claim 1(v) and claim 39. Barney et al teach that the engineered RPE cells typically comprise an exogenous nucleic acid sequence (page 11, lines 19-22) which meets the limitation of claim 9.
Barney et al do not teach a hydrogel capsule comprising a barrier compartment surrounding the cell-containing compartment and comprising a second polymer composition which comprises alginate covalently modified with at least one of the afibrotic compounds of claim 25 and an extended release formulation of a glucocorticoid, wherein the extended release formulation is present in the barrier compartment as required in claim 27, or that the barrier compartment comprises an alginate covalently modified with the afibrotic compound 101 as required in claims 25(b) and 35, or that the barrier compartment further comprises an unmodified alginate as required in claim 37, or that the barrier compartment has an average thickness of about 10 to 300 microns 2-150 microns or 40-75 microns as required in claim 36, or that the glucocorticoid is a compound of formula IV required in claim 29, or that the device of claim 1 comprises a barrier compartment comprising a hydrogel polymer as required in claim 18.
The abstract of Khaliq teaches that proliferation of retinal pigment epithelial cells is stimulated by hypoxia. One of skill in the art would understand that the transfected RPE or ARPE-19 cells in the implanted hydrogel capsule producing Il-10 or Il-22 would be subject to low oxygen conditions and that said RPE cells within the hydrogel capsule would be expected stay viable under the low oxygen conditions versus other host cells which do not thrive under low oxygen conditions.
Kalo et al teach a method of treating a subject having an inflammatory bowel disease comprising administering to the subject an Il-22 fusion protein (claim 1 of ‘140). Kalo et al teach that IL-22 Fc fusion protein is a fusion protein of human IL-22 linked to the Fc of human IgG4 to increase its stability and half-life in vivo (page 154, lines 2-3).
Alabbas et al teach that recombinant Il-22 administered interperitoneally into mice had an ~30 min half-life. One of skill in the art would conclude that treatment of an inflammatory bowel disease in a human would benefit from continuous exposure to Il-22 over time.
Anderson et al teach a composition comprising a microcapsule comprising a biocompatible hydrogel having encapsulated therein (a) one or more mammalian secretory, metabolic, or structural cells; and (b) one or more anti-inflammatory drugs encapsulated in or on polymeric particles dispersed on or within the biocompatible hydrogel, wherein the anti-inflammatory drug is released over a course of 10-90 days in an amount effective to prevent fibrosis of the composition; and wherein the one or more mammalian cells are encapsulated within a core comprising a biocompatible hydrogel; an envelope comprising the biocompatible hydrogel wherein the envelope surrounds the core, wherein the anti-inflammatory drug loaded particles are encapsulated within the envelop (claims 1, 2 and 4 of ‘982). The envelope comprising the core of Anderson meets the limitations of the cell containing compartment surrounded by a barrier compartment in instant claim 17, wherein the barrier and the cell containing compartment comprise hydrogels in claims 18 and 19; the requirement for a barrier compartment surrounding the cell containing compartment in claim 25(b). Anderson et al teach that the mean diameter of the particles may be selected and optimized based on the particular drug, dosage and release rate required (page 6, lines 22-24), thus meeting the limitation of an extended release formulation present in the barrier compartment in claims 1, 25(c), and 27. Anderson et al teach a particularly preferred composition which is a microcapsule containing cells immobilized in a core of alginate with a polylysine shell, wherein additional external alginate layer form the envelope resulting in a multi-layer alginate/polylysine-alginate/alginate-cell microcapsule (page 15, lines 3-7)
Anderson et al teach an embodiment wherein the encapsulated cells are engineered to express a recombinant, secreted protein (page 7, lines 29-31). Anderson et al teach that the anti-inflammatory drugs include glucocorticoids wherein a particular preferred drug is dexamethasone (page 8, first paragraph), which meets the limitations of claims 13 and 29.
It would have been prima facie obvious to preparing a hydrogel envelop/barrier from a polymer solution which comprises at least one afibrotic hydrogel-forming polymer for the formation of the envelop structure of Anderson, wherein the afibrotic compounds associated with the envelop are in contact with the immune cells of the subject rather than the core which is surrounded by the envelop. One of skill in the art would have been motivated to provide an afibrotic compounds of compounds 100-120 on the envelop rather than relying on the glucocorticoid extended release from the microcapsule because the glucocorticoid will eventually be depleted, whereas the afibrotic compounds are a permanent part of the structure of the envelop. One of skill in the art would be motivated to maintain the afibrotic surface of the envelop/barrier for the duration of time that the RPE cells produce the Il-10 and Il-22.
Regarding the extended release glucocorticoid in the envelope, Dudley et al teach that ,steroids such as budesonide, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone are known agent for treating ulcerative colitis (paragraph [0006]) Further, Chibout et al teach that triamcinolone hexacetonide is a specific ester for treating inflammatory bowel disease (Table 1).
It would be prima facie obvious to one of skill in the art at the time prior to the effective filing date to retain the extended release formulation of dexamethasone, or substitute the dexamethasone with budesonide, hydrocortisone, methylprednisolone, prednisolone, prednisone triamcinolone or triamcinolone hexacetonide in the envelop/barrier compartment. One of skill in the art would have been motivated to do so in order to provide the anti-inflammatory compounds for the treatment of inflammatory bowel disease in addition to the Il-22 being secreted by the recombinant retinal pigment epithelial cells in the core, thus rendering obvious claims 14, 15, and 30-32.
Regarding claim 2, wherein the period of delivery of il-10 or il-20 from the implanted device is, in part, at least 90 days, Anderson et al teach that the one or more anti-inflammatory drugs are released from the composition for at least 90 days (page 5, lines 17-21). The anti-inflammatory drug of Anderson are the glucocorticoids. Instant claim 2 requires the immunomodulatory protein of Il-10 or Il-22. The delivery of the immunomodulatory Il-10 or Il-22 from device of claim 1 would be expected to continue for more than 90 days since the RPE cells expressing and secreting the Il-22 thrive under low oxygen conditions, and because the afibrotic compounds on the envelop of the microcapsule are not depleted by diffusion out of the microcapsule as are the glucocorticoids. Thus claim 2 is obvious over the combined teachings.
Anderson et al teach microcapsules containing cells are coated onto a medical device suitable for implantation and the administration of the microcapsule device to the peritoneum of the subject (page 10, lines 11-13) which meets that limitation in claims 45 and 46. Anderson et al teach that compartmentalization of the anti-inflammatory drug to the surface of the composition minimizes interference with the mammalian cells within the core (page 12, line 31 to page 13, line 4). Anderson et al do not specifically teach an excipient used in composition comprising the microcapsules, but it would have been obvious to use sterile PBS for injection of the microcapsules into the peritoneum, thus rendering obvious that limitation in claim 43.
This, it would have been prima facie obvious to administer to the peritoneum of a subject with IBD the microcapsules comprising the hydrogel envelope modified with alginate attached to the afibrotic compounds 100-120, wherein the envelop contained a hydrogel cell compartment comprising RPE cells expressing and secreting Il-22, and glucocorticoids in particles of an extended release formulation, wherein the particles were in the envelope rather than the cell compartment, wherein the microcapsules were in sterile PBS. One of skill in the art would have been motivated to do so in because Anderson et al teaches adhering the microcapsules to the peritoneum, and because one of skill in the art would understand that the inventive microcapsules in the peritoneum provides a cavity for spacio-localisation of the secreted Il-22 and glucocorticoid adjacent to the pathological tissue to be treated. One of skill in the art would understand that this is preferable to systemic treatment which would be associated with undesired side effects due to Il-22 and the glucocorticoid..
Regarding claim 44 and the requirement for less than 10 ml of the composition of claim 43, it is within the purview of one of skill in the art to determine the maximum volume of the composition for peritoneal injection of the device of claim 1.
Regarding claim 36, and the requirement for a barrier compartment having an average thickness of 10-300 microns, 20-150 microns or 40 to about 75 microns, it is within the purview of one of skill in the art to determine the thickness of the envelope containing the hydrogel cell compartment and the extended release glucocorticoid to optimize the thickness preserve the envelop integrity during implantation in a subject or injection of the composition of the hydrocapsules into a subject, and also allows for the passage of the immunomodulators and released glucocorticoids.
Claims 1-4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Barney et al, Kalo et al, Alabbas et al, the abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al as applied to claims 1, 2, 4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 above, and further in view of Bandukwala et al (WO2021/226137).
Claim 3 requires that the heterologous signal peptide expressed by the nucleic acid encoding the immunomodulatory protein of Il-20 is SEQ ID NO:21.
Bandukawa et al teach an implantable device for providing a continuous delivery of a secreted antigen comprising a first APC that is engineered to express and secrete the antigen with the secretory signal peptide of SEQ ID NO: 1 (claim 1 of ‘137) which is identical to the instant SEQ ID NO: 21 Bandukawa et al teach that the implanted device comprises a surface compound which mitigates the foreign body response (claim 1 of ‘137).
It would have been prima facie obvious to use the signal peptide of Bandukawa et al for expression of the Il-10 or Il-22 immunomodulatory proteins in the microcapsule device e rendered obvious by the combined teachings of Barney et al, Kalo et al, Alabbas et al, abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al. One of skill in the art would have been motivated to so because same signal peptide was used in an analogous invention. Thus, there would be a reasonable expectation of success.
Claims 1-5, 9, 13, 14, 15, 17, 18, 19-25, 27, 29, 30-32, 35-37-39, and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Barney et al, Kalo et al, Alabbas et al, Anderson et al, Dudley et al, Chibout et al and Bandukwala et al as applied to claims 1-4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 above, and further in view of Hamady et al (Inflammatory Bowel diseases, 2011, vol. 17, pp. 1925-1935).
Claim 5 requires feature (i) and (ii) of claim 1. Feature (i) requires a second plurality of mammalian cells genetically modified to express and secrete at least one immunomodulatory protein that is different from the immunomodulatory protein secreted by the firs plurality of cells. Feature 2 requires that the immunomodulatory protein secreted by the first plurality of genetically modified cells comprises a heterologous secretory signal peptide.
Claim 20 requires that the implantable device of claim 1 comprises two or more cell-containing compartments
Claim 38 requires the hydrogel capsule of claim 2 wherein a portion of the living cells are genetically modified to continuously express and secrete a second immunomodulatory protein.
The combined teachings of Barney et al, Kalo et al, Alabbas et al, the abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al render obvious the instant claims to the extent that the at least one immunomodulatory protein expressed by the RPE cells is Il-22. The combined teachings do not provide for a second cell compartment comprising RPE cells expressing a second immunomodulatory protein for the treatment of an inflammatory bowel disease.
Hamady et al teach that TGFβ is an immunosuppressive cytokine having great potential for the treatment of IBD, its systemic use is hampered by its rapid clearance and degradation in the liver, kidney and spleen requiring multiple doses to sustain therapeutic systemic levels leading to unwanted and unexpected complications (page 1925, under the heading of “Background” and page 192 first column, lines 1-9). Hamandy et al teach an alternative means of delivery of TGFβ for the treatment of experimental colitis through controlled expression of TGFβ by the colonic microbiota resulting in safe, localized , regulated tissue specific delivery system for TGFβ for the treatment of colitis (page 1934, last paragraph).
It would have been prima facie obvious at the time prior to the effective fling date to provide a second RPE cell compartment within the envelope comprising the first Il-22 expressing and secreting RPE cells in the hydrogel envelop rendered obvious by the teachings of Barney et al, Kalo et al, the abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al). One of skill in the art would have been motivated to do so in order to treat IBD manifest as ulcerative colitis by using two different immunomodulatory proteins both known to be beneficial in the treatment of IBD.
.
Claims 1, 2, 4, 9, 13-15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, 41 and 43-46are rejected under 35 U.S.C. 103 as being unpatentable over Barney et al, Kalo et al, Alabbas et al the abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al as applied to claims 1, 2, 4, 9, 13-15, 17-19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 above, and further in view of Carrier et al (WO2010025369).
Claim 41 requires, in part, that the IL-22 protein is encoded by the exogenous nucleic acid sequence of SEQ ID NO: 10.
None of Barney et al, Kalo et al, the abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al teach that the Il-22 protein encoded by the exogenous nucleic acid sequence is SEQ ID NO: 10.
Carrier et al teach that the term “Il-22” includes an amino acid sequence which is encoded by a naturally occurring mammalian IL-22 nucleotide sequence of SEQ ID NO:2 (page 14, lines 9-11 of paragraph [051]). SEQ ID NO: 2 is identical to the instant SEQ ID NO: 10.
It would have been prima facie obvious at the time prior to the effective filing date to use SEQ ID NO: 10 as the exogenous nucleic acid or the transfection of the RPE cells in the cell compartment of the hydrogel microcapsule. One of skill in the art would have been motivated to do so by the teachings of Carrier et al on SEQ ID NO: 10 encoding Il-22.
Claims 1, 2, 4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Barney et al (WO2019/169245) in view of Presta et al (U.S. 2006/0269516), abstract of Khaliq (Investigative Ophthalmology & visual Science, 1996, Vol. 37, pp. 436-443), Anderson et al (WO2012/112982), Dudley et al (U.S. 2016/0303133) and Chibout et al (U.S. 2003/0119797).
Claim 1 is drawn to an implantable device comprising an extended release formulation of a glucocorticoid and a plurality of mammalian cells genetically modified to express and excrete one or more immunomodulatory proteins selected from an Il-10 protein or an Il-22 protein, wherein the device, after implantation, (a) prevents the contact of the genetically modified cells with the immune cells of the subject; (b) prevents the genetically modified cells from migrating out of the device; and (c)allows for the delivery of immunomodulatory protein to the subject in an amount and for a time to induce an anti-inflammatory immune response in the subject, wherein the device comprises, in part, (v) a first plurality of genetically modified cells that are genetically modified ARPE-19 cells. Claim 2 specifies that the time in which the immunomodulatory protein is delivered is at least 30 days. Claim 4 specifies that the anti-inflammatory immune response comprises an increase in Il-10 in the plasma of the subject. Claim 6 requires that the device comprises features (iii), (iv) and (v). Claim 9 specifies that the plurality of genetically modified cells comprise an exogenous nucleotide sequence encoding Il-10 or Il-22. Claim 13 requires that the glucocorticoid of claim 1 is of formula (IV). Claim 17 specifies that the plurality of genetically modified cells is surrounded by a barrier compartment.
Claim 18 requires that the barrier compartment comprises a hydrogel. Claim 19 requires that the cell containing compartment comprises a hydrogel.
Claim 21 requires that the FBR-mitigating compound is a compound of Formula (I). Claim 22 specifies that the FBR compounds of claim 21 are selected, in part, from compounds 100-121. Compound 23 requires that the FBR-mitigating compound of claim 22 is compound 101. Claim 24 requires that the FBR-mitigating compound of claim 22 is compound 100.
Claim 25 is drawn to a hydrogel capsule comprising (a) a cell containing compartment comprising genetically modified cells which continuously express or secrete a first immunomodulatory protein which is Il-10 or Il-22; (b) a barrier compartment surrounding the cell-containing compartment which comprises an alginate covalently modified with compounds selected from a group including compounds 100, 101, 110 and 112-114; and (c) an extended-release formulation of a glucocorticoid, wherein the hydrogel capsule has a spherical shape and a diameter of 0.5mm to 5mm.
Claim 27 requires, in part, that the extended release formulation is present in the barrier compartment. Claim 29 specifies that the glucocorticoid is a compound of formula (IV). Claim 35 specifies that the barrier compartment comprises an alginate covalently modified with the FBR mitigating compound of compound 101. Claim 37 requires that the barrier further comprises an unmodified alginate. Claim 39 requires that the genetically modified cells are ARPE-19 cells.
Claim 43 is drawn to a composition comprising a preparation of hydrogel capsules of claim 25 and a pharmaceutically acceptable excipient. Claim 44 requires that the composition has a volume of less than 10 ml.
Claim 45 is drawn to a method of treating a subject in need of therapy with an immunomodulatory protein, comprising administering to said subject the device of claim 1. Claim 46 specifies that the administration of claim 45 is by implantation into the peritoneum.
Barney et al teach a composition comprising spherical hydrogel capsules encapsulating cells which have a diameter of between 1.35 and 1.65 mm (claim 15 of ‘245) which meets the same limitation of instant claim 25, part (c). Barney et al teach biocompatible hydrogel capsules which encapsulate cells producing Il-10 or Il-22 (page 52, line 6), which meets the immunomodulatory protein in claim 1 and 25(a). The delivery of the encapsulated cells when implanted meets the limitation of claim 4 requiring Il-10 or Il-20 in the plasma of the subject. Barney et al teach a process for preparing a hydrogel capsule from a polymer solution which comprises at least one afibrotic hydrogel-forming polymer , wherein the polymer solution further comprises a cell suspension comprising a plurality of cells (claim 11 of ‘245) and wherein the afibrotic hydrogel-forming polymer comprises a compound of Formula (i) (claim 12 of ’25) which meets the limitations in claim 21. Barney et al teach that the afibrotic polymer comprises an alginate modified with an afibrotic compound and an unmodified alginate (page 4, lines 12-13 and 15-16). Barney et al teach the afibrotic compounds 100-120 (Table 2, pages 43-46) which meet the limitations of instant claims 22, 23, 24 and the modified alginates in claim 25(b). Barney et al teach an embodiment wherein the polymer solution comprises a mixture of a n afibrotic alginate and an unmodified alginate (page 4, lines 15-16) which meet that limitation in claim 37. Barney et al teach that that the cells in the encapsulated suspension are RPE cells engineered to express the therapeutic protein (page 4, lines 29-30). Barney et al teach that “RPE” cells include cells derived from ARPE-19 (page 13, lines 4-6) which meets the limitations of claim 1(v) and claim 39. Barney et al teach that the engineered RPE cells typically comprise an exogenous nucleic acid sequence (page 11, lines 19-22) which meets the limitation of claim 9.
Barney et al do not teach a hydrogel capsule comprising a barrier compartment surrounding the cell-containing compartment and comprising a second polymer composition which comprises alginate covalently modified with at least one of the afibrotic compounds of claim 25 and an extended release formulation of a glucocorticoid, wherein the extended release formulation is present in the barrier compartment as required in claim 27, or that the barrier compartment comprises an alginate covalently modified with the afibrotic compound 101 as required in claims 25(b) and 35, or that the barrier compartment further comprises an unmodified alginate as required in claim 37, or that the barrier compartment has an average thickness of about 10 to 300 microns 2-150 microns or 40-75 microns as required in claim 36, or that the glucocorticoid is a compound of formula IV required in claim 29, or that the device of claim 1 comprises a barrier compartment comprising a hydrogel polymer as required in claim 18.
The abstract of Khaliq teaches that proliferation of retinal pigment epithelial cells is stimulated by hypoxia. One of skill in the art would understand that the transfected RPE or ARPE-19 cells in the implanted hydrogel capsule producing Il-10 or Il-22 would be subject to low oxygen conditions and that said RPE cells within the hydrogel capsule would be expected stay viable under the low oxygen conditions versus other host cells which do not thrive under low oxygen conditions.
Presta et al teach a method of treating IBD, Crohn’s disease or ulcerative colitis comprising administering to a subject in need thereof a therapeutically effective amount of an IL-10-IgG4 fusion protein (paragraph 0131]. Presta et al teach that IL-10 cytokine has a short half-life (paragraph [0012]).
Anderson et al teach a composition comprising a microcapsule comprising a biocompatible hydrogel having encapsulated therein (a) one or more mammalian secretory, metabolic, or structural cells; and (b) one or more anti-inflammatory drugs encapsulated in or on polymeric particles dispersed on or within the biocompatible hydrogel, wherein the anti-inflammatory drug is released over a course of 10-90 days in an amount effective to prevent fibrosis of the composition; and wherein the one or more mammalian cells are encapsulated within a core comprising a biocompatible hydrogel; an envelope comprising the biocompatible hydrogel wherein the envelope surrounds the core, wherein the anti-inflammatory drug loaded particles are encapsulated within the envelop (claims 1, 2 and 4 of ‘982). The envelope comprising the core of Anderson meets the limitations of the cell containing compartment surrounded by a barrier compartment in instant claim 17, wherein the barrier and the cell containing compartment comprise hydrogels in claims 18 and 19; the requirement for a barrier compartment surrounding the cell containing compartment in claim 25(b). Anderson et al teach that the mean diameter of the particles may be selected and optimized based on the particular drug, dosage and release rate required (page 6, lines 22-24), thus meeting the limitation of an extended release formulation present in the barrier compartment in claims 1, 25(c), and 27. Anderson et al teach a particularly preferred composition which is a microcapsule containing cells immobilized in a core of alginate with a polylysine shell, wherein additional external alginate layer form the envelope resulting in a multi-layer alginate/polylysine-alginate/alginate-cell microcapsule (page 15, lines 3-7)
Anderson et al teach an embodiment wherein the encapsulated cells are engineered to express a recombinant, secreted protein (page 7, lines 29-31). Anderson et al teach that the anti-inflammatory drugs include glucocorticoids wherein a particular preferred drug is dexamethasone (page 8, first paragraph), which meets the limitations of claims 13 and 29.
It would have been prima facie obvious to preparing a hydrogel envelop/barrier from a polymer solution which comprises at least one afibrotic hydrogel-forming polymer for the formation of the envelop structure of Anderson, wherein the afibrotic compounds associated with the envelop are in contact with the immune cells of the subject rather than the core which is surrounded by the envelop. One of skill in the art would have been motivated to provide an afibrotic compounds of compounds 100-120 on the envelop rather than relying on the glucocorticoid extended release from the microcapsule because the glucocorticoid will eventually be depleted, whereas the afibrotic compounds are a permanent part of the structure of the envelop. One of skill in the art would be motivated to maintain the afibrotic surface of the envelop/barrier for the duration of time that the RPE cells produce the Il-10 and Il-22.
Regarding the extended release glucocorticoid in the envelope, Dudley et al teach that ,steroids such as budesonide, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone are known agent for treating ulcerative colitis (paragraph [0006]) Further, Chibout et al teach that triamcinolone hexacetonide is a specific ester for treating inflammatory bowel disease (Table 1).
It would be prima facie obvious to one of skill in the art at the time prior to the effective filing date to retain the extended release formulation of dexamethasone, or substitute the dexamethasone with budesonide, hydrocortisone, methylprednisolone, prednisolone, prednisone triamcinolone or triamcinolone hexacetonide in the envelop/barrier compartment. One of skill in the art would have been motivated to do so in order to provide the anti-inflammatory compounds for the treatment of inflammatory bowel disease in addition to the Il-10 being secreted by the recombinant retinal pigment epithelial cells in the core, thus rendering obvious claims 14, 15, and 30-32.
Regarding claim 2, wherein the period of delivery of il-10 or il-20 from the implanted device is, in part, at least 90 days, Anderson et al teach that the one or more anti-inflammatory drugs are released from the composition for at least 90 days (page 5, lines 17-21). The anti-inflammatory drug of Anderson are the glucocorticoids. Instant claim 2 requires the immunomodulatory protein of Il-10 or Il-22. The delivery of the immunomodulatory Il-10 or Il-22 from device of claim 1 would be expected to continue for more than 90 days since the RPE cells expressing and secreting the Il-10 thrive under low oxygen conditions, and because the afibrotic compounds on the envelop of the microcapsule are not depleted by diffusion out of the microcapsule as are the glucocorticoids. Thus claim 2 is obvious over the combined teachings.
Anderson et al teach microcapsules containing cells are coated onto a medical device suitable for implantation and the administration of the microcapsule device to the peritoneum of the subject (page 10, lines 11-13) which meets that limitation in claims 45 and 46. Anderson et al teach that compartmentalization of the anti-inflammatory drug to the surface of the composition minimizes interference with the mammalian cells within the core (page 12, line 31 to page 13, line 4). Anderson et al do not specifically teach an excipient used in composition comprising the microcapsules, but it would have been obvious to use sterile PBS for injection of the microcapsules into the peritoneum, thus rendering obvious that limitation in claim 43.
This, it would have been prima facie obvious to administer into the peritoneum of a subject with IBD the microcapsules comprising the hydrogel envelope modified with alginate attached to the afibrotic compounds 100-120, wherein the envelop contained a hydrogel cell compartment comprising RPE cells expressing and secreting Il-10, and glucocorticoids in particles of an extended release formulation, wherein the particles were in the envelope rather than the cell compartment, wherein the microcapsules were in sterile PBS. One of skill in the art would have been motivated to do so because Anderson et al teaches adhering the microcapsules to the peritoneum, and because one of skill in the art would understand that the inventive microcapsules in the peritoneum provides a cavity for spacio-localisation of the secreted Il-10 and glucocorticoid adjacent to the pathological tissue to be treated. One of skill in the art would understand that this is preferable to systemic treatment which would be associated with undesired side effects due to Il-10 and the glucocorticoid..
Regarding claim 44 and the requirement for less than 10 ml of the composition of claim 43, it is within the purview of one of skill in the art to determine the maximum volume of the composition for peritoneal injection of the device of claim 1.
Regarding claim 36, and the requirement for a barrier compartment having an average thickness of 10-300 microns, 20-150 microns or 40 to about 75 microns, it is within the purview of one of skill in the art to determine the thickness of the envelope containing the hydrogel cell compartment and the extended release glucocorticoid to optimize the thickness preserve the envelop integrity during implantation in a subject or injection of the composition of the hydrocapsules into a subject, and also allows for the passage of the immunomodulators and released glucocorticoids.
Claims 1, 2, 4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, 40 and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Presta et al, the abstract of Khaliq (Investigative Ophthalmology & visual Science, 1996, Vol. 37, pp. 436-443), Anderson et al (WO2012/112982), Dudley et al (U.S. 2016/0303133) and Chibout et al, as applied to claims 1, 2, 4, 9, 13, 14, 15, 17, 18, 19, 21-25, 27, 29, 30-32, 35-37, 39, and 43-46 above, and further in view of Gorby et al (WO2021/181091, priority to GB2020-3428).
Claim 40 requires that the first immunomodulatory protein is an Il-10 protein encoded by SEQ ID NO: 7.
The combined teachings of Barney et al, Presta et al, the abstract of Khaliq, Anderson et al, Dudley et al and Chibout et al render obvious the instant clams to the extent that the first plurality of RPE cells express and secrete Il-10 through transfection with the exogenous nucleic acid encoding Il-10. The combined teachings do not address the sequence of the exogenous nucleic acid.
Gorby et al teach the IL-10 mutein of SEQ ID NO: 11 is superior to wild type IL-10 in binding affinity to the IL-10Rβ subunit of the receptor (page 4, lines 1-3 of second full paragraph). SEQ ID NO: 11 of Gorby et al is identical to the instant SEQ ID NO: 7.
It would have been prima facie obvious at the time prior to the effect fling date to transfect the RPE cells of the first plurality with the exogenous nucleic acid encoding the SEQ ID NO: 11 of Gorby et al. One of skill in the art would have been motivated to do so because Gorby et al teach that SEQ ID NO: 11 is superior to wild-type IL-10.
Allowable Subject Matter
Claims 33 and 34 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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