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 .
1. Claims 1-10 and 12-20 are currently pending and under examination.
Priority
2. Application claims the benefit and priority of PCT/IL2022/050536 filed on 5/23/2022 which claims the benefit and priority of provisional application 63/192,049 filed on 5/23/2021. The application is granted the benefit of 63/192,049 and the effective filing date of 5/23/2021.
Claim Objections
3. Claim 1 is objected to because of the following informalities: in line 4 “said, HSP90AA1,” should read “said HSP90AA1,”. Appropriate correction is required.
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.
4. Claims 6, 9, and 13 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 6 recites the limitation "said under-expression of PAK1" in line 6. Claim 5 depends from claim 1 which does not recite expression of PAK1. There is insufficient antecedent basis for this limitation in the claim. For the sake of compact prosecution, examiner will interpret this claim as depending from claim 2.
Claim 9 recites the limitation "said mesenchymal cells" in 2. There is insufficient antecedent basis for this limitation in the claim because claim 1 recites both a target mesenchymal cell population and a control mesenchymal cell population. For the sake of compact prosecution, examiner will interpret this claim as referring to both the target and control mesenchymal cell populations.
Claim 13 recites the limitation "the method of claim 11" in line 1. There is insufficient antecedent basis for this limitation in the claim because claim 11 has been cancelled. For the sake of compact prosecution, examiner will interpret claim 13 as being dependent on claim 12.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
5. Claims 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
The claims recite mesenchymal cell populations expressing various genes as compared to each other including BCL2, FGF7, HSP90AA1, MTOR, AKT1, PAK1, THBD, EDIL3, AMOT, and the IL6R gene. Claims 9 and 10 fail to add limitations that contribute to significantly more because they recite natural sources of mesenchymal cells and conditions that mesenchymal cells in the body could be exposed to including hypoxia, starvation, oxidative stress, hypothermia, and hyperthermia.
This judicial exception is not integrated into a practical application because the claimed invention recites practically using, administering, or applying the naturally occurring composition. The claimed mesenchymal cell composition is not structurally or functionally different from a product of nature, and the claims do not recite additional elements that amount to significantly more than what occurs in nature. Evidence shows mesenchymal cell populations naturally express varying levels of gene expression in response to different natural stimuli. For example, Baer, et al. (J. of Tissue Engineering and Regenerative Medicine, 2013, 7:271-278) Niu, et al., (Experimental Dermatology, 2016, 41:pp533-540), Zhou et al. (Aging Clin Exp Res, 2015, 27:595-601), Granchi, et al. (Tissue Engineering, 2010, 16(3):511-524), Ullah, et al. (Differentiation, 2013, 85:78-90), Tanabe, et al. (J. Biochem, 2008, 144:399-408), Izadpanah, et al. (Cancer Res., 2008, 68(11):4229-4238) all demonstrate the modification of populations of mesenchymal stem cells (MSCs) and observe the varying expression of genes as compared to a control population of MSCs in response including the genes BCL2, FGF7, HSP90AA1, MTOR, AKT1, PAK1, THBD, EDIL3, AMOT, and IL6R.
Further, Uccelli, et al. (Nature Rev. Immunology, 2008, 8:727-736) and Jiang et al. (Frontiers in Cell and Developmental Biology, 2020, 8:697) teach that MSCs have immunomodulatory properties that inhibit both the innate and the adaptive immune system, inhibit pro-inflammatory cytokine release, inhibiting the activity of CD4+ and CD8+ cells, and possess migratory ability that benefits in repairing tissue injury and regeneration. (See Uccelli, pg. 726, abstract, pg. 727, “The Effects of MSCs on immune Cells”, and pg. 731-2 “Migratory Features of MSCs”; also See Jiang, pg. 2). Thus, the claims do not include any limitations that are not related to a product of nature or describing properties already known to be possessed by a product of nature.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed composition fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
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.
6. Claims 1-4, 6, 8-10, and 18-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al. (Aging Clin Exp Res, 2015, 27:595-601).
Zhou discloses a comparison of the genetic expression of MSCs of patients diagnosed with osteoporosis to MSCs of normal donors that have not been diagnosed with osteoporosis (a control). As shown in the table below, the MSCs of the osteoporosis patients were observed to have overexpression of BCL2, by at least 1.5 fold increase, and FGF7, underexpression of HSP90AA1, MTOR by at least 1.5 fold decrease, and AKT1. The MSCs further expressed underexpression of PAK1 by at least 1.4 fold decrease, and THBD by at least 22% decrease. The MSCs further expressed overexpression of EDIL3, AMOT, by at least 1.5 fold increase, and IL6R. (See Zhou, Introduction, data obtained from Affymetrix data GSM878096, GSM878107).
Regarding claims 9-10 and 18-19, Zhou teaches that MSCs can be derived from bone marrow, that a fundamental mechanism of osteoporosis is oxidative stress, and that MSCs are cellular sources of fracture healing. (See Zhou, pg. 596 column 1, paragraphs 1-2).
Table 1. Zhou et al. (GSM878096, GSM878107)
Probe
MSC osteoporosis patient #572
Donor #353
Fold Change
BCL2 (207005_s_at)
299
111.5
+2.7
FGF7 (205782_at)
6732.4
2404.8
+2.8
HSP90AA1 (214328_s_at)
28626.3
39996.5
-1.4
MTOR (215381_at)
32.8
83.6
-2.5
AKT1 (207163_s_at)
3718.7
4141.8
-1.1
PAK1 (209615_s_at)
360.5
614
-1.7
THBD (237252_at)
23.4
84.1
-72%
EDIL3 (225275_at)
41592.3
34417.6
+1.2
AMOT (209521_s_at)
142.6
12.7
+11.2
IL6R (226333_at)
360.9
21.1
+17.1
7. Claims 1-3, 6, 8-10, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Granchi, et al. (Tissue Engineering, 2010, 16(3):511-524).
Granchi discloses a comparison of the genetic expression of MSCs as they reach confluency as compared to the genetic expression 4 days after isolation from an MNC population. As shown in the table below, the confluent MSCs express overexpressed BCL2 and FGF7, by at least a 5-fold increase, and underexpression of HSP90AA1, MTOR, and AKT1. Granchi also discloses the underexpression of PAK1 by at least 1.4 and THBD by at least 22%. Granchi also discloses the overexpression of EDIL3, by at least 7.3-fold increase, and AMOT. (See Granchi, abstract, data obtained from Affymetrix data GSE12267).
Regarding claims 9-10, Granchi discloses the bone marrow as a source for MSC and that the MSC had experienced confluency.
Table 2. Granchi et al. (GSE12267)
Probe
Isolated MSCs- 4 days after MNC seeding of patient 3002
1st confluency of patient 3002
Fold Change
BCL2 (203684_s_at)
1
1.210466
+1.2
FGF7 (205782_at)
0.19333902
2.854034
+14.8
HSP90AA1 (214328_s_at)
1.3280927
0.911557
-1.5
MTOR (202288_at)
0.8357752
0.775562
-1.1
AKT1 (207163_s_at)
0.87574446
0.72809124
-1.2
PAK1 (209615_s_at)
1.0818162
0.798623
-1.4
THBD (203887_s_at)
1.8661505
0.353837
-83%
EDIL3 (207379_at)
0.14940865
2.321903
+15.5
AMOT (209521_s_at)
0.8685123
1.018693
+1.2
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.
8. Claims 1-10, 12-14 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Granchi, et al. (Tissue Engineering, 2010, 16(3):511-524) in view of Jiang et al. (Frontiers in Cell and Developmental biology, 2020, 8:697) and Ullah et al. (Differentiation, 2013, 85:78-90).
The limitations of claim 1 are disclosed by Granchi as discussed above.
Granchi suggests a potential use of MSCs for restoration of function in damaged skeletal tissue and tissue engineering applications based on the genetic expression profile of MSCs related to differentiation and mineralization. (See Granchi, abstract, also Table 4).
Granchi does not disclose the composition of claim 1 where the target MSCs are further characterized by increased cell granularity and a larger proportion of cells in the G1 phase of a cell cycle compared to control MSCs (claim 5) and under-expression of PAK1 gene by at least 1.8 fold decrease (claim 7). Granchi does not teach the mesenchymal cells are characterized by overexpression of IL6R gene compared to control MSCs (claim 4).
Jiang teaches that MSCs promote granulation tissue formation among their other therapeutic effects (claim 5) for treating wound healing disorders, which further include angiogenesis and re-epithelialization (claims 18-19). Further, MSCs establish a regenerative environment, inhibiting a fibrotic environment (claim 20). (See Jiang, pg. 2 column 1 paragraph 3). Jiang also teaches that MSCs ability to differentiate and transdifferentiate to replace damaged tissue is a main reason for studying it’s therapeutic potential. (See Jiang, pg. 2 column 2 paragraph 2).
Regarding claims 8-9, Jiang teaches that MSCs reside in different tissues including skin, can be isolated from the tissues, and have developed as a potential therapy for wound healing disorders in skin and other tissues. (See Jiang pg. 2 column 1, paragraphs 2-3). Jiang further teaches that MSCs can adapt in response to environmental factors and conditions including oxidative stress and cellular mechanical stress including hydrostatic pressure and dynamic or cyclic pressure. (See Jiang, pg. 7 column 2, paragraph 2, also Fig. 2).
Regarding claims 12-14 and 17, Jiang teaches that MSCs act to suppress inflammation in local wound environments including by the suppression of cytokines, the promotion of innate macrophages to an anti-inflammatory M2 phenotype. (See Jiang, pgs. 3-4 “MSCs Function as Guardians of Inflammation During Granulation Tissue Formation”).
Regarding claims 18-20, Jiang teaches that MSCs are a potential promising therapy for wound healing disorders by inducing a tissue regeneration in an injured or degenerated tissue. Jiang teaches that MSCs have been administered to acute wound models in preclinical studies and observed to enhance the wound healing process. The wound healing effect is attributed to the MSCs ability to promote granulation tissue formation, angiogenesis, re-epithelialization, and inhibition or controlling of tissue fibrosis in the microenvironment. (See Jiang, pg. 2 column 2 paragraph 2).
Jiang does not teach MSCs as comprising a larger proportion of cells in the G1 phase of a cell cycle compared to a control MSC population or the under-expression of the PAK1 gene by at least 1.8 fold. Jiang does not teach the mesenchymal cells are characterized by overexpression of IL6R gene compared to control MSCs.
Ullah teaches the differentiation and transdifferentiation process of MSC populations. Ullah teaches that the transdifferentiation process takes MSC populations from an arrested cell cycle to an active G1 phase cell cycle. (See Ullah, pg. 79 column 1 paragraph 3). Ullah also discloses transdifferentiated MSCs that can overexpress BCL2 by at least a 1.5 fold increase, underexpression of HSP90AA1 by at least 2 fold decrease, MTOR by at least 1.5 fold decrease, AKT1 by at least 1.5 fold decrease, underexpression of PAK1 by at least 1.8 fold decrease, THBD by at least 22% decrease, overexpression of AMOT by at least 1.5 fold increase, and overexpression of IL6R, as compared to undifferentiated MSCs. (See Table below, data obtained from Affymetrix data GSE36923).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to combine the cells of Granchi with the use of MSCs as taught in Jiang for the present claimed composition and its claimed therapeutic uses. It would have been obvious because Granchi suggests a potential use of MSCs in tissue regeneration based on their genetic expression, Jiang teaches characteristics of MSCs including wound healing, re-epithelialization, and an inhibition or control of tissue fibrosis in the wound healing environment, and Jiang teaches it is known in the art that MSCs are capable of possessing the ability to enhance tissue regeneration through the suppression of inflammation including the innate immune response and cytokines and through anti-fibrotic activity. It would have a reasonable expectation of success because isolated MSCs are known to have therapeutic use and adaptive to an environment characterized with inflammation and damaged tissue, MSCs have already demonstrated enhanced wound healing in preclinical studies, and MSCs are known to be responsive to oxidative stress and mechanical stresses expressed in the environment. Therefore, it would have been obvious for a person of ordinary skill in the art prior to the effective filing date to use the cells of Granchi for the therapeutic uses taught in Jiang with a reasonable expectation of success in developing a composition for administration to either inhibit an immune response in a subject or induce tissue regeneration in a subject of the present claimed invention.
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to use the invention of Granchi and Jiang with the disclosed cells and teachings of Ullah for the present claimed invention. It would have been obvious because Jiang teaches that transdifferentiated MSCs have been studied for their therapeutic use, Ullah identifies genetic expression in samples of MSCs that have undergone transdifferentiation and express similar profiles to the cells of Granchi, and Ullah teaches that transdifferentiation activates the cell cycle so MSCs are in the G1 phase and Jiang teaches that MSCs contribute to wound healing through the promotion of tissue granulation formation. It would have a reasonable expectation of success because Granchi, Ullah, and Jiang all teach that MSCs are useful for tissue regeneration through wound healing. Therefore, it would have been obvious for a person of ordinary skill in the art prior to the effective date to use the invention disclosed and taught through Granchi and Jiang with the teachings of Ullah to produce a cell as disclosed by the present invention with a reasonable expectation of success at the cell having increased cell granularity and a larger proportion of cells in the G1 phase as claimed in the present invention.
Table 3. Ullah et al. (GSE36923)
Probe
Undifferentiated MSCs
Dedifferentiated MSCs Day 35
Fold Change
HSP90AA1 (211968_s_at)
2161.98
280.949
-7.7
MTOR (202288_at)
92.978
23.3137
-4.0
AKT1 (207163_s_at)
207.174
59.7166
-3.5
PAK1 (1565772_at)
31.424
14.7527
-2.1
THBD (237252_at)
9.15534
4.96875
-45.7%
AMOT (209521_s_at)
2.23764
6.16032
+2.8
IL6R (217489_s_at)
1.05944
5.75457
+5.4
9. Claims 12-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (Aging Clin Exp Res, 2015, 27:595-601) in view of Khosrojerdi et al. (Shock, April 2021, 55(4):423-440).
The limitations of claim 1 are disclosed by Zhou as discussed above.
Zhou does not disclose the use of MSCs to inhibit an immune response by administering the cells to reduce inflammation either through the adaptive or innate immune response to a subject afflicted with a cytokine storm, cytokine release syndrome, SEPSIS, SIRS, or at risk of developing one of the conditions, through the inhibition of CD4+ or CD8+ cells, and the inhibition of cytokine production.
Khosrojerdi teaches the use of MSCs for their immunomodulatory and anti-inflammatory properties in treating Sepsis. (See Khosrojerdi, abstract). Specifically, Khosrojerdi discloses that MSCs interact and regulate both the innate and adaptive immune system. In an inflammatory environment, MSCs are known to adopt an anti-inflammatory phenotype which can induce T regulatory cell development, inhibit T cell proliferation and inhibit their secretion of cytokines. (See Khosrojerdi, pg. 425 column 1 paragraph 1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to combine the cells of Zhou for the administration and therapy as taught in Khosrojerdi. It would have been obvious because Khosrojerdi teaches the use of MSCs in the inflammatory environment as producing an immunomodulatory and anti-inflammatory response. It would have a reasonable expectation of success because Khosrojerdi teaches that it is known in the art for MSCs to respond to an inflammatory environment with an anti-inflammatory response. Therefore, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date to use the cells disclosed in Zhou for the purposes taught in Khosrojerdi with a reasonable expectation of success at treating Sepsis with the present claimed invention.
Conclusion
10. Claims 1-10 and 12-20 are rejected.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642
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