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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant’s response filed May 18, 2026 has been received and entered into the application file. All arguments have been fully considered.
Claims 8-12, 17-18, and 29-30 of the claim set filed May 18, 2026 are pending. Claims 1-7, 13-16, and 19-28 are cancelled. Claim 30 is withdrawn by Examiner as being drawn to a non-elected species. Please see below.
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 drawings have not been filed.
Objection(s)/Rejection(s) Withdrawn
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.
RE: 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.
As stated in the previously filed OA, p8:
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)
In regards to limitation d) and the term “comparing”, Applicant amended claim 8 to now require “comparing” via the active step of assaying expression levels or presence of mRNA, proteins, or disease markers. In regards to limitation e) and the term “identifying”, Applicant amended the claim language to now state “selecting”. In addition, Examiner has found Applicant remarks to be persuasive in regards to the invention as a whole.
Thus, Applicant amendments have overcome the previously filed rejections. As such, the previously filed rejections are withdrawn.
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.
RE: 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.
Applicant amended claim 9 to now state: TGF-ß in amounts between 1nM and 10nM, IL-10 in amounts between 10 pg/ml and 100 pg/ml, and IL-4 between 1 pg/ml and 10 pg/ml. Thus, Applicant amendment has overcome the previously filed rejection and as such, said rejection is withdrawn.
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.
RE: 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.
Applicant amended claim 9 to now state: TGF-ß in amounts between 1nM and 10nM, IL-10 in amounts between 10 pg/ml and 100 pg/ml, and IL-4 between 1 pg/ml and 10 pg/ml. Thus, Applicant amendment has overcome the previously filed rejection and as such, said rejection is withdrawn.
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 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.
Examiner has found Applicant remarks persuasive in regards to the teachings of CET. Applicant noted CET does not teach adding a cytokine cocktail but rather CET relies on the MSCs/exosomes to produce the cytokines. I.e., the cytokines are endogenous and not exogenous. As such, the previously filed rejection is withdrawn.
RE: 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.
For the reasons discussed above, the obviousness rejection over Shenzen, CET and Pluristem is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn.
New Ground(s) of Rejection
Election of Species
Applicant amendment added new claims 29 and 30. Examiner notes claim 29 is drawn to wherein the screening comprises administering… to subjects intravenously, intranasally, intra-arterially, or orally. Claim 30 is drawn to wherein the screening comprises administering… directly on tendons or cartilage.
The Restriction/Species election filed on 4/2/2025 required Applicant to elect a single species of screening (p6). Species 1 was drawn to wherein the screening comprises administering …intravenously, intranasally, intra-arterially, or orally. Species 2 was drawn to wherein the screening comprises administering… directly on tendons, cartilage, or burned or denuded surfaces of skin. Applicant Remarks filed 5/21/2025 elected species 1, i.e., drawn to wherein the screening comprises administering …intravenously, intranasally, intra-arterially, or orally (p2).
Examiner notes newly added claim 30 is drawn to species 2 and thus if said claim was presented originally, would have been included in the election of species filed 4/2/2025. As such, claim 30 is withdrawn as being drawn to a non-elected species.
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, 17, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Shenzen in view of 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 (point a). Shenzen teaches of isolating a plurality of diverse MSC-derived exosome populations for said MSC cultures (point b). 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) (point c). Shenzen teaches of comparing, via H&E staining, the therapeutic effectiveness of said exosome populations in treating a neurological disorder to determine the relative efficacy among the populations (point d). Lastly, Shenzen teaches of selecting 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), i.e. for use in further screening, treatment, or formulation of a pharmaceutical composition (point e).
Shenzen does not teach the use of IL-10 and TGF-ß, nor does Shenzen teach specifically of comparing, via assaying expression levels or presence of mRNA, proteins, or disease markers.
As to why a POSITA would use IL4, IL10 and TGF-ß, Examiner references the teachings of Pluristem, in combination with the teachings of Shenzen.
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. Additionally, Pluristem teaches (Ex 20) of comparing, by assaying expression levels or presence of mRNA, proteins, or disease markers, or any combination thereof, the therapeutic effectiveness of said plurality of diverse MSC-derived mixed exosome populations in treating NMO (i.e., a neurological disorder) (point d of the instant application).
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 one 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].
Examiner respectfully notes Shenzen teaches of inflammatory cytokines for treating neurological and autoimmune disorders, specifically SLE, which is known to affect adaptive immune responses, is a quintessential immune mediated disease, and aggressively impacts the nervous system. As discussed supra, Shenzen further teaches of pre-treating with IL4 and notes said cytokine has anti-inflammatory activity against the neurological and autoimmune disorder SLE. As noted supra, Pluristem teaches treating immune-mediated and neurological diseases. Pluristem teaches of 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. Examiner respectfully notes Pluristem thus teaches screening MSC-derived mixed exosome populations for treating a variety of autoimmune disorders and neurological disorders via pretreating with one or more than one of IL-2, IL-4, IL-5, TGF-beta, IL-10 or IFN-gamma.
Thus, both Shenzen and Pluristem teach of IL4 as an anti-inflammatory cytokine for treating an immune mediated neurological disease. Both Shenzen and Pluristem teach of pretreating with IL4 and screening for therapeutic effectiveness in treating said immune mediated neurological disease.
Pluristem does not teach different culture medias containing different combinations of IL4, IL10, and TGFbeta, such that at least one of the concentrations of said cytokines differs between each culture medium. As Shenzen teaches screening different culture medias containing different combinations of cytokines, to include IL4, to treat an autoimmune/neurological disorder, it is thus conceivable a POSITA would be led to combine the teachings of Shenzen and Pluristem in order to test various combinations of cytokines at various concentration levels for their therapeutic effectiveness in treating immune/neurological disorders, which both Pluristem and Shenzen teach treating. As Pluristem teaches pretreating with one or more of IL-2, IL-4, IL-5, TGF-beta, IL-10 or IFN-gamma, and Shenzen teaches pretreating with IL4, it is thus conceivable that a POSITA would find it obvious to pretreat with various combinations and concentrations of the cytokines IL4, IL10 and TGFbeta.
Thus, Pluristem provides a motivation to precondition the MSCs of Shenzen with the cytokines IL4, IL10, and TGF-ß to treat autoimmune/neurological disorders.
To respectfully reiterate, as Shenzen and Pluristem both 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 autoimmune/neurological disorders, and further Pluristem teaches 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 autoimmune/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 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 autoimmune/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 autoimmune/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. Claim 8 requires 0.1nM – 10nM, i.e., 2.5ng/ml- 250 ng/ml of TGFbeta. Thus, Pluristem makes obvious the claimed range of TGFbeta. Claim 8 requires IL10 between 1pg/ml – 100 pg/ml, i.e., 0.001ng/ml – 0.1 ng/ml. Pluristem teaches a range of cytokine from 0.1-10ng/ml. Thus, the claimed range of IL10 overlaps with the range of Pluristem [0048].
Pluristem does not teach the claimed range of IL4, i.e., 0.4 pg/ml (0.0004ng/ml) – 40 pg/ml (0.04 ng/ml).
Examiner respectfully notes however, and as can be seen above by the cited cytokine ranges of Pluristem, the claimed ranges of cytokine concentrations are a result effective variable and a matter of routine optimization. As a POSITA will appreciate, cytokine concentrations are a result effective variable based on multiple parameters such as volume size, time spent in culture, etc. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that cytokine concentration is a result effective variable and Examiner notes that the optimization of cytokine concentration would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical."[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, the above cited references teach the method of claim 8. Further, Pluristem teaches TGFbeta in amounts between 1 nM (25 ng/ml) – 10nM (280 ng/ml). Pluristem teaches cytokines in a range from 10-300 ng/ml [0048]. Thus, making obvious the claimed range of TGFbeta. Pluristem further teaches cytokines in a range from 10 pg/ml (0.01 ng/ml) – 100 pg/ml (0.1ng/ml). Pluristem teaches a range of cytokine from 0.1-10ng/ml. Thus, the claimed range of IL10 overlaps with the range of Pluristem [0048].
Pluristem does not teach the claimed range of IL4.
Examiner respectfully notes however, and as can be seen above by the cited cytokine ranges of Pluristem, the claimed ranges of cytokine concentrations are a result effective variable and a matter of routine optimization. As a POSITA will appreciate, cytokine concentrations are a result effective variable based on multiple parameters such as volume size, time spent in culture, etc. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that cytokine concentration is a result effective variable and Examiner notes that the optimization of cytokine concentration would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical."[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 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.
In regards to claim 29, the above cited references teach the method of claim 8. Further, Pluristem teaches administering 10-500 million cells, or 150 million to 300 million cells (i.e., exosomes) [0199] intravenously [0189] for screening.
Thus, the claim is properly rejected.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Shenzen in view of 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 Shenzen 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.
Response to Applicant Remarks
RE: Rejections Under 103
In regards to point a) of Applicant remarks, as noted supra, Examiner withdrew the teachings of CET and as such Applicant remarks directed to the teachings of CET are moot. In regards to Applicant remarks stating the teachings of Pluristem do not provide a reason to modify Shenzen’s SLE-specific cytokine compositions by replacing IL-21 and IL-27 with cytokines drawn from Pluristem’s list for treatment of different diseases, Examiner respectfully directs Applicant to the above discussed rejection of claim 8 in which Examiner provides a rational and motivation as to why the teachings of Pluristem, combined with the teachings of Shenzen, teach the instant invention.
In regards to point b) of Applicant remarks, Examiner respectfully notes Applicant remarks directed to the teachings of CET are now moot. In further regard to point b), Examiner respectfully directs Applicant to the above discussed rejection of claim 8 in which Examiner discusses why the teachings of Shenzen, in combination with the teachings of Pluristem, provide a motivation to combine said teachings as well as to why said combination would have a reasonable expectation of success.
In regards to point c) of Applicant remarks addressing routine optimization, Examiner respectfully notes, absent any teaching of criticality, as noted supra, cytokine concentrations are a result effective variable and a matter of routine optimization. Please see the above discussed rejection of claims 8 and 9 for more details.
Conclusion
No claim is allowed. No claim is free of the prior art.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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