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 .
Claim Objections
The examiner has reviewed and found the applicant’s claim 4 amendment correcting the typographical error to be satisfactory. The objection has been withdrawn.
Drawings
The examiner has reviewed and found the applicant’s amendment correcting the drawings to be sufficient. The objection has been withdrawn.
CLAIM INTERPRETATION
For the purposes of examination “stem cell” is interpreted in accordance with the applicant’s definition of stem cells found in paragraph 0037-0045 of the specification. “Islet-like clusters” is interpreted to mean cells growing in circular colonies (Figure 7, Figure 8, Figure 9). A “subject” is interpreted to mean any mammal (paragraph 0088) who is at risk or having a disorder described in the current disclosure (paragraph 0079). This includes diabetes. “Administered” is interpreted to include using “pharmaceutically acceptable carrier compositions” (paragraph 0090), and using “pharmaceutically acceptable carrier compositions” is interpreted to include “capsules” (paragraph 0091). Claim 9 is interpreted as a “product by process” claim (MPEP 2113), where the process of making only imposes structure equivalent to “a cell that can secrete insulin”. The term “end portion of the time” in claim 7 has been interpreted to include the Endocrine/ Stage 5 portion of the protocol as defined as culture with a ALK5 inhibitor II.
Claim Rejections - 35 USC § 102
Response to Arguments
The examiner has reviewed and found the applicant’s arguments persuasive. The applicant argues that the rejection of claims 1-2 and claims 6-9 under 35 U.S.C. 102(a)(1) in view of US PUB ‘693 and Asignbrey et al is invalid. They applicant argues the cited prior does not disclose the use of only the laminin-111 ECM protein, or only laminin-111 and collagen IV ECM proteins when differentiating stem cells into insulin-producing beta cells (iSC-B). Instead, they argue the art discloses the use of Matrigel as a plate coating agent, which is a heterogenous mixture that contains more than just ECM proteins. The examiner agrees that claims 1-2 and claims 6-9 are no longer anticipated by US PUB ‘693 or Asignbrey et al.
The rejection to claims 1-2 and claims 6-9 under 35 U.S.C. 102(a)(1) are hereby withdrawn
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
Response to Arguments
The examiner has reviewed and found the applicant’s arguments persuasive. The applicant argues that the rejection of claims 3-5 under 35 U.S.C. 103 in view of Xu is invalid because Xu does not provide a reasonable teaching/suggestion/motivation to use only one or two well defined ECM proteins as plate coating agents during the in vitro stem cell[Wingdings font/0xE0] iSC-B cell differentiation process. Specifically, Xu provides no direction, example, suggestion, or indication that would inform a person of ordinary skill in the art to expect success using only a single laminin isoform, laminin-111, or laminin-111 isoform with collagen IV, as a plate coating during the entire process of differentiating stem cells to iSC-B cells. They argue that a person of ordinary skill in the art would not expect successful/predictable results because the Matrigel composition has numerous additional and favorable components not present in individual ECM protein coatings (aka growth factors/enzymes/ect) that significantly aid in the development process.
Therefore, the rejections of claims 3-5 under 35 U.S.C 103 are hereby withdrawn.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Maria Horejs C, et al. 2014, Hogrebe N, et al. 2020, and Webber, L et al. 2008.
Maria Horejs C, et al. 2014 discloses using a coating of only laminin-111 for stages 0-3 in the differentiation of stem cells into iSC-B cells. They show that laminin-111 regulates human stem cell epithelial to mesenchymal transition (EMT) through integrin mediated signaling generated by ECM remodeling. They also show that laminin-111 specifically has an essential role in the epithelial the mesenchymal cell transition (see Figure 3 and 4). The regulated and controlled entry and progression through the EMT leads to stem cells primitive gut cells which can then be differentiated into pancreatic progenitors, as supported by Hogrebe et al 2020.
Maria Horejs C, et al. 2014 does not disclose the remaining stages of stem cell differentiation to iSC-B cells (aka stage 4 aka primitive gut tube to-stage 6 iSC-B cells). They also do not disclose the use of the combination of laminin-111 with collagen IV in a defined ratio, nor the particular 6 step method of stem cell[Wingdings font/0xE0]iSC B cell differentiation. Finally, they do not disclose a method of treating a subject by administering the cells of claim 1 to s ubject.
Hogrebe N, et al. discloses coating cell culture plates with a single ECM protein and differentiating stem cells from stage 4 to stage 6 (see Supp Fig 1A and Fig 1A). Importantly, they try several single ECM protein coatings while carrying out the differentiation of pancreatic progenitors into iSC-B cells. Note laminin-111, collagen 1, and collagen IV are a few of the ECM proteins tested (supplementary figure 1). Hogrebe N, et al. also discloses a 6-step protocol to differentiate iPSCs into insulin secreting beta cells (iSC-B cells) (See figure 1 and figure 4 and methods section). Importantly, Hogrebe N et al. also uses the stem-cell derived iSC-B cells to treat mice suffering from diabetes. “Transplantation of islet-sized aggregates of these cells rapidly reversed severe preexisting diabetes in mice at a rate close to that of human islets and maintained normoglycemia for at least 9 months.” (abstract).
Webber, L et al. 2008 teaches using collagen IV ECM coating in addition to laminin to increase the in vitro viability of insulin secreting beta cells (Figure 2 and 3). They also show that when beta cells are cultured on plates coated with both laminin and collagen IV in a 3:1 ratio, there is a net increase in insulin responsiveness (Figure 6). “Finally, β-cell function in hydrogels presenting both collagen type IV and laminin revealed synergistic interactions…three gel compositions of varying ratios of collagen type IV to laminin (25:75, 50:50, and 75:25) were tested. In the presence of 25 μg/mL of collagen type IV and 75 μg/mL of laminin, β-cell insulin secretion was greater than with laminin or collagen type IV individually. These results demonstrate that specific, rationally designed extracellular environments promote isolated β-cell survival and function.” (abstract).
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to use the singular/double ECM protein plate coating/cell differentiation procedure taught by Hogrebe N et al 2020, (in particular using the coatings laminin-111/collagen I/collagen IV) and to modify that protocol by conducting the first 3 stages of the differentiation process (stage 0-stage 3) according to Maria Horejs C, et al. 2014’s laminin-111 ECM plate-coating method. Modifying the Hogrebe N et al 2020 protocol so the entire differentiation process can be performed in adherent cell culture. This modification provides a cheaper, simpler, easier, and more malleable alternative to using the bioreactor and treatment regime as disclosed in the first 3 steps by Hogrebe N et al 2020. Additionally, the use of only laminin-111 and/or collagen IV ECM protein coating throughout the entire process removes the therapeutic inapplicability of iSC-B cells developed using Matrigel. This renders claims 1-3,5 obvious.
It would also be obvious to a person of ordinary skill in the art, before the effective filing date, to modify the ECM protein plate-coating composition and differentiation methodology outlined above to include laminin-111 and collagen IV at a 3:1 ratio, as disclosed by Webber, L et al. 2008. The addition of collagen IV results increased insulin responsiveness of beta cells when stimulated by glucose. This is a highly desirable trait and would make it obvious to a person of ordinary skill in the art, before the effective filing date, to use the insulin producing beta cells created in in the aforementioned method/protocol and use them to treat mice suffering from diabetes, as outlined in Hogrebe N et al 2020. Therefore, claims 4,6-9 are obvious.
Importantly, Hogrebe N, et al. 2020 details their protocol for the differentiation process and their disclosures read on the remaining claims (claims 10-20). Specifically, Hogrebe N, et al. 2020 discloses coating cell culture plates with a single ECM protein and differentiating stem cells from stage 4 to stage 6 (see Supp Fig 1A and Fig 1A). Importantly, hey try several single ECM protein coatings while carrying out the differentiation of pancreatic progenitors into iSC-B cells. Note laminin-111, collagen 1, and collagen IV are a few of the ECM proteins tested (supplementary figure 1). Hogrebe N, et al. also discloses a 6-step protocol to differentiate iPSCs into insulin secreting beta cells (iSC-B cells) (See figure 1 and figure 4 and methods section). The 6-step process used by Hogrebe N, et al. mirrors the 6-step process disclosed in the instant application. The following summary of the 6-step protocol disclosure can be found in paragraph “Planar Protocol” under the “SC-β Cell Differentiation” subsection, which is in the methods section. Additionally, ECM expansion on Matrigel can be found in paragraph “Stem Cell Culture” in the methods section. Importantly, the method disclosed by Hogrebe N, et al expands stem cells on ECM before stage 1 (claim 10), cultures cells in activin a during stage 1 (claim 11), cultures with KGF in step 2 (claim 12), cultures cells in Retinoic acid, KGF, SANT1 (hedgehog signal inhibitor), TPPB (a PKC Activator), and LDN193189 (BMP inhibitor) in stages 3/4 (claim 13, claim 17-claim20), cultures cells in Latrunculin A (actin-depolymerizing agent) in stage 5 (claim 14 and claim 20), and culturing cells in Enriched serum-free medium (ESFM) during stage 6 (claim 15). They also disclose resizing clusters by single cell dispensing on day 1 of stage 6 and then reaggregating them into islet-like clusters. (paragraph “Suspension Protocol” in methods section) (claim 16). Therefore, claims 10-20 are obvious.
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.
Response to Arguments
The examiner has reviewed and found the applicant’s amendment to be sufficient. The rejection has been withdrawn.
Claim Rejections - 35 USC § 112b – Necessitated by Amendment
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 6 states (as amended), that the “ECM comprises only the two proteins collagen I or collagen IV. It is unclear if the applicant’s original intention was to refer to collagen I and IV in the alternative or in unison, particularly because claim 1 is limited to single proteins or a specific combination of two proteins. If applicant intends to refer to collagen I and IV in the alternative, the identity of the second protein is unclear. This leaves the metes and bounds of the claim un clear. (MPEP 2173) (See in: Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898 (2014)).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ADAM MICHAEL SMITH whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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