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 .
This action is in response to the papers filed 07/26/2024.
Claims 1-20 are pending in the application. Claim 1 is independent as set forth in the claim set filed 07/26/2024.
Therefore, claims 1-20 are examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed parent provisional applications 63/580,657 filed 09/05/2023 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is September 05, 2023.
Claim objection
Claims 17-20 recite “said pluripotent stern cells”. Each of these claims depend on claim 1 which recites “a pluripotent stern cell” and not the plural form. For consistency, the claims should recite the singular or plural form of the cells. Appropriate correction is requested.
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 1-20 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.
Claim 1 recites a series of steps, however two of the method steps are numbered “b)” in lines 2 and 3. This renders the metes and bounds of the invention unclear as the steps could be performed simultaneously or sequentially. For the purpose of examination, it is determined that the second “b)” is “c)” and the sequential numbering continues from that step.
Claim 5 is indefinite in its recitation “differentiation of said pluripotent stem cell into said insulin producing cell” . Claim 5 depends on claim 1 which requires “differentiating said pluripotent stern cell into a mesendoderm cell”. Thus, it is unclear if the differentiation of pluripotent stem cell into insulin producing cells requires the intermediate step of differentiation into a mesendoderm cell. As such the metes and bounds of the claim are indefinite.
Claim 6 recites the term “said dedifferentiation factor” however claims 1 and 5 on which it depends do not recite “dedifferentiation factor.” Therefore, the term lacks antecedent basis.
Claims 10, 11 and 12 each of them depending on claim 1 recite “said insulin producing cells”. There is not proper antecedent bases for “said insulin producing cells”. Claim 1 recites “a beta cell., or beta-like cell”.
Claim 13 recites the term “said immunogenic molecule is CD40.” Claim 13 depends on claim 11, however claim 11 does not recite the term “immunogenic molecule.” Therefore, claim 13 lacks antecedent basis. Claim 12 recites the term, and therefore, it is interpreted that claim 13 should be dependent on claim 12.
Claim 19 is indefinite in its recitation of “of adventitial viral components”. The phrase “adventitial viral components” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite “adventitial”, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Moreover, a Google® search of this term does not give any hits which demonstrates that this is a not commonly used phrase. Appropriate action is required.
Therefore, claims 1, 6, 13, and all dependent claims thereof are rejected as indefinite.
Claim Rejections - 35 USC § 102
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.
Claims 1-4, 10-11 and 17-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hua (US20180237751A1)
Regarding claim 1, Hua teaches a method of generating insulin producing cells (Abstract, para. 0055).
Regarding claim 1 steps a-b, Hua teaches that iPS cells/IPSCs (induced pluripotent stem cells) are made through obtaining somatic cells such as fibroblasts (para. 0049).
Regarding claim 1 step b-c, Hua teaches differentiation of iPSCs towards beta-like cells and pancreatic endoderm cells (para. 0026). Table 4 details the media at the different stages of differentiation, showing the cells are differentiated to mesendoderm cells and then definitive endoderm cells and pancreatic endoderm cells (para. 0214-0216, Table 4).
Regarding claim 1 step d, Hua teaches endoderm cells are differentiated to beta-like cells (para. 0214-0216, para. 0178, Table 4).
Regarding claim 2, Hua teaches iPSCs inherently express one or more key pluripotency markers such as SEA4, OCT4, and NANOG (para. 0149). Hua generates iPSCs which specifically express Nanog, Oct4 and SSEA4 (para. 0022, 0049).
Regarding claims 3-4, Hua teaches that the endoderm cells express PDX-1 and NKx6.1 (para. 0073, 0271).
Regarding claim 10-11, the claims do not further provide active steps to the method and therefore are determined to be also anticipated by Hua. Hua discloses that the insulin producing cells may be altered by transfection (para. 0125).
Regarding claim 17-18, Hua teaches utilizing SeV methods which are non-integrating and produce karyotypically normal IPSCs (para. 0022, 0268).
Regarding claim 19-20, Hua teaches that the pluripotent stem cells can be differentiated and produce insulin (para. 0042). As the cells functioned and were differentiated successfully, it is interpreted that they demonstrate no adventitial viral components.
Therefore, the invention would be anticipated by Hua at the time of the effective filing date.
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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) as applied to claims 1-4, 10-11 and 17-20, in view of Kroon (Nature Biotechnology volume 26, pages 443–452 (2008)).
Regarding claim 5, Hua anticipates the method of claim 1 as discussed in the 102 rejection above and incorporated herein in its entirety. The broadest reasonable interpretation of claim 5 is that at any stage before the beta cell production, the pluripotent stem cells can be administered to a subject for in vivo differentiation into beta-like cells.
However, Hua does not teach in vivo differentiation to beta-like cells.
Kroon teaches engrafting hES cell (i.e. pluripotent cell) derived pancreatic endoderm into an immune compromised mouse (p. 444, 2nd column). The pancreatic endoderm cell then differentiated further to functional endocrine cells such as insulin expressing cells which functioned as beta-like cells (Abstract, p. 443, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to place the endodermal cells generated by Hua into a subject for in vivo differentiation into insulin producing cells as taught by Kroon with a reasonable expectation of success. An artisan would be motivated to do so as Kroon teaches that it is a known alternative method of producing functional beta-like islet cells.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) in view of Kroon (Nature Biotechnology volume 26, pages 443–452 (2008) as applied to claims 1 and 5, and in further view of Zemelko (Cell Tiss. Biol. 6, 1–11 (2012) and Kubara (2018, Stem Cell Reports, Vol. 11, 380–394)
Regarding claim 6, Hua and Kroon make obvious the method of claim 1 and 5 as discussed in the 103 rejection above and incorporated herein in its entirety. As addressed in the 112b rejection. It is unclear what step dedifferentiation factors are used and MSCs are introduced or how they are used as there is no antecedent basis. Therefore, it is interpreted that when pluripotent stem cells are produced through dedifferentiation, OCT4 and k-RAS are utilized in a co-culture with mesenchymal stem cells (MSC).
Hua and Kroon do not teach culturing pluripotent cells in the presence of MSCs.
Zemelko teaches utilizing MSCs obtained from menstrual blood (eMSC) as a feeder layer for human embryonic stem cells (hESC) (Abstract, p. 4). Moreover, Zemelko teaches eMSCs are perfect feeder cells for maintenance hESCs because they sustain the hESC pluripotent status that verified by expression of Oct4, alkaline phosphatase and SSEA4 markers and the hESCs cocultured with the eMSCs retain their morphology and proliferative rate (abstract). Zemelko teaches the easy and noninvasive isolation of the eMSCs from menstrual blood, their multipotency and high proliferative activity in vitro without karyotypic abnormalities demonstrate the potential of use in regenerative medicine (Abstract).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to co-culture the iPSCs of Hua on a feeder layer of eMSCs as taught by Zemelko during dedifferentiation with a reasonable expectation of success. An artisan would be motivated to do so as Zemelko discusses the advantages of utilizing eMSCs such as pluripotent stem cells sustaining pluripotent status.
Regarding claim 6, Hua teaches utilizing dedifferentiation factors such as Oct4, however, the combined teachings of Hua, Kroon and Zemelko do not teach additionally utilizing dedifferentiation factors such as k-RAS.
Kubara teaches that KRAS plays an essential role in stemness maintenance in iPSCs which express OCT4 (Abstract, p. 381, 1st column). Kubara showed that activated KRAS conferred retained self-renewal of undifferentiated cells and difficulty in differentiation into neurons (p. 390, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to additionally utilize k-Ras as a dedifferentiation factor as taught by Kubara, in the dedifferentiation protocol taught by Hua, Kroon, and Zemelko with a reasonable expectation of success. An artisan would have been motivated to utilize k-Ras as it is known in the art to play a role in stemness in iPSCs and retain properties such as self-renewal.
Regarding claim 7, Hua, Kroon, Zemelko and Kubara make obvious claim 6. Moreover, Zemelko teaches the eMSCs are isolated from menstrual blood (Abstract).
Regarding claim 8, Hua, Kroon, Zemelko and Kubara make obvious claim 7. Moreover, Zemelko teaches the eMSCs were selected/determined suitable and satisfactory for MSCs with their expression of CD73 (p. 5, phenotypic characteristics).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) in view of Kroon (Nature Biotechnology volume 26, pages 443–452 (2008)), Zemelko (Cell Tiss. Biol. 6, 1–11 (2012)) and Kubara (2018, Stem Cell Reports, Vol. 11, 380–394) as applied to claims 1 and 5-8 above, and in further view of Doucet (JOURNAL OF CELLULAR PHYSIOLOGY 205:228–236 (2005)).
Regarding claim 9, Hua, Kroon, Zemelko and Kubara make obvious the method of claims 1 and 5-8 as discussed in the 103 rejection above and incorporated herein in its entirety.
However, the above references do not teach wherein the MSCs are expanded in the presence of platelet lysate.
Doucet teaches expanding MSCs in platelet lysate (Abstract). Moreover, Doucet teaches that platelet lysate is enriched in growth factors which promote MSC expansion over that of other media such as fetal calf serum (Abstract, Table 1, Figure 1). The MSCs expressed CD90, CD105, and CD73 (p. 232, last paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to expand the MSCs of Hua, Kroon, Zemelko, and Kubara in platelet lysate as taught by Doucet with a reasonable expectation of success. Doing so would provide growth factors which promote MSC expansion over other media such as fetal calf serum.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) as applied to claims 1 and 10, and in view of zhang (Biomaterials, Volume 217, October 2019, 119302).
As discussed in the 102 rejection above and incorporated herein in its enteriety, Hua teaches a method of producing insulin producing cells which reads on claim 1. Moreover, Hua discloses that the insulin producing cells may be altered by transfection (para. 0125).
However, Hua does not teach that the insulin producing cells are gene edited to remove immunogenic molecules such as CD40.
Zhang teaches utilizing CRISPR in dendritic cells in order to disrupt CD40 because blocking the costimulatory molecule CD40 in transplanted cells inhibits T cell activation and induces transplant tolerance (Abstract, p. 2, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to gene edit with CRISPR targeting CD40 as taught by Zhang in the cells produced by the method of Hua with a reasonable expectation of success. An artisan would have been motivated to remove CD40 from the insulin producing cells because Zhang teaches that disruption of CD40 inhibits T cell activation and induces transplant tolerance (Abstract).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) as applied to claims 1 and 11 above, in view of Amatya (Molecular Therapy, 2017; 26, 184-198)
As discussed in the 102 rejection above and incorporated herein in its enteriety, Hua teaches a method of producing insulin producing cells which reads on claim 1. Moreover, Hua discloses that the insulin producing cells may be altered by transfection to express a suitable gene of interest (para. 0125).
However, Hua does not teach that the insulin producing cells are transfected with FOXP3.
Amatya teaches insulin producing cells are destroyed by autoreactive T lymphocytes caused by defective immune intolerance (Abstract). A construct comprising FOXP3 and PDX1 was provide to T cells and hepatocyte like stem cells which resulted in the FOXP3 protein abrogating diabetogenic autoimmunity through Treg induction (p. 192, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to transduce the insulin producing cells as taught by Hua with FOXP3 with a reasonable expectation of success. An artisan would have been motivated to transduce FOXP3 into the insulin producing cells as providing FOXP3 is known in the art to abrogate immune responses.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 15 is rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) in view of Xu ( MOLECULAR MEDICINE REPORTS 12: 3881-3889, 2015)
As discussed in the 102 rejection above and incorporated herein in its enteriety, Hua teaches a method of producing insulin producing cells which reads on claim 1. Moreover, Hua discloses that the insulin producing cells may be altered by transfection (para. 0125).
However, Hua does not teach that the insulin producing cells are transfected with IL-10.
Xu teaches transfection of IL-10 to mice in order to demonstrate the ability to protect bet a cells against autoimmune damage and a reduction of apoptosis (p. 3882. 2nd column). It has been shown in previous studies that IL-10 when transferred in vitro to beta cells inhibits nitric oxide production and apoptosis (p. 3882, 1st column). These beta cells were found to retain their insulin secretion function (p. 3882, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to transfect the insulin producing cells taught by Hua with IL-10 with a reasonable expectation of success. An artisan would have been motivated to transfect the insulin producing cells with IL-10 as Xu teaches it has been shown to inhibit apoptosis in vitro.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 16 is rejected under 35 U.S.C. 103 as being unpatentable over Hua (US20180237751A1) in view of Maharlooei (Iran J Med Hypotheses Ideas, 2009, 3:31)
As discussed in the 102 rejection above and incorporated herein in its enteriety, Hua teaches a method of producing insulin producing cells which reads on claim 1. Moreover, Hua discloses that the insulin producing cells may be altered by transfection (para. 0125).
However, Hua does not teach that the insulin producing cells are transfected with HLA-G.
Maharlooei teaches transfection of HLA-G cDNA into insulin producing cells (IPCs) (p. 3, 2nd column). Moreover, Maharlooei teaches that expression of HLA-G inhibits NK cells, cell lysis and cell-mediated immune reaction (p. 4, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to transfect the cells taught by Hua with HLA-G as taught by Maharlooei with a reasonable expectation of success. An artisan would have been motivated to transfect insulin producing cells with HLA-G as Maharlooei teaches that expression of HLA-G inhibits NK cells, cell lysis and cell-mediated immune reaction (p. 4, 2nd column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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