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 .
Claims 1-13 and 31-47, of record 11/20/2024, are pending and subject to prosecution.
Priority
The instant application is a CON of 17/988257 (filed 11/16/2022), which is a CON of 17/390839 US patent 12049645, filed 7/30/2021), which claims benefit of provisional application 63/059433 (filed 7/31/2020).
Specification
The use of the terms B-27, RetroNectin, Synth-a-Freeze, Istodax, Farydak, and Kevetrin, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5, 8-9, 31-34, 36-38, 41, and 44 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hebrok et al. (US 20190177697 A1).
Regarding claims 1, 8-9, 41, and 44: Hebrok et al. teach methods for the invitro production of mature beta cells from human pluripotent stem cells via pancreatic progenitors (See Abstract and ¶0069). Differentiated clusters of cells yielded a population of C-peptide-positive cells (which reads on “a plurality of cells that express insulin”) isolated by flow cytometry wherein 86±5% of the cells expressed ISL1 and 75±20% expressed NKX6.1 (See ¶0041 and 0137 and fig. 4F). The sorted cells exhibited fewer MAFA transcripts (which reads on “express lower levels of MAFA than NKX6.1-positive, ISL1-positive cells from the pancreas of a heathy control adult subject”) and more MAFB transcripts (which reads on “express higher levels of MAFB than NKX6.1-positive, ISL1-positive cells from the pancreas of a heathy control adult subject” than beta cells in human islets (See ¶0138 and fig. 5B).
Regarding claim 5: Following the discussion of claims 1, 8-9, 41, and 44, the 86±5% of ISL1-positive cells taught by Hebrok et al. reads on the limitation “at least 90% of the cells in the population are ISL1-positive cells”. Prior art that discloses with sufficient specificity a range that overlaps a claimed range anticipates the claimed invention. See MPEP 2131.03(II).
Regarding claims 31-34: Following the discussion of claims 1, 8-9, 41, and 44, Hebrok et al. teach culturing of the cell clusters in medium comprising about 5.5 mM glucose (which corresponds to approximately 0.1% and reads on “a sugar at a concentration of between about 0.05% and about 1.5%”), such as CMRL medium (See ¶0069).
Regarding claims 36-38: Following the discussion of claims 1, 8-9, 41, and 44, Hebrok et al. teach that sorted cells are reaggregated into 100-150 µm clusters (which reads on “at most 200 microns in diameter”, “at most 150 microns in diameter”, and “between 100 and 150 microns in diameter”) (See ¶0069). Prior art that discloses with sufficient specificity a range that overlaps a claimed range anticipates the claimed invention. See MPEP 2131.03(II).
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.
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 1-10, 31-34, 36-38, 41, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Hebrok et al. (US 20190177697 A1).
The teachings of Hebrok et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 2-4, 6-7, and 10: Following the discussion of claims 1, 5, 8-9, 31-34, 36-38, 41, and 44, Hebrok et al. disclose clusters of insulin-expressing cells expressing ISL1 and NKX6.1 but do not teach less than 10%, 6%, or 4% of the cells or between 3-6% of the cells as being NKX6.1-/ISL1-. However, Hebrok et al. teach that markers such as ISL1 and NKX6.1 are key β-cell markers (See ¶0056 and 0063). One of ordinary skill in the art would therefore be motivated to include few to no NKX6.1-/ISL1- cells in the clusters in order to optimize the number of β- or β-like cells, thereby optimizing functionality. There would be a reasonable expectation of success in doing so because gating specifically for cells that are positive for both ISL1 and NKX6.1 during cell sorting could be readily performed.
Claims 1-10, 31-34, 36-38, 41, 43-44, and 46-47 are rejected under 35 U.S.C. 103 as being unpatentable over Hebrok et al. (US 20190177697 A1) in view of Agulnick et al. (Stem Cells Translational Medicine, 2015).
The teachings of Hebrok et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 43 and 46-47: Following the discussion of claims 1-10, 31-34, 36-38, 41, and 44, Hebrok et al. teach a composition comprising insulin-secreting cell clusters and that they can be administered in encapsulated form (See ¶0023 and 0035) but do not expressly teach their use in an implantable encapsulation device.
Agulnick et al. teach the transplantation of in vitro-generated insulin-producing cell clusters in a microencapsulation device (See page 1218, col. 2, full ¶1 and fig. 7).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the teachings of Hebrok et al. to comprise administration of the cell clusters in an implantable microencapsulation device, such as that taught by Agulnick et al. One would have been motivated to make this modification because Agulnick et al. teach that it can circumvent the need for immune suppression with transplantation of the cells (See page 1215, col. 1, full ¶1). There would be a reasonable expectation of success in doing so because Agulnick et al. teach that the implanted cells can mature and function normally (See page 1215, col. 1, full ¶1).
Claims 1-10, 31-34, 36-38, 41, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Hebrok et al. (US 20190177697 A1) in view of Bhoumik et al. (US 20190015487 A1).
The teachings of Hebrok et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 45: Following the discussion of claims 1-10, 31-34, 36-38, 41, and 44, Hebrok et al. teach a composition comprising insulin-secreting cell clusters but do not teach β-2-microglobulin gene disruption.
Bhoumik et al. teach universal donor pancreatic endoderm cells (See Abstract). Cell graft rejection can be prevented by disruption, deletion, modification, or inhibition of at least one MHC gene, such as β-2-microglobulin (See ¶0008).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cells of Hebrok et al. to comprise disruption of the β-2-microglobulin gene. One would have been motivated to make this modification because Bhoumik et al. teach that it can prevent rejection of transplanted cells (See ¶0008). There would be a reasonable expectation of success in doing so because Bhoumik et al. demonstrate that pancreatic endocrine cells can be derived from β-2-microglobulin-knockout stem cells (See ¶0284-0288).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP 2159. See MPEP 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13 and 31-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 15, 17, 19-20, and 22-32 of U.S. Patent No. 12049645. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1-10: Patented claim 13 recites a population of in vitro differentiated cells comprising NKX6.1-positive, ISL1-positive cells and NKX6.1-negative, ISL1-positive cells; wherein less than 6% of the cells in the population are NKX6.1-negative, ISL1-negative cells; and wherein the population of cells are in one or more cell clusters. Patented claim 15 recites the population of patented claim 13, wherein at least 60%, at least 65%, at least 70%, at least 73%, at least 75%, or at least 80% of the cells in the population are ISL1-positive cells. Patented claim 17 recites the population of patented claim 13, wherein 50-90%, 50-85%, 50-80%, 50-75%, 50-70%, 50-60%, 60-90%, 60-85%, 60-80%, 60-75%, 60-70%, 65-90%, 65-85%, 65-80%, 65-75%, 65-70%, 70-90%, 70-85%, 70-80%, 70-75%, 75-90%, 75-85%, 75-80%, 80-90%, 80-85%, or 85-90% of the cells in the population are ISL1-positive cells. Patented claim 29 recites the population of patented claim 13, wherein the population comprises NKX6.1-positive, ISL1-positive cells that express lower levels of MAPA than NKX6.1-positive, ISL1-positive cells from the pancreas of a healthy control adult subject. The combined limitations of the patented claims render obvious the instant claims.
Regarding claims 11-13: Following the discussion of claims 1-10, patented claim 19 recites the population of patented claim 13, wherein at least 40% of the cells in the population are NKX6.1-negative, ISL1-positive cells. Patented claim 20 recites the population of patented claim 13, wherein at least 45%, at least 50%, about 40-50%, about 45-55%, or about 50-55% of the cells in the population are NKX6.1-negative, ISL1-positive cells.
Regarding claims 31-35: Following the discussion of claims 1-10, patented claim 23 recites the population of patented claim 13, further comprising a medium. Patented claim 24 recites the population of patented claim 23, wherein the medium comprises a sugar. Patented claim 25 recites the population of patented claim 24, wherein the medium comprises the sugar at a concentration of between about 0.05% and about 1.5%. Patented claim 26 recites the population of patented claim 23, wherein the medium is a CMRL medium; or wherein the medium is a cryopreservation media.
Regarding claims 36-40: Following the discussion of claims 1-10, patented claim 27 recites the population of patented claim 13, wherein the cell cluster is between about 125 and about 225 microns in diameter, between about 130 and about 160 microns in diameter, between about 170 and about 225 microns in diameter, between about 140 and about 200 microns in diameter, between about 140 and about 170 microns in diameter, between about 160 and about 220 microns in diameter, between about 170 and about 215 microns in diameter, or between about 170 and about 200 microns in diameter.
Regarding claim 41: Following the discussion of claims 1-10, patented claim 30 recites the population of patented claim 13, wherein the population comprises NKX6.1-positive, ISL1-positive cells that express higher levels of MAFB than NKX6.1-positive, ISL1-positive cells from the pancreas of a healthy control adult subject.
Regarding claim 42: Following the discussion of claims 1-10, patented claim 31 recites the population of patented claim 13, wherein the population comprises NKX6.1-positive, ISL1-positive cells that express higher levels of SIX2, HOPX, IAPP and/or UCN3 than NKX6.1-positive, ISL1-positive cells from the pancreas of a healthy control adult subject.
Regarding claims 43 and 46-47: Following the discussion of claims 1-10, patented claim 32 recites the implantable encapsulation device comprising the population of patented claim 13.
Regarding claim 44: Following the discussion of claims 1-10, patented claim 22 recites the population of patented claim 13, wherein the population of cells is derived from stem cells in vitro.
Regarding claim 45: Following the discussion of claims 1-10, patented claim 28 recites the population of patented claim 13, wherein the population has a genetic disruption in the beta-2-microglobulin gene.
Claims 1-13, 36-41, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99, 170, 176, 184, 188, and 192-195 of co-pending Application No. 18786200 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1, 5, and 8-9: Co-pending claim 99 recites a method of treating a subject having diabetes, comprising treating the subject with: a) tacrolimus and b) a composition comprising a population of cells, wherein the population of cells comprises a plurality of cells that express NKX6.1 and ISL1, wherein the composition comprises about 1 X 10⁸ to about 10 X 10⁸ cells. Co-pending claim 170 recites, in part, the method of co-pending claim 99, wherein: (a) 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50-60%, 60-90%, 60-80%, 60-70%, 70-90%, 70- 80%, 70-90%, 70-80%, or 80-90% of the cells in the composition express C-peptide (which reads on “insulin”) and ISL1 but not VMAT1. Co-pending claim 192 recites the method of co-pending claim 99, wherein at least a portion of the cells in the population of cells are present in plurality of cell clusters. Co-pending claim 195 recites the method of co-pending claim 99, wherein the composition comprises a plurality of NKX6.1-positive; ISL1-positive cells, wherein the NKX6.1-positive; ISL1-positive cells express SIX3, MAFA, CHGB, RBP4 and/or FXYD2 at a lower (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% lower) level than a NKX6.1-positive, ISL1-positive cell from the pancreas of a healthy control adult subject. The combined limitations of the composition of the co-pending method claims render obvious the instant claims.
Regarding claims 2-4, 6-7, and 10: Following the discussion of claims 1, 5, and 8-9, co-pending claim 184 recites the method of co-pending claim 99, wherein less than 6% or between 0-6%, 0-4%, 0-2%, 0-1%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-3%, or 3- 6% of the cells in the composition are NKX6.1-/ISL1- cells, as determined by flow cytometry. The co-pending claims render obvious the instant claims.
Regarding claims 11-13: Following the discussion of claims 1, 5, and 8-9, co-pending claim 176 recites the method of co-pending claim 99, wherein no less than 40%, 35%, 30%, 26 %, 25%, or 20% of the cells in the composition are NKX6.1 /ISL1+ cells, as determined by flow cytometry. The co-pending claims render obvious the instant claims.
Regarding claims 36-40: Following the discussion of claims 1, 5, and 8-9, co-pending claim 193 recites the method of co-pending claim 192, wherein the cell clusters are about 50 µm to about 500 µm, about 50 µm to about 400 µm, about 50 µm to about 300 µm, about 60 µm to about 400 µm, about 60 um to about 300 µm, about 60 um to about 250 µm, about 75 µm to about 400 µm, about 75 µm to about 300 µm, about 75 µm to about 250 µm, about 125 µm to about 225 µm, about 130 µm to about 160 µm, about 170 µm to about 225 µm, about 140 µm to about 200 µm, about 140 µm to about 170 µm, about 160 µm to about 220 µm, about 170 µm to about 215 µm, or about 170 um to about 200 µm in diameter. The co-pending claims render obvious the instant claims.
Regarding claim 41: Following the discussion of claims 1, 5, and 8-9, co-pending claim 194 recites the method of co-pending claim 99, wherein the composition comprises a plurality of NKX6.1-positive; ISL1-positive cells, wherein the NKX6.1-positive; ISL1-positive cells express higher (e.g., at least 10%, 30%, 50%, 70%, 100%, 125%, 150%, or 200% higher) levels of MAFB, CHGA, ESRRG, SIX2, HOPX, IAPP and/or UCN3 than NKX6.1-positive; ISL1-positive cells from the pancreas of a healthy control adult subject. The co-pending claims render obvious the instant claim.
Regarding claim 44: Following the discussion of claims 1, 5, and 8-9, co-pending claim 188 recites the method of co-pending claim 99, wherein the population of cells are generated from stem cells in vitro. The co-pending claims render obvious the instant claim.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
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