DETAILED ACTION
Applicant’s response filed 12/22/2025 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 8-12 and 17-18 from the claim set filed 12/22/2025 are pending. Examiner acknowledges claims 1-7, 13-16, and 19-28 are canceled.
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
A claim for benefit of a prior-filed application under 35 U.S.C. 119(a)-(f) or under 35
U.S.C. 120, 121, 365(a)-(c), 386 (a) or 386(c) has been made. The effective filing date of the
present application is January 20, 2024.
Information Disclosure Statement
Examiner notes an IDS has not been filed.
Drawings
Examiner notes no drawings have been filed.
REJECTION(S) WITHDRAWN
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.
RE: Claims 8-12 and 16-18 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claims 9-12 and 16-18 are rejected by virtue of their dependency to claim 8 and for not rectifying the issue at hand.
The metes and bounds of claim 8 cannot be determined with the language of the claim as currently written. Claim 8 is directed to a method of identifying an exosome population for testing or treatment of with respect to a specific disease or condition, the method comprising: screening a plurality of diverse MSC-derived exosome populations for efficacy in treatment of a specific disease or condition. However, claim 8 does not recite ANY specific steps regarding how a POSITA is to perform said method.
Applicant amended claim 8 to know include specific steps regarding how a POSITA is to perform said method. As such, the previously filed rejections are withdrawn. Examiner notes claim 16 has been canceled via Applicant amendment thus making the rejection of said claim moot. Examiner further notes Applicant amendment to claim 9 has necessitated new grounds of rejection, as set forth below.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
RE: Claims 8-12 and 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Examiner finds Applicant remarks to be persuasive in regards to the specification providing written description demonstrating possession of the claimed invention. As such, the previously filed rejections are withdrawn. Examiner notes claim 16 has been canceled via Applicant amendment thus making the rejection of said claim moot.
RE: Claims 8-12 and 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification, while being enabling for screening/testing of the therapeutic exosomes that are derived from MSCs and further being enabled for administering those exosomes to the various recited subjects, via the various recited delivery routes, does not reasonably provide enablement for the genus of a method of identifying an exosome population for testing or treatment of with respect to ANY specific disease or condition, the method comprising: screening a plurality of diverse mesenchymal stromal cell (MSC)-derived mixed exosome populations for efficacy in treatment of ANY specific disease or condition, as stated in claim 8. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim. Dependent claims 9-12 and 16-18 either depend directly or indirectly from claim 8.
Applicant amended to claim 8 to now state: “A method of identify [identifying] a mesenchymal stromal cell (MSC)-derived mixed exosome population for treatment of Long Covid, spinal injury, or neurological disorder…” Applicant remarks note the specification provides substantial guidance for these specific diseases, including disease pathologies and mechanism ([0026], [0040], [0058]), appropriate animal models ([0074]-[0076]0, detailed screening protocols ([0073]-[0078]), specific cytokine combination and concentration ranges ([0009], [0067]-[0070], administration routes and dosing regimens ([0076]), and evaluation methodologies tailored to these conditions ([0030]-[0034], [0075], [0077]). As such, the previously filed rejections are withdrawn. Examiner notes Applicant amendment has canceled claim 16 thus making the rejection of said claim moot.
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.
(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.
RE: Claims 8-10 and 16-17 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Pluristem.
Applicant amended claim 8 significantly and as such Pluristem does not teach all the limitations now required by amended claim 8. Therefore, the previously filed rejections are withdrawn. Applicant amendment canceled claim 16 making the rejection of said claim moot. Applicant amendment has necessitated new grounds of rejection, as set forth below.
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.
RE: Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Pluristem, as applied to claims 8-10 and 16-17 above.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Pluristem in view of Herman.
For the reasons discussed above, the anticipation rejection over Pluristem is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection as set forth below.
New Ground(s) of Rejections, Necessitated by Amendment
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.
Claims 8-12 and 17-18 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
The rationale set forth below conforms to current Office practice for examination of claims under § 101.
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category. MPEP 2106.03. The claim recites at least one step or act of identifying an MSC-derived mixed exosome population for treatment of long Covid, spinal injury, or neurological disorder. Thus, the claim is a process, which is a statutory category of invention. (Step 1: YES)
Step 2A, Prong One: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. As explained in MPEP 2106.04, subsection II, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Limitation d) in the claim recites “comparing the therapeutic effectiveness of said plurality of diverse MSC-derived mixed exosome populations in treating Long Covid, spinal injury, or neurological disorder to determine relative efficacy among the populations”. Under its broadest reasonable interpretation consistent with the specification, the plain and ordinary meaning of this limitation encompasses the mental process of observation as there is not any additional active step, other than comparing, in the claim language as currently written. The claim does not further recite any specific type of comparison such as an assay. Thus, this limitation falls into the “mental process” grouping of abstract ideas because the “comparing” can be practically performed in the human mind.
Limitation e) in claim 8 recites “identifying one or more of said MSC-derived mixed exosome populations having superior therapeutic effectiveness for treatment of Long Covid, spinal injury, or neurological disorder based on said comparing”. Under its broadest reasonable interpretation consistent with the specification, the plain and ordinary meaning of this limitation encompasses the mental process of observation as there is not any additional active step, other than identifying, in the claim language as currently written. The claim does not further recite any specific type of identifying such as through a muscle test, an ELISA assay, etc. Thus, this limitation falls into the “mental process” grouping of abstract ideas because the “identifying” can be practically performed in the human mind. (Step 2A, Prong One: YES)
Step 2A, Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (2) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. MPEP 2106.04(d).
As discussed supra, the claim does not recite any extra steps in sufficient detail that would integrate the comparing and identifying into a practical application. As currently written, the steps of comparing and identifying encompass mental judgements and evaluations as they do not have an active step of, for example, identifying via a muscle test or an ELISA assay. Examiner notes the claim recites the additional elements of “culturing”, “isolating”, and “screening”. The additional elements of “culturing” and “isolating” are an insignificant extra-solution activity that amounts to mere data gathering incidental to limitations d) and e). The additional element of “screening” also represents mere data gathering because all uses of the judicial exception require screening the collected sample (the mental processes in limitations d) and e) use the screening to determine an exosome population). As such, screening the sample is also an insignificant extra-solution activity.
Therefore, the remaining limitations of culturing, isolating and screening fail to meaningfully limit the claim because they do not require any particular application of the abstract idea. Thus, even when considering the elements in combination, the claim as a whole does not integrate the recited exceptions into a practical application. (Step 2A, Prong Two: NO). Thus, claim 8 is directed to a judicial exception. (Step 2A: YES).
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05.
Examiner notes, as discussed supra, the claim recites the additional elements of “culturing”, “isolating”, and “screening”. The additional elements of “culturing” and “isolating” are an insignificant extra-solution activity that amounts to mere data gathering incidental to limitations d) and e). The additional element of “screening” also represents mere data gathering because all uses of the judicial exception require screening the collected sample (the mental processes in limitations d) and e) use the screening to determine an exosome population). As such, screening the sample is also an insignificant extra-solution activity.
Therefore, the remaining limitations of culturing, isolating and screening fail to meaningfully limit the claim because they do not require any particular application of the abstract idea.
Consequently, for the reasons discussed above, the additional elements individually or in combination with the judicial exception do not provide an inventive concept; so, the claim as a whole does not amount to significantly more than a generic instruction to “apply” the judicial exception. (Step 2B: NO). The claim is not eligible.
In regards to the dependent claims, Examiner notes claims 9-12 and 17-18 do not rectify the issues discussed supra and as such said claims are included in the rejection.
Claim Rejections - 35 USC § 112b
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.
Claim 9 is rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 9 recites “wherein the different combinations of negative acting cytokines comprise TGF-P in amounts between 0.1 nM and 100[[0]] 10 nM, IL-10 in amounts between 0.4 pg/ml and 40[[0]] pg/ml.” Examiner notes said claim language is unclear as to what is meant by the recited ranges. For example, the claimed range for TGF-ß is between 0.1 nM and 100[[0]] 10 nM. It is unclear whether the range is meant to state 0.1 nM and 100 nM or whether the claimed range is meant to state 0.1 nM and 10 nM. If the range is meant to be 0.1 nM and 100 nM, Examiner notes said range is broader than the claimed range of claim 8 and thus would not be further limiting in scope.
If the claimed range is meant to be 0.1 nM and 10 nM for TGF-ß, Examiner notes this would cause claim 9 to not be further limiting of claim 8 as the ranges for IL10 and IL4 are the same ranges as the ranges found in amended claim 8.
Thus, the claims are considered indefinite as there is a question or a doubt as to whether the features introduced are broadening the claim language or are not further defining the claim language of claim 8. Thus, the claim is indefinite.
In the interest of compact prosecution, claim 9 is interpreted as 0.1 nM and 10 nM for TGF-ß and as thus being not further limiting of claim 8. However, despite the above interpretation, such treatment does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claim is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
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.
Claim 9 is rejected under 35 U.S.C. 112(d), 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.
As discussed supra in regards to claim 9, if the claimed range is meant to be 0.1 nM and 10 nM for TGF-ß, Examiner notes this would cause claim 9 to not be further limiting of claim 8 as the ranges for IL10 and IL4 are the same ranges as the ranges found in amended claim 8. If the range is meant to be 0.1 nM and 100 nM for TGF-ß, Examiner notes said range is broader than the claimed range of claim 8 and thus would not be further limiting in scope. Thus, claim 9 does not further limit claim 8.
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 § 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.
Claims 8-12 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Shenzen Beike Biotechnology Co (hereinafter Shenzen) (CN115161276A, published 10-11-2022; English Translation provided PTO 892) in view of Cell Exosome Therapeutics Inc (hereinafter CET) (WO 2021/200744 A1, published 7-10-2021; PTO 892) and Pluristem.
In regards to claim 8, Shenzen teaches a method of identifying a MSC-derived mixed exosome population for treatment of a neurological disorder.
Shenzen teaches of refractory systemic lupus erythematosus (SLE), i.e., an autoimmune and neurological disorder (p2, Background Technique, 1st paragraph).
Shenzen teaches the activation of MSCs is the key problem to improving/enhancing the therapeutic effect of MSCs. Shenzen teaches the research proves that after receiving the stimulation of corresponding cytokines in vitro, MSCs will show the change in the corresponding biological characteristics, and will bring different effects based on the type, concentration, and degree of stimulation of the cytokine (p3, 1st paragraph).
Example 1 (p4) teaches of the preparation method of human umbilical cord MSCs and exosomes that are pretreated with a cytokine composition. Shenzen teaches of the isolation and culture of the human umbilical cord MSCs. Shenzen teaches (p5) of the pretreatment of said cells with a cytokine composition. Shenzen teaches different cytokines are added to the cell culture medium in stages and at corresponding concentrations in a combined manner (p5). Shenzen teaches the cell culture medium is supplemented with a cytokine composition of at least two cytokines from IL4, IL21, and IL27 (p5).
Shenzen teaches of several cytokine combinations for treating the pathological characteristic of SLE disease. Shenzen specifically teaches of 3 cytokine combination/compositions: the cytokine composition of IL4 and IL21, referred to as cytokine composition 1; the cytokine composition IL21 and IL27, referred to as cytokine composition 2; the cytokine composition IL4 and IL27, referred to as cytokine composition 3 (p5). Further, Shenzen teaches the cytokine concentration ranges are as follows: IL4- 25-150 ng/ml, IL21- 100-300 ng/ml, and IL27- 50-250 ng/ml (p5).
Lastly, Example 1 teaches of isolating the exosomes from said MSCs (p6).
In regards to point a) and specifically in regards to a plurality of different culture media containing different combinations of cytokines to produce a plurality of diverse MSC-derived mixed exosome populations, wherein each of said different culture media contains a different combination of cytokines such that at least one of the concentrations or presence of the cytokines differs between each culture medium, Shenzen teaches MSCs were pretreated with different cytokine concentrations and pretreated with different cytokine compositions under the same culture time and same in vitro culture conditions. Different cytokine concentrations and different cytokine combinations were investigated, i.e., screened (p6).
Fig 4 shows different cytokine concentrations of separate cytokine components used for the expression of human umbilical cord mesenchymal stem cells and their exosomes.
FIGURE 4:
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Fig 7 teaches of varying concentrations of cytokine combinations and their effect on in vitro immunosuppression in regards to SLE treatment (p6). As can be seen, at least one of the concentrations between the varying cytokines differs between each culture.
FIGURE 7:
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Example 3 teaches administering via injecting into the tail vein, the exosomes extracted from the MSCs of the 3 cytokine compositions and the varying cytokine concentrations, and their effect on a SLE mouse model via H&E staining (p6-7).
Thus, Shenzen teaches of culturing purified MSCs in different combinations of cytokines, to include IL4, such that at least one of the concentrations or presence of the cytokines differs between each culture medium. Shenzen teaches of isolating a plurality of diverse MSC-derived exosome populations for said MSC cultures. Shenzen teaches of screening said exosome populations for efficacy in treatment of a neurological disorder through both in vitro and in vivo means. Shenzen teaches of administering each population to mouse models of SLE and of evaluating the therapeutic effectiveness for treating a neurological disorder via pathological testing (i.e., H&E staining). Shenzen teaches of comparing the therapeutic effectiveness of said exosome populations in treating a neurological disorder to determine the relative efficacy among the populations. Lastly, Shenzen teaches of identifying one or more of said exosome populations having a superior therapeutic effectiveness for treatment of a neurological disorder based on comparing (i.e., comparing H&E staining).
Shenzen does not teach the use of IL-10 and TGF-ß.
As to why a POSITA would use IL4, IL10 and TGF-ß, Examiner notes CET teaches TGF-ß, IL4 and IL10 are known to have anti-inflammatory effects [0120] and specifically teaches the use of said cytokines in regards to a therapeutic treatment for treating spinal injuries and neurological disorders [0134].
CET teaches stem cells, such as mesenchymal stem cells, are known to secrete cell-derived components such as … exosomes, that may be applied as a medical treatment [0004]. Further, CET teaches of culturing human mesenchymal stem cells to produce cell-derived components (hereinafter also referred to as "cell products") such as … exosomes and administering them to humans for the treatment of diseases [0015]. CET teaches a therapeutic agent containing the mesenchymal stem cell population of the present invention or the culture supernatant (i.e., exosomes) of the present invention can be used for the treatment of: arthritis, such as rheumatoid arthritis, spinal disc herniation (i.e., a spinal injury), and osteoarthritis; inflammatory diseases such as nephritis, keratitis, and cytokine storm; and mental disorders such as autism and insomnia (i.e., neurological disorders) that are expected to stem from neuroinflammation as one cause, due to TGF-ß, IL-4, IL-10, and IL-13 being known to have anti-inflammatory effects [0134].
In regards to concentrations, CET teaches in a preferred embodiment, each of the culture supernatant according to the first embodiment and the culture supernatant according to the second embodiment can further contain 200 pg/mL or more of TGF-ß (transforming growth factor-ß), 5 pg/mL or more of IL-4 (interleukin-4), and 10 pg/mL or more of IL-10 (interleukin-10). Each of the culture supernatant according to the first embodiment and the culture supernatant according to the second embodiment can further contain: TGF-ß in an amount of, for example, 200 pg/mL or more, preferably 300 pg/mL or more, and more preferably 500 pg/mL or more; IL-4 in an amount of, for example, 5 pg/mL or more, preferably 10 pg/mL or more, and more preferably 20 pg/mL or more; and IL-10 in an amount of, for example, 8 pg/mL or more, preferably 10 pg/mL or more, and more preferably 12 pg/mL or more. Each of the culture supernatant according to the first embodiment and the culture supernatant according to the second embodiment can further contain: TGF-ß in an amount of, for example, 200 to 100,000 pg/mL, preferably 300 to 100000 pg/mL, and more preferably 500 to 100,000 pg/mL; IL-4 in an amount of, for example, 5 to 100000 pg/mL, preferably 10 to 100000 pg/mL, and more preferably 20 to 100000 pg/mL; and IL-10 in an amount of, for example, 8 to 100000 pg/mL, preferably 10 to 100000 pg/mL, and more preferably 12 to 100000 pg/mL [0120].
Thus, CET provides a motivation to precondition the MSCs of Shenzen with the cytokines IL4, IL10, and TGF-ß.
Further, and as was discussed in the previously filed non-final office action, Pluristem teaches of mesenchymal-like adherent stromal cells (ASC) [0007]. Pluristem teaches the ASC that are exposed to cytokine treatment are mesenchymal stromal cells (MSC). Pluristem teaches said MSCs may be human MSC as defined by The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy [0067]. Pluristem teaches of extracellular vesicles, i.e., exosomes, secreted by the described ASC and that methods of isolating extracellular vesicles are well known in the art [0179]. Pluristem teaches the vesicles are harvested from a bioreactor in which the ASC (i.e., MSC) have been incubated in the presence of inflammatory cytokines [0180].
Pluristem teaches a method of treating, ameliorating, inhibiting, or preventing an immune-mediated disease in a subject in need thereof, comprising the step of administering to the subject a pharmaceutical composition comprising the described ASC (i.e., MSC). Pluristem further teaches the use of the MSC in the preparation of a medicament for treating, ameliorating, inhibiting, or preventing an immune-mediated disease [0200]. Moreover, Pluristem teaches a method of treating, ameliorating, inhibiting, or preventing an immune-mediated disease in a subject in need thereof, comprising the step of administering to the subject a pharmaceutical composition comprising the described exosomes [0207]. Pluristem teaches for any preparation used in the described methods, the therapeutically effective amount or doses can be estimated initially from in vitro and cell culture assays and often a dose is formulated in animal models to achieve a desired concertation or titer. Toxicity and therapeutic efficacy of the active ingredients (i.e., exosomes) can be determined by standard pharmaceutical procedures in vitro, in cell cultures, or in experimental animals [0191]-[0192]. Further, Examples 17-25 teach of testing (i.e., screening) ASC (i.e., MSC, i.e., MSC-derived mixed exosome populations) for efficacy in treatment of a specific disease or condition, such as IBD, DTH, CP/CPPS, NMO, Scleroderma, Limb Ischemia, Bone Marrow Migration, HSC Engraftment and Pulmonary Fibrosis.
Thus, Pluristem teaches a method of identifying an exosome population for testing or treatment of with respect to a specific disease or condition [0191]-[0193] and further teaches a method comprising screening a plurality of diverse mesenchymal stromal cell (MSC)-derived mixed exosome populations for efficacy in treatment of a specific disease or condition.
Pluristem teaches of incubating ASC (i.e., MSC) in a 3D culture apparatus in a growth medium, wherein one or more pro-inflammatory cytokines have been added to the growth medium [0030]. Additionally, Pluristem teaches the cytokine, or in other embodiments at least one of the cytokines if more than on is present, is an inflammatory cytokine that affects adaptive immune responses. In further embodiments, the cytokine is one of, or in other embodiments more than one of, IL-2, IL-4, IL-5, TGF-beta, IL-10 or IFN-gamma [0040].
Thus, Pluristem provides a motivation to precondition the MSCs of Shenzen with the cytokines IL4, IL10, and TGF-ß.
As Shenzen, CET, and Pluristem all relate to the effects of preconditioning MSCs with cytokines and then extracting exosomes from said MSCs to be used as therapeutic treatments in regards to neurological disorders, and further CET and Pluristem teach the use of IL4, IL10 and TGF-ß as cytokines to be used when preconditioning MSCs for exosome extraction to be used as therapeutic agents for treating neurological disorders, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Shenzen, CET, and Pluristem in order to have a preconditioning treatment with the cytokines IL4, IL10, and TGF-ß so that the preconditioning treatment was targeted to treating neurological disorders. As Shenzen teaches of screening multiple combinations and concentrations of the exosomes produced from the MSCs preconditioned with said cytokines in order to find the most therapeutically beneficial concentration and combination of cytokines with which to pretreat the MSCs with in order to treat neurological disorders, a POSITA would have been motivated to screen the exosomes produced from the preconditioned MSCs, as is claimed in claim 8. A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field of exosome therapeutic treatments.
In regards to wherein TGF-ß is present in amounts between 0.1 nM (i.e., 2.5 ng/ml) and 10nM (i.e., 250 ng/ml), IL10 is present in amounts between 1 pg/ml (i.e., .001 ng/ml) and 100 pg/ml (i.e., .1 ng/ml), and IL4 is present in amounts between 0.4 pg/ml (.0004 ng/ml) and 40 pg/ml (.04 ng/ml),” Examiner notes Pluristem teaches when more than one cytokine is present, each of them is present in an amount independently selected from the amounts listed in [0048], which may be freely combined. In various other embodiments, the amounts of each of the proinflammatory cytokines present are each within one of the above ranges [0048]. It is noted the ranges disclosed by Pluristem are disclosed with sufficient specificity to make obvious the ranges disclosed in claim 8 in regards to TGF-ß and IL10. Pluristem teaches one of the aforementioned cytokines is present in the medium in an amount of 2-10 ng/ml (i.e., makes obvious the claimed range of TGF-ß) and 0.1-10 ng/ml (i.e., the claimed range of IL10 overlaps) [0048].
In further regards to concentrations, CET teaches in a preferred embodiment, each of the culture supernatant according to the first embodiment and the culture supernatant according to the second embodiment can further contain 200 pg/mL or more of TGF-ß (transforming growth factor-ß), 5 pg/mL or more of IL-4 (interleukin-4), and 10 pg/mL or more of IL-10 (interleukin-10). Each of the culture supernatant according to the first embodiment and the culture supernatant according to the second embodiment can further contain: TGF-ß in an amount of, for example, 200 pg/mL or more, preferably 300 pg/mL or more, and more preferably 500 pg/mL or more; IL-4 in an amount of, for example, 5 pg/mL or more, preferably 10 pg/mL or more, and more preferably 20 pg/mL or more; and IL-10 in an amount of, for example, 8 pg/mL or more, preferably 10 pg/mL or more, and more preferably 12 pg/mL or more. Each of the culture supernatant according to the first embodiment and the culture supernatant according to the second embodiment can further contain: TGF-ß in an amount of, for example, 200 to 100,000 pg/mL, preferably 300 to 100000 pg/mL, and more preferably 500 to 100,000 pg/mL; IL-4 in an amount of, for example, 5 to 100000 pg/mL, preferably 10 to 100000 pg/mL, and more preferably 20 to 100000 pg/mL; and IL-10 in an amount of, for example, 8 to 100000 pg/mL, preferably 10 to 100000 pg/mL, and more preferably 12 to 100000 pg/mL [0120]. Thus, CET makes obvious the claimed ranges of IL4 and IL10.
In addition, Examiner notes, and as can be seen above by the prior art cited (i.e., Shenzen, CET and Pluristem), that the claimed ranges of cytokine concentrations are a result effective variable and a matter of routine optimization. Said optimization would have been well within the purview of the ordinarily skilled artisan at the time of filing.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). “A change in form, proportions, or degree will not sustain a patent" see Smith v. Nichols, 88 U.S. 112, 118-19 (1874).
"It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." In re Williams, 36 F.2d 436, 438 (CCPA 1929)
Thus, the claim is obvious and is properly rejected.
In regards to claim 9, please see the rejection under 35 USC 112(b) above. The amendment to claim 9 has made said claim unclear. As such, Examiner believes claim 9 to not be further limiting of claim 8. Thus, the claim is properly rejected.
In regards to claim 10, the above cited references teach the method of claim 8. Further, and as discussed supra, Shenzen teaches the use of both in vivo and in vitro techniques. Fig 7 shows the results of in vitro testing and Example 3 teaches administering via injecting into the tail vein, the exosomes extracted from the MSCs of the 3 cytokine compositions and the varying cytokine concentrations, and their effect on a SLE mouse model via H&E staining (p6-7). Further, Pluristem teaches of administering to a human subject [0318, Examples 17-22]. This reads on human trials. Thus, the claim is obvious and is properly rejected.
In regards to claims 11 and 12, Pluristem teaches the method of claim 8. Further, Pluristem teaches the data obtained from the in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician [0193]. Pluristem teaches depending on the severity and responsiveness of the condition to be treated, dosing can be of a single, or a plurality of administrations [0194]. Pluristem teaches administering the composition in a systemic manner or administering the composition locally, for example, via injection. In other embodiments, the composition is administered intravenously [0189]. Further, CET teaches a method of administering the therapeutic agent is not particularly limited [0139].
Thus, the above cited references do not expressly disclose the method comprising by multiple routes of administration to identify optimal delivery routes. However, it would have been obvious to a POSITA to have optimized the method of the above cited references during the normal course of experimentation with model organisms and this would necessarily include experimenting with multiple routes of administration to identify optimal delivery routes in order to best treat the particular disease.
Thus, the claims are obvious and are properly rejected.
In regards to claim 17, the above cited references teach the method of claim 8. Further, Pluristem teaches in various embodiments, is provided a method of treating, ameliorating, inhibiting, or preventing an immune-mediated disease in a subject in need thereof [0200]. Pluristem teaches in some embodiments, the immune-mediated disease is selected from the group consisting of rheumatoid arthritis (i.e., which is well known to be linked to the central nervous system), … multiple sclerosis (neurological disorder), …Guillain-Barre Syndrome (i.e., a neurological disorder), …systemic Lupus Erythematosus (SLE) (a neurological disorder), … [0201]. Additionally, Pluristem teaches of the immune-mediated disease neuromyelitis optica which is described as chronic, inflammatory demyelinating disease of the CNS and is a neurological disorder [0202]. Pluristem teaches a method of treating, ameliorating, inhibiting, or preventing an immune-mediated disease in a subject in need thereof, and further teaches the immune-mediated disease may be characterized by chronic inflammation [0200], [0206], [0207]. Pluristem further teaches a composition for use in treating or inhibiting transplant rejections [0209]. Pluristem teaches of enhancing the repopulation of HSCs [0218], of enhancing engraftment of exogenous HSC [0221], and further teaches of treatment of ischemia (i.e., a vascular disease) [0212]. Thus, the MSC-derived exosome population is screened for effectiveness in modulating one or more of immune response inflammation and mediation of cellular restoration or neuroprotective vascular healing and regenerative effects.
In addition, Shenzen teaches the exosomes extracted from the MSCs of the 3 cytokine compositions and the varying cytokine concentrations, and their effect on a SLE mouse model via H&E staining (p6-7) and thus teaches of cellular restoration.
Thus, the claim is properly rejected.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Shenzen Beike Biotechnology Co (hereinafter Shenzen) (CN115161276A, published 10-11-2022; English Translation provided PTO 892) in view of Cell Exosome Therapeutics Inc (hereinafter CET) (WO 2021/200744 A1, published 7-10-2021; PTO 892) and Pluristem, and further in view of Herman.
In regards to claim 18, the above cited references teach the method of claim 8. Further, Pluristem teaches a method of treating, ameliorating, inhibiting, or preventing an immune-mediated disease in a subject in need thereof, comprising the step of administering to the subject a pharmaceutical composition comprising the described exosomes [0207]. Pluristem teaches administering the composition in a systemic manner or administering the composition locally, for example, via injection. In other embodiments, the composition is administered intravenously, intravascularly, subcutaneously, or intraperitoneally [0189]. Pluristem teaches administration of the ASC (i.e., MSC, i.e., MSC-derived exosomes) in a dosage between from about 10 million to about 500 million cells per administration [0199].
Neither Pluristem nor the other cited references teach intranasal administration nor do they teach 0.5 ml. However, Pluristem does disclose that a source of MSC-derived mixed exosomes may be from the nasal regions [0029]. Additionally, it would have been obvious to a POSITA to have optimized the method of the above taught references during the normal course of experimentation with model organisms and this would necessarily include experimenting with multiple routes of administration such as intranasal via a vapor, aerosol spray, etc. applied to the surrounding tissue such as nares, upper respiratory tract etc. to identify the most optimal delivery route in order to best treat the particular disease. Said optimization would have been well within the purview of the ordinarily skilled artisan at the time of filing.
Further, with regards to the limitation of intranasal administration of in about 0.5 ml, this volume of administered MSC-derived exosomes would be reached during the normal course of experimentation with the method of the above cited references, as Pluristem does provide for optimizing the dosage when treating the particular disease [0192]. Again, said optimization would have been well within the purview of the ordinarily skilled artisan at the time of filing.
Additionally, it is noted Herman teaches intranasal administration of extracellular vesicles, i.e., exosomes, isolated from mesenchymal stem cells (MSC) has gained much attention in recent years as having therapeutic benefits. Intranasal administration of EVs, i.e., exosomes, provides a noninvasive method to bypass the blood-brain barrier and target specific pathological regions (Significance Statement). Further, in regards to the dosage amount of 0.5ml, Herman teaches it is crucial to adapt the treatment dose of EVs to each animal model (3.3). Thus, said dosage amount is a result effective variable and a matter of routine optimization. Said optimization would have been well within the purview of the ordinarily skilled artisan at the time of filing.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). “A change in form, proportions, or degree will not sustain a patent" see Smith v. Nichols, 88 U.S. 112, 118-19 (1874).
"It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." In re Williams, 36 F.2d 436, 438 (CCPA 1929)
Therefore, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Herman and the above cited references to deliver the MSC-derived exosomes intranasally for an optimum therapeutic treatment. A POSITA would have been so motivated due to wanting to find the most therapeutically effective treatment.
A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field of exosome administration for a therapeutic benefit.
Thus, the claim is obvious and is properly rejected.
Conclusion
No claims are allowable. No claims are free of the prior art.
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 extension fee 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 date of this final action.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633