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 1-7, 9-11, 15-16, 19-21, 24-25, 29-30, and 33 are pending and under examination in the instant application.
Priority
The instant application, filed 01/03/2024 is a national stage entry under 35 USC 371 of
PCT/IL2022/050718 (filed 07/05/2022), which claims priority to US Provisional Application 63/218,541 (filed 07/06/2021). Thus, the earliest possible priority for the instant Application is 07/06/2021.
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 6, 9-10, 20-21, 24-25, 29-30, 33 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 6, it recites “said culturing duration”. There is insufficient antecedent basis for this limitation in the claim. Claim 4, from which claim 6 depends, recites “culturing said population….., wherein culturing is affected under conditions…” and there is no recitation of “culturing duration” in claim 4 or independent claim 1, from which dependent claim 4 depends. See MPEP 2173.05(e). In view of the substantial issues of indefiniteness related to lack of antecedent basis for a number of terms recited in claim 4, the metes and bounds of the method recited in this claim cannot be determined.
Regarding claim 9, it recites “The method according to claim 1, further comprising M2 media comprising DMEM L-Glutamine and Sodium Pyruvate supplemented with Ascorbic Acid”. This is a method claim, however, it does not recite method steps and it is unclear how the M2 media relates to the claimed method. This introduces ambiguity, and renders the claim indefinite since it is unclear if it the differentiating medium or a different medium. Therefore, the metes and bounds of the method recited in this claim cannot be determined.
Regarding claim 10, it recites “harvesting MSC-NTF cells”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 10 depends, recites “cells which secrete neurotrophic factors (NTFs)” and “mesenchymal stem cells (MSCs)” and there is no recitation of “MSC-NTF cells” in claim 1, from which dependent claim 10 depends. It is unclear if MSC-NTF cells refers to the generated population of cells that secrete NTFs or to the starting population of mesenchymal stem cells. See MPEP 2173.05(e). Therefore, the metes and bounds of the method recited in this claim cannot be determined.
Regarding claim 20, it recites “A method of treating a disease for which administration of neurotrophic factors is beneficial in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the isolated population of cells according to claim 16…”. The claim recites both administering “neurotrophic factors” and “the isolated population of cells according to claim 16”. This introduces ambiguity, and renders the claim indefinite since it is unclear if the neurotrophic factors are directly administered to the subject or if the isolated population of cells, which secrete neurotrophic factors is what is actually being administered. Claims 21, 24, 25, 29, 30, and 33, which directly or indirectly depends from claim 20 are similarly rejected.
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 5 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 5 recites “The method of claim 4, wherein said population of undifferentiated mesenchymal stem cells (MSCs) is cultured in a functionally closed and automated hollow-fiber bioreactor system”. However, claim 1 from which claim 5 indirectly depends, recites the same limitation “a functionally closed and automated hollow-fiber bioreactor system”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) 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.
(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.
Claim(s) 16 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kadouri et al. (US Patent 8,663,987 B2, filed on 05/26/2009, and issued on 03/04/2014).
Regarding claim 16, Kadouri et al. teaches an isolated population of cells, which secrete neurotrophic factors (Abstract, claims 1-6). Also, claim 16 recites “An isolated population of cells, which secrete neurotrophic factors, generated according to the method of claim 1”. Regarding the recitation “generated according to the method of claim 1”, this is a product-by-process limitation that claim isolated population of cells produced by the method of claim 1 by inducing differentiation of a population of undifferentiated mesenchymal stem cells (MSCs) in a differentiating medium supplemented with ascorbic acid. MPEP 2113 states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In this case, the method of generating these cells doesn’t change the structure or the characteristics of the cells produced.
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.
Claim(s) 1, 4- 7, 9-11, 16, 20-21, 24-25, 29-30, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kadouri et al. (US Patent 8,663,987 B2, filed on 05/26/2009, and issued on 03/04/2014), in view of Mizukami et al. (Mizukami et al. "A Fully-Closed and Automated Hollow Fiber Bioreactor for Clinical-Grade Manufacturing of Human Mesenchymal Stem/Stromal Cells". Stem Cell Rev and Rep 14, 2018. Pages 141–143).
Regarding claim 1, Kadouri et al. teaches a method for generating cells which secrete neurotrophic factors (NTFs) comprising inducing differentiation of a population of undifferentiated mesenchymal stem cells (MSCs) in a differentiating medium (Abstract and claims 1-6, column 3, lines 51-63, and column 16, lines 11-14) supplemented with ascorbic acid (Column 12, lines 53-60 and Table 2).
However, Kadouri et al. fails to teach that the method of generating the cells is carried in a functionally closed and automated hollow-fiber bioreactor system.
However, Mizukami et al. teaches that hollow fiber bioreactors are considered a viable option for MSC expansion, due to their relatively homogeneous culture environment, excellent mass transfer properties and low level of shear stress (page 141, column 2, paragraph 2). Also, Mizukami et al. teaches that hollow fiber bioreactors operate in a perfusion mode and thus there was no depletion of key nutrients (glucose and glutamine) and toxic by-products (lactate and ammonia) did not reach cell growth-inhibitory levels (page 143, column 1, paragraph 4).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method of Kadouri et al. to induce the differentiation of the population of undifferentiated mesenchymal stem cells (MSCs) in a functionally closed and automated hollow-fiber bioreactor system with a reasonable expectation of success. One would have been motivated to have done so because closed and automated hollow-fiber bioreactor systems are used for MSC expansion, due to their relatively homogeneous culture environment, excellent mass transfer properties, and their operation in perfusion mode permits for no depletion of key nutrients as taught by Mizukami et al.
Regarding claim 4: Following discussion of claim 1 above, Kadouri et al. teaches that the method of generating cells secreting neurotrophic factors, comprises the step of incubating mesenchymal stem cells in a serum free medium comprising platelet lysate to generate propagated mesenchymal stem cells (column 3, lines 51-63). This reads on the claimed limitation culturing said population of undifferentiated mesenchymal stem cells (MSCs) prior to said induction of differentiation, wherein said culturing is affected under conditions that do not promote cell differentiation.
Regarding claim 5: Following discussion of claim 4 above, Mizukami et al. teaches that hollow fiber bioreactors are considered a viable option for MSC expansion, due to their relatively homogeneous culture environment, excellent mass transfer properties and low level of shear stress (page 141, column 2, paragraph 2).
Therefore, Mizukami et al. provides motivation to culture the population of undifferentiated mesenchymal stem cells (MSCs) in a functionally closed and automated hollow-fiber bioreactor system. It would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have cultured the cells in the method of Kadouri et al. in a functionally closed and automated hollow-fiber bioreactor system with a reasonable expectation of success. One would have been motivated to have done so because closed and automated hollow-fiber bioreactor systems are used for MSC expansion, due to their relatively homogeneous culture environment, excellent mass transfer properties, and their operation in perfusion mode permits for no depletion of key nutrients as taught by Mizukami et al.
Regarding claim 6: Following discussion of claim 4 above, Mizukami et al. teaches that culturing duration is based on lactate parameters (level/concentration) (page 141, column 2, paragraph 2, last 10 lines).
Regarding claim 7: Following discussion of claim 1 above, Kadouri et al. teaches that the differentiating medium comprises DMEM, L-Glutamine, dibutyryl cyclic AMP (dbcAMP), human Basic Fibroblast Growth Factor (bFGF), human platelet derived growth factor (PDGF) (Table 2 and column 24, paragraphs 2-3). According to the specification of the instant application, the S2M medium comprises DMEM, L-Glutamine, di- butyryl cyclic AMP (dbcAMP), human Basic Fibroblast Growth Factor (bFGF), human platelet derived growth factor (PDGF-AA) (instant specification, paragraph 0042). Therefore, the differentiating medium of Kadouri et al. meets the claimed limitation wherein said differentiating medium is designated S2M media.
Regarding claim 9: Following discussion of claim 1 above, Kadouri et al. further teaches M2 differentiation medium comprising DMEM, L-Glutamine supplemented with Ascorbic Acid (Table 2 and column 24, paragraphs 2-3).
Regarding claim 10: Following discussion of claim 1 above, Kadouri et al. further teaches seeding MSC in growth media (PM), propagating MSC using a feeding program, replacing the PM with the differentiating mediim (S2M) twice weekly after seeding, incubating the cultures for additional days, harvesting the MSC cells secreting the NTFs (column 1, last 2 paragraphs and column 2, paragraph 1). Mizukami et al. further teaches propagating MSC by using a feeding program based on lactate level measurements (level/concentration) (page 141, column 2, paragraph 2, last 10 lines).
Regarding claim 11: Following discussion of claim 1 above, Kadouri et al. further teaches analyzing the expression of CD73, CD90 and CD105 surface markers (claim 1 and column 10, lines 30-36, and column 25, lines 30-34).
Regarding claim 16: Following discussion of claim 1 above, Kadouri et al. teaches an isolated population of cells, which secrete neurotrophic factors (Abstract, claims 1-6).
Regarding claim 20: Following discussion of claim 16 above, Kadouri et al. teaches a method of treating a disease for which administration of neurotrophic factors is beneficial in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the isolated population of cells which secrete neurotrophic factors (column 3, lines 25-31 and lines 64-67 and column 4, lines 1-2).
Regarding claim 21: Following discussion of claim 20 above, Kadouri et al. teaches that the cells are ex vivo differentiated from MSCs which are autologous, or allogenic to said subject (column 9, lines 29-33 and column 18, lines 46-49).
Regarding claim 24: Following discussion of claim 20 above, Kadouri et al. teaches that the disease is a neurodegenerative disease (column 4, lines 53-54).
Regarding claim 25: Following discussion of claim 24 above, Kadouri et al. teaches that the neurodegenerative disease is Parkinson's, multiple sclerosis, epilepsy, amyotrophic lateral sclerosis (ALS), stroke, autoimmune encephalomyelitis, glaucomatous neuropathy, Alzheimer's disease, and Huntington's disease (column 4, lines 60-65, column 17, lines 59-64, and column 18, lines 39-45).
Regarding claim 29: Following discussion of claim 20 above, Kadouri et al. teaches that the administration is intramuscularly or intrathecally (column 21, lines 39-43, column 19, lines 30-32).
Regarding claim 30: Following discussion of claim 29 above, Kadouri et al. teaches that the amount of a composition to be administered will, be dependent on the individual being treated, the severity of the affliction, the manner of administration; for example, a treated Parkinson's patient will be administered with an amount of cells which is sufficient to alleviate the symptoms of the disease (column 22, lines 34-43), but does not specifically teach that a total amount of 20-100 x106 cells is administered to a subject when administration is intramuscularly, a total amount of 100-125 x106 cells is administered to a subject when administration is intrathecally, and a total amount of 25-500 x106 cells is administered to a subject when administration is intramuscularly and intrathecally. However,
However, it would have been prima facie obvious to one of the ordinary skills in the art before the effective
filing date of the claimed invention to have modified the amount of cells administered to the subject in need based on the route of administration with a reasonable expectation of success. One would have been motivated to have optimized the amount of cells administered in the method of Kadouri et al. to alleviate the symptoms of the disease
since Kadouri et al. establishes that the amount of cells administered to the subject in need would have required only routine experimentation.
Regarding claim 33: Following discussion of claim 20 above, Kadouri et al. teaches that the administration is a single administration or a plurality of administrations (column 22, lines 29-32).
Claim(s) 1-3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kadouri et al. (US Patent 8,663,987 B2, filed on 05/26/2009, and issued on 03/04/2014), in view of Mizukami et al. (Mizukami et al. "A Fully-Closed and Automated Hollow Fiber Bioreactor for Clinical-Grade Manufacturing of Human Mesenchymal Stem/Stromal Cells". Stem Cell Rev and Rep 14, 2018. Pages 141–143), as applied to claim 1 above, and further in view of Bhandi et al. (Bhandi et al., "Effect of Ascorbic Acid on Differentiation, Secretome and Stemness of Stem Cells from Human Exfoliated Deciduous Tooth (SHEDs)". J Pers Med. 2021 Jun 22;11(7):589).
Regarding claim 1, the teachings of Kadouri et al. and Mizukami et al. are set forth in detail above.
Regarding claim 2: Following discussion of claim 1 above, Kadouri et al. in view of Mizukami et al. fails to teach that the yield of said cells is improved in comparison to generation said cells in a differentiation medium without ascorbic acid.
However, Bhandi et al. teaches that ascorbic acid impacts stem cell plasticity and the ability to sustain pluripotent activity (Abstract). Bhandi et al. further teaches that ascorbic acid treatment results in an increased secretion of growth factors necessary for the tissue regeneration and homeostases, such as VEGF, SCF, IGF-1, HGF, bFGF, Ang-1, and EGF. Ascorbic acid treatment of the SHEDs (a type of mesenchymal stem cells (MSCs)) enhanced the secretion of a diverse panel of bone metabolism factors responsible for the development and growth of the bone (page 7, section 3.5. Ascorbic Acid Treatment Augments Growth Factors and Cytokines Secretion by SHEDs). Ascorbic acid is an antioxidant and anti-inflammatory agent that can modify the cell culture microenvironment. It has been widely used as an additive in the culture medium for cell growth and differentiation (page 10, paragraph 3).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method of Kadouri et al. to differentiate the cells in a differentiating medium supplemented with ascorbic acid to improve the yield of differentiated cells with a reasonable expectation of success. One would have been motivated to have done so as ascorbic acid was found to promote stem cell growth and differentiation as taught by Bhandi et al.
Regarding claim 3: Following discussion of claim 1 above, Kadouri et al. teaches in Table 2 that 200 μM ascorbic acid was used, but does not specifically teach that the ascorbic acid concentration in the differentiating medium is 250 µM.
However, it would have been prima facie obvious to one of the ordinary skills in the art before the effective
filing date of the claimed invention to have modified the concentration of ascorbic acid in the differentiation medium of Kadouri et al. to 250 µM with a reasonable expectation of success. One would have been motivated to have optimized the concentration of ascorbic acid in the method of Kadouri et al. to improve cell growth and differentiation since Bhandi et al. establishes that the concentration of ascorbic acid would have required only routine experimentation.
Claim(s) 1, 15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Kadouri et al. (US Patent 8,663,987 B2, filed on 05/26/2009, and issued on 03/04/2014), in view of Mizukami et al. (Mizukami et al. "A Fully-Closed and Automated Hollow Fiber Bioreactor for Clinical-Grade Manufacturing of Human Mesenchymal Stem/Stromal Cells". Stem Cell Rev and Rep 14, 2018. Pages 141–143), as applied to claim 1 above, and further in view of Gothelf et al. (Gothelf et al., “miRNA profiling of NurOwn®: mesenchymal stem cells secreting neurotrophic factors”. Stem Cell Res Ther. 2017 Nov 7;8(1):249)
Regarding claim 1, the teachings of Kadouri et al. and Mizukami et al. are set forth in detail above.
Regarding claims 15 and 19: Following discussion of claim 1 above, Kadouri et al. in view of Mizukami et al. fails to teach that the method further comprising analyzing VEGF specific productivity and wherein said cells secrete not less than 7000 pg VEGF/106 cells.
However, Gothelf et al. teaches a culture-medium based method for inducing MSCs to secrete enhanced levels of multiple neurotrophic factors (NTFs) including glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). MSC-NTF cells have been successfully used in clinical trials for amyotrophic lateral sclerosis (ALS) patients (page 1, column 1, paragraph 2). NTFs are small, naturally occurring polypeptides that support the development and survival of neurons (page 1, column 2, paragraph 2). NTF secretion was evaluated by ELISA for GDNF (DuoSet, R&D Systems, Minneapolis, MN, USA) VEGF and HGF (Quantikine, R&D Systems) in cell culture supernatant before and after MSC differentiation into MSC-NTF cells (page 3, column 1, section NTF secretion and Figure 1). Figure 1 shows that MSC-NTF cells secrete not less than 7000 pg VEGF/106 cells.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method of Kadouri et al. to further analyze VEGF specific productivity with a reasonable expectation of success. One would have been motivated to have done so as
VEGF is a master regulator of vascularization, cell fate, and it supports the development and survival of neurons and tissue repair, and MSC secreting NTFs, such as VEGF have been successfully used in clinical trials for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) as taught by Gothelf et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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