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 .
Priority
This application is a national stage entry (35 USC 371) of PCT/US2023/063714 (filed on 03/03/2023), which claims benefit to provisional application 63/316,201 (filed on 03/03/2022).
Claims Status
Claims 1,2,4,5,10,12-13,15,17,19,22,24,28-29,31-32,34,41,43, and 49 are pending and have been examined on the merits.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
The file must be submitted in bytes not kilobytes.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112(b)
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.
Claim 49 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.
Regarding claim 49, the underlined phrases in lines 6-7 of the claim recites, “regulatory T cells (CD4+/CD25+/Foxp3+)” and in lines 7-8 “T effector cells (CD4+ or CD8+)” renders the claim indefinite because it is unclear whether the limitations in parentheses are part of the claimed invention (See, MPEP § 2173.05(d)). The terms in the parentheses are drawn to a narrower subset of the T cell populations that are recited in the claim. Specifically, for the regulatory T cells, CD4+/CD25+/Foxp3+ regulatory T cells are the most common type of regulatory T cells, but there are also CD8+ regulatory T cells, and Tr1 and Th3 cells. For the T effector cells, CD4+ and CD8+ cells are subpopulations of helper and/or regulatory T cells, respectively, but there are minor subpopulations of T effector cells that are neither CD4+ nor CD8+ (e.g. double-negative T cells, NKT cells, gamma-delta T cells). This makes it unclear if applicants are claiming the broader term or the narrower subset in parentheses; as it is not clear if the limitations in the parenthesis are limiting or providing examples.
Appropriate action is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 22 as currently written is dependent on claim 18, which was canceled on amendment filed on 08/27/2024.
For purposes of compact prosecution, claim 22 is being interpreted as being dependent on claim 19.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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.
Claims 1, 12, 13,15, 17, 19, 22, 24 ,31, 32, 34, 41, and 43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mundra et al (PloS one, 2013).
Mundra et al teaches the over expression of human vascular endothelial growth factor (hVEGF) and human interleukin-1 receptor antagonist (hIL-1Ra) in human bone marrow derived mesenchymal stem cells (hBMSCs); that are co-transplanted with human islet cells in diabetic mice (See, Abstract).
Regarding claims 1 and 13, Mundra et al teaches hBMSCs transduced with Adv-hVEGF-hIL-1Ra, such that the hBMSCs over express hVEGF and hIL-1Ra. This reads on, a recombinant mesenchymal stromal cell that expresses one or more immunomodulatory proteins or polypeptides of claim 1, as hBMSCs are MSCs and VEGF is an immunomodulatory protein. This also reads on, wherein the recombinant MSC are human of claim 13.
Regarding claim 12, following the discussion above, Mundra et al teaches that the hBMSCs were transduced with a replication deficient adenovirus, Adv-hVEGF-hIL-1Ra containing a cytomegalovirus (CMV) promoter before the cDNA of hVEGF and hIL-1Ra (See, p2 col 1 paragraph 2). This reads on, wherein the recombinant MSC comprises… a heterologous transgene comprising a constitutive promoter upstream of a coding sequence of the immunomodulatory protein or polypeptide of claim 12.
Regarding claim 15, following the discussion above, Mundra et al teaches that the primary hBMSCs were purchased (See, p2 col 1 paragraph 2). This reads on, wherein the MSCs are isolated from a patient sample and then transformed with one more recombinant expression vectors, as primary hBMSCs are derived from a patient and they were transformed with Adv-hVEGF-hIL-1Ra.
Regarding claim 17, following the discussion above, Mundra et al teaches that transduction of hBMSCs resulted in overexpression of hVEGF and hIL-Ra that was tested through ELISA from the cell culture medium of transduced cells (See, p 3 col 2 paragraph 1, Figure 3). This reads on, wherein the recombinant MSC overexpress one of the immunomodulatory proteins or polypeptides on the cell surface and secretes one of the immunomodulatory proteins.
Regarding claims 19, 22, and 24, following the discussion above, Mundra et al teaches the co-transplantation of islet cells and transduced hBMSCs under the kidney capsule of STZ induced diabetic mice (See, p2 col 2 paragraph 4). This reads on, a mixed cell population comprising one or more recombinant MSCs according to claim 1, and one or more cell types distinct of the recombinant MSCs of claim 19, as islet cells are distinct from recombinant hBSMCs. This also reads on, wherein the one of more cells types distinct of the recombinant MSCs are islet cells of claim 22. This also lastly reads on, wherein the islet cells are present in the form of an islet or multiple islets of claim 24.
Regarding claims 31, 32, and 34, following the discussion above, Mundra et al teaches the co transplantation of islet cells and transduced hBMSCs into the kidney capsule of STZ induced diabetic mice (See, p2 col 2 paragraph 4). This reads on, a method of improving survival of transplanted cells comprising implanting (i) one or more recombinant MSCs according to claim 1, and (ii) one or more cell types distinct of the recombinant MSCs into an individual at the same locus of claim 31. Mundra et teaches that the co-transplantation resulted in improved glycemic control based on blood glucose level. Mundra et al also teaches that when islet cells are co-transplanted with transduced hBMSCs, there was a reduction in cell death of the islet cells (see, p 3 col 2 paragraph 3, Figure 4). This reads on, …whereby the implanted one or more cells types distinct of the recombinant MSCs exhibit improved survival compared to said one or more cell types implanted in the absence of the one or more recombinant MSCs at the same locus of claim 31.
This also reads on, wherein the method is carried out (i) in the absence of administering immunosuppressive agents to the individual of claim 32, Mundra et al does not administer those to the subject.
This lastly reads on, wherein the one or more cell types distinct of the recombinant MSCs are islet cells of claim 33.
Regarding claims 41 and 43, following the discussion above, Mundra et al teaches co-transplanting islet and transduced hBMSCs into STZ induced diabetic mice without the use of immunosuppressive agents. Mundra et al teaches that the mice co-transplanted with islets and transduced hBMSCs had high levels of insulin and c-peptide (See, p5 col 1 paragraph 1, Figure 7). Mundra et al teaches that the transplanted islet cells were positive for insulin, when tested in the kidney section that where it was transplanted (See, p5 col 1 paragraph 3, Figure 9). Mundra et al also teaches that co-transplantation improved diabetic reversal ration and normoglycemia (See, p 8 col 1 paragraph 2). Therefore, this reads on, a method of treating a diabetic subject, comprising, implanting a mixed population of cells according to claim 22, into the diabetic subject, whereby the islet cells express insulin,… to treat the diabetic subject of claim 41. This also reads on, wherein said method is carried out (i) in the absence of administering immunosuppressive agents to the diabetic subject of claim 43.
Therefore, claims 1,12-13,15,17,19,22,24,31-32,34,41, and 43 are anticipated by Mundra et al.
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.
Claims 2 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Mundra et al (PloS one, 2013) as applied to claims 1, 12-13, 15, 17, 19, 22, 24, 31-32, 34, 41, and 43 above, evidenced by Bourhis et al (Frontiers in immunology, 2021) and in further view of Chandra et al (Stem cells, 2009).
The teachings of Mundra et al are set forth above.
Regarding claim 2, Mundra et al teaches hBMSCs transduced with Adv-hVEGF-hIL-1Ra, such that the hBMSCs over express hVEGF and hIL-1Ra. The transduced cells are then transplanted into diabetic mice with islet cells to restore normoglycemia.
Mundra et al, does not teach that the MSCs are CD29+ CD44+ and Sca1+.
Chandra et al teaches a homogenous cell population of mesenchymal cells (MSCs) derived from adipose tissue-derived stem cells (ASCs) that are CD29+ CD44+ and Sca1+ surface antigen expression; murine epididymal (mE)-ASC) (See, Abstract). Chandra et al teaches that the isolation of the mE-ASCs is from fat pads of mice, and 6 clones were expanded and confirmed for having CD29+ CD44+ and Sca1+ surface antigen expression and multipotency (See, p1943 col 2 paragraph 4 – p1944, Figure 1). Chandra et al also teaches a differentiation protocol of the mE-ASC to generate insulin expressing islet-like cell aggregates (ICAs); that when administered to a diabetic mouse model, restored normoglycemia in 2 weeks (See, Abstract). This reads on, wherein the mesenchymal stromal cell is CD29+ CD44+ and Sca1+ of claim 2.
Given that Mundra et al and Chandra et al both teach methods of treating diabetic mice, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute the hBMSC of Mundra et al with the mE-ASC cell as taught in Chandra et al, as taught for a similar purpose. Although Chandra et al further differentiates the mE-ASC cell, utilizing the cells in the method of Mundra et al to be transduced and co-transplanted with islet cells, would be advantageous as it would make the implantation of the mixed cell populations partially allogenic.
Both Mundra et al and Chandra et al teach methods for treating subjects with diabetes. The use of known cell population that is allogenic is a predictable use of prior art elements according to their established functions, leading to predictable result of treating diabetes. This rationale aligns with the principle of KSR for simple substitution of one known element for another to obtain predictable results (See, MPEP 2143).
Regarding claim 49, following the discussion above, Mundra et al teaches that that hBMSCs prevent the proliferation and activation of alloreactive T cells, and showed a decrease in T cell proliferation in islets with hBMCs than just islets (See, p8 col 2 paragraph 3, Supplemental Figure S1). Therefore, Mundra et al teaches a method of implanting an in individual one or more recombinant MSCs according to claim 1, whereby one of more recombinant MSCs cause, relative to an allograft in the absence of the one or more recombinant MSCs, (i) an increase in the percentage of regulatory T cells present in the implant graft, and (ii) a reduction in the number of T effector cells present in the implanted graft. While Mundra et al is silent on percentage of regulatory T cells, Bourhis et al teaches that VEGF-A directly promote regulatory T cell proliferation (See, p2 col 1). Therefore, it would be inherent that in the method taught by Mundra et al, where the hBMSCs overexpress VEGF-A, there would be an increase in the percentage of regulatory T cells.
Following the substitution of the hBMSCs with the mouse mE-ASC cells for transduction and then co-transplantation, as taught and substituted above, the MSC implanted would be an allograft. Therefore, it would read on, ...implanting an allograft into an individual with one or more recombinant MSC according to claim 1. As the individual is STZ induced mouse, the mE-ASC are derived from mice and per the teachings of Mundra et al, they would have been transduced to overexpress VEGFA and IL-1Ra.
Therefore, claims 2 and 49 are rendered obvious by Mundra et al in view of Chandra et al and evidenced by Bourhis et al.
Claims 4, 5, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Mundra et al (PloS one, 2013) as applied to claims 1, 12-13, 15, 17, 19, 22, 24, 31-32, 34, 41, and 43 above, and further in view of (El Khatib et al, Gene therapy, 2015; as cited in IDS filed on 08/27/2024).
The teachings of Mundra et al are set forth above.
Regarding claims 4, 5, and 10, following the discussion above, Mundra et al does not teach a recombinant MSC such that they expresses programed death ligand-1 (PD-L1) and/ or cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4-Ig).
El Khatib et al teaches the use of AAV8 based vectors to overexpress PDL1-CTLA4-Ig in islet cells. The islet cells expressing PDL1-CTLA4-Ig were transplanted into drug-induced diabetic mice and the islets were protected from rejection for at least 120 days (See, Abstract).
Given that Mundra et al teaches using recombinant MSCs with overexpression of proteins to co-transplant with islet cells to treat diabetic mice, one would have been motivated to modify the hBMSCs to overexpress PDL1-CTLA4-Ig as taught by El Khatib to improve the outcomes of the co-transplantation. It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Mundra et al to have the hBMSCs overexpress PDL1-CTLA4-Ig as taught by El Khatib. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification of the hBMSC recombination, due to the reduction of the rejection and immune response of transplanted islet cells as taught by El Khatib. While El Khatib teaches the modification to the islet cells, Mundra et al teaches that adenovirus transduction of islet cells results in immune response that is multiplicity of infection (MOI) dependent to get the desired transgene expression, thus transducing the hBMSCs removes that limitation and hBMSCs have been shown to provide immune an anti-inflammatory protection to islet grafts (See, p1 col 2 paragraph 2). One would have had a reasonable expectation of success evidenced by Mundra et al and El Khatib et al.
This reads on, wherein one or more immunomodulatory protein... comprises a combination of PD-L1 and CTLA4-Ig fusion protein of claim 4.
This reads on, wherein the MSC overexpresses PD-L1 and CTLA4-Ig of claim 5.
This also reads on, wherein the one or more immunomodulatory proteins… comprises PD-L1and CTLA4-Ig of claim 10.
Therefore, claims 4, 5, and 10 are rendered obvious by Mundra et al in view of El Khatib et al.
Claims 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Mundra et al (PloS one, 2013) as applied to claims 1, 12-13, 15, 17, 19, 22, 24, 31-32, 34, 41, and 43 above, and further in view of Kogawa et al (Biomedicines, 2020).
The teachings of Mundra et al are set forth above.
Regarding claims 28 and 29, following the discussion above. Mundra et al teaches the transplantation of a mixed cell population comprising recombinant MSCs and islet cells. Mundra et al does not teach an implantable cell culture device comprising mixed population of cells of (recombinant MSCs and a distinct cell population).
Kogawa et al teaches the use of a mesh pocket implanted into the peritoneal cavity of the diabetic mice; that was then filled with pancreatic islets, microencapsulated islets, microencapsulated islets and MSC-CellSaic. The glucose levels were monitored, and the mesh bag was shown to enhance the efficacy of islet transplantation (See, Abstract).
Kogawa et al teaches that the transplantation pocket comprises a silicon plate placed in a nylon mesh bag that was sealed (See, p3 paragraph 2.5). Kogawa et al teaches the insertion of the nylon mesh pocket for implantation in Figure 2, into peritoneal cavity of mice. The silicon plate was removed after 4 weeks and cells were inserted (See, Figure 2). One month after the implantation of the cells in the mesh pocket, the group with encapsulated islets and MSC-CellSaic, significantly reduced blood glucose levels (See, p7 and Figure 3). Kogawa et al teaches that the mesh-bag-like device reduces pancreatic islet necrosis and poor nutrient penetration that typically results from other devices used for transplantation; and the mesh bag creates a pocket for islet cells that has a reduced immune reaction due to the mesh implant being there 4 weeks before the cells are introduced (See, p2 paragraph 4).
Given that Mundra et al teaches treating diabetic mice with transplantation of hBMSCs and islet cells by implanting them under the kidney capsule and Kogawa et al teaches implanting the mesh device with islet cells and MSC-CellSaic in peritoneal cavity, one would have been motivated to utilize a cell culture device to implant the cells to provide islet and MSCs to treat diabetic mice. It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of co-transplantation of mixed population of cells as taught by Mundra et al such that the cells are implanted in the mesh bag as taught by Kogawa et al. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to co-transplantation of Mundra et al to include the mesh device, to contain the cells together and reduce immune response, as evidenced by Kogawa et al. One would have had a reasonable expectation of success evidenced by Kogawa et al.
This reads on, an implantable cell culture device comprising the mixed cell population according to claim 19 of claim 28.
This reads on, wherein the cell culture device comprises (i) at least one cell culture chamber that contains the mixed cell population of claim 29.
Therefore, claims 28 and 29 are rendered obvious by Mundra et al in view of Kogawa et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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