DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-20 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 09/13/2026 is acknowledged. A replacement sheet of Figure 7 was filed to correct the figure label relative to the graph.
Election/Restrictions
Applicant’s election without traverse of Species iv (miRNA) in the reply filed on 06/25/2026 is acknowledged.
Claim(s) 3-4 and 6-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/25/2026.
Claim(s) 1-2, 5, and 9-20 are under consideration.
Priority
Acknowledgement is made that this application is a divisional application of 16/630,954 filed 01/14/2020 which is a 371 of PCT/IL2018/050783 filed 07/16/2018 and claims priority based on provisional application(s) filed as 62/533,056 on 07/16/2017.
All claims are given the priority date of 07/16/2017.
Information Disclosure Statement
Receipt of information disclosure statements, filed on 11/10/2025, 06/25/2026, and 08/07/2023 (two of them) are acknowledged.
The information disclosure statement(s) filed 08/07/2023 (two of them), fail to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed.
#1 on the Foreign Documents, CN 101341244 (translated abstract) is missing; and
#5 on NPL, Qinnan et al., (2014) is missing.
Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Drawings
The substitute drawing of Figure 7 was received on 09/13/2023.
Figure 4 should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP § 608.02(g). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Minor informalities
The disclosure is objected to because of the following informalities:
In the brief description of the figures on page 14, “Figure 2” does not have a period after the “2”. It would be remedial to add a period for consistency with the other described figures;
It would be remedial to address the arrows in Figure 5, as to what they are pointing to;
There are two commas after “inhibitor” in line 6 on page 23. It would be remedial to remove one of these commas.
Appropriate correction is required.
Trademark and/or Tradenames
The use of the following term(s), which is/are a trade name or a mark used in commerce, has been noted in this application.
Plasma Lyte (p.16, line 4); and
Q exactive (p.22, line 28)
The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Embedded Hyperlinks
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See page 28, line 3.
Claim Objections
Claim 2 is objected to because of the following informalities:
In section (iv) the following microRNAs recite a “S” instead of “5”:
hsa-miR-191-Sp (line 3);
hsa-miR-100-Sp (line 3-4);
hsa-miR-379-Sp (line 4-5);
hsa-miR-28-Sp (line 6);
hsa-miR-155-Sp (line 9); and
hsa-miR-888-Sp (line 10).
Claim 9 is objected to because of the following informalities:
“pharmaceutical” should be inserted before composition for consistency between claims.
Claim 14 is objected to because of the following informalities:
“iatrogenic” should be inserted before “injury” for consistency between claims.
Claim(s) 15-19 are objected to because of the following informalities:
A comma should be added after “The method of claim X”, for consistency between all of the claims.
Claim 15 is objected to because of the following informalities:
It appears that in claim 15, “ischemic organ” starts on a new line unintentionally. It would be remedial to “backspace” to have “ischemic organ” on the same line as the claim.
Claim 18 is objected to because of the following informalities:
The phrase “. . . via a route selected from the group consisting of: topically, subcutaneously, intramuscularly, intraarterial, intraperitoneal, intrathecal, intravenously or directly injected in any tissue at the site in need.”, the “or” should be an “and” due to the closed nature of “consisting of”.
Claim 20 is objected to because of the following informalities:
It appears that in claim 15, “ischemic organ” starts on a new line unintentionally. It would be remedial to “backspace” to have “ischemic organ” on the same line as the claim.
“naive” in claim 20 should be “naïve”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – lack of enablement
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim(s) 1-2, 5, and 9-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of treating diabetic-related dermal wounds comprising administering topically or intravenously to a subject in need thereof a cell-free pharmaceutical composition comprising stromal cell-derived factor 1 (SDF1) protein, together with at least one carrier, excipient, or diluent, wherein the method involved tissue remodeling, tissue repair or tissue regeneration;
A method of treating spinal cord injury comprising administering intrathecally to a subject in need thereof a cell-free pharmaceutical composition comprising SDF1 protein, together with at least one carrier, excipient, or diluent, wherein the method involved tissue remodeling, tissue repair or tissue regeneration (not supported by the original disclosure but taught by the prior art); or
A method of treating diabetic-related dermal wounds comprising administering topically or intravenously to a subject in need thereof a cell-free pharmaceutical composition consisting of a human oral mucosa stem cell (hOMSC)-derived secretome, together with at least one carrier, excipient, or diluent, wherein the method involves tissue remodeling, tissue repair or tissue regeneration.
does not reasonably provide enablement for (a) all diseases/disorders, (b) all forms of administration, (c) a cell-free pharmaceutical composition comprising microRNA without the other components secreted from hOMSCs. 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 these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is drawn to A method of treating a disease or disorder comprising administering to a subject in need thereof a cell-free pharmaceutical composition comprising substances secreted from human oral mucosa stem cells (hOMSC-derived secretome), together with at least one carrier, excipient, or diluent, wherein the method involves tissue remodeling, tissue repair or tissue regeneration. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration.
Claim(s) 2 and 5 is drawn to the method of claim 1, wherein the cell-free pharmaceutical composition comprises over 30 different microRNA (of (iv)). The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by all of those microRNA secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration.
Claim 11 is drawn to the method of claim 1, comprising at least one process selected from the group consisting of enhancing wound healing, preventing or reducing scar formation, enhancing scar healing or enhancing cartilage- or bone- formation; enhancing repair or regeneration of the central nervous system or the peripheral nervous system caused by trauma, neurodegenerative disease or vascular diseases of the neural system; and enhancing neo angiogenesis and neovascularization of an ischemic organ. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration related to any of the processes listed above.
Claim 12 is drawn to the method of claim 11, comprising repair or regeneration of organs and tissues that were totally or partially destroyed by at least one iatrogenic injury. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration related to any of the processed listed above in claim 11 by any form of iatrogenic injury that either totally destroys the organs and/or tissues or partially destroys them.
Claim 13 limits claim 12 to wherein the at least one iatrogenic injury is caused by mechanical trauma, chemical injury, chemotherapy, radiation or heat. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration related to any of the processed listed above in claim 11 either caused by mechanical trauma, chemical injury, chemotherapy, radiation and/or heat that either totally destroys the organs and/or tissues or partially destroys them.
Claim 14 limits claim 12 to wherein the at least one injury is selected from the group consisting of: contusion of the central nervous system, spinal injuries, section of the spinal cord, peripheral nerve crush or section, burns, neuropathy, cardiopathy, bone fractures, tendon and ligament rupture. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration related to any of the processed listed above in claim 11 either caused contusion of the central nervous system, spinal injuries, section of the spinal cord, peripheral nerve crush or section, burns, neuropathy, cardiopathy, bone fractures, tendon and ligament rupture that either totally destroys the organs and/or tissues or partially destroys them.
Claim 15 limits claim 12 to wherein tissue remodeling, tissue repair, or tissue regeneration comprises at least one process selected from the group consisting of enhancing wound healing, preventing or reducing scar formation, enhancing scar healing or enhancing cartilage- or bone- formation; enhancing repair or regeneration of the central nervous system or the peripheral nervous system caused by trauma, neurodegenerative disease or vascular diseases of the neural system; and enhancing neo angiogenesis and neovascularization of an ischemic organ. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration related to any of the processed listed above by any form of iatrogenic injury that either totally destroys the organs and/or tissues or partially destroys them.
Claim 16 is drawn to the method of claim 15, wherein the ischemic organ is selected from a group consisting of heart, brain, peripheral nerves, and kidney. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via any/all routes of administration, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration related to an ischemic organ selected from a group consisting of heart, brain, peripheral nerves, and kidney, by any form of iatrogenic injury that either totally destroys the organs and/or tissues or partially destroys them.
Claim 18 further limits claim 1, wherein the cell-free pharmaceutical composition is administered to a subject in need thereof via a route selected from the group consisting of: topically, subcutaneously, intramuscularly, intraarterial, intraperitoneal, intrathecal, intravenously or directly injected in any tissue at the site in need. The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from hOMSCs via the routes of administration listed above, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration.
Claim(s) 19 and 20 further limit the hOMSCs cells to (a) autologous or allogeneic hOMSC (of claim 19) or naïve cells (of claim 20). The nature of the invention is complex in that “disease or disorder” encompassed by the broad genus of diseases or disorders that must be treated in a subject by any/all substances secreted from (autologous or allogenic and/or naïve cells) hOMSCs via the routes of administration listed above, and must be capable of tissue remodeling, tissue repair, and/or tissue regeneration.
Breadth of the claims:
The broadest reasonable interpretation of claim 1 is that it encompasses a method of treating any disease or any disorder comprising administering via any route to a subject in need thereof a cell-free pharmaceutical composition comprising any/all substances secreted from human oral mucosa stem cells (hOMSC-derived secretome), together with at least one carrier, excipient, or diluent, wherein the method involves tissue remodeling, tissue repair or tissue regeneration.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification:
Looking to the specification for guidance on “diseases/disorders”, routes of administration, any/all substances secreted from hOMSCs, and cell-free.
Disease/disorders:
Pages 11-12 teach different diseases/disorders the treatment of the claimed invention would be useful for including but not limited to the following:
Inflammatory, autoimmune, blood vessel, cardiac, respiratory, skeletal system, gastrointestinal tract, kidney, urinary tract, skin, ageing-associated, peripheral nerve and skeletal muscle, diseases of the central nervous system, eye disease, diseases of the endocrine system, and dental or oral diseases.
Page 12 – the disorder is a diabetic wound or cosmetic.
Routes of administration:
Page 13 – “any suitable route of administration, including but not limited to
topically, subcutaneously, intramuscularly, intravenously, intra-arterially, intraarticulary, intralesionally, intratumorally or parenterally. According to some embodiments, for wound healing, topical administration may be used. Pharmaceutical and cosmetic compositions according to the present invention are thus formulated to fit the specific route of administration used. For example, for topical administration, the compositions may be formulated as creams, foams, gels, lotions, and ointments, using methods known in the art.
The definition of administration is found on page 19.
Substances secreted from hOMSCs:
Page 17-18 “Secretome according to the present invention is a composition comprising soluble and insoluble substances in their various forms that are secreted or released into the culture medium from human oral mucosa derived stem cells. Amongst others these substances include: 2. Soluble molecules as: a. Proteins, b. Peptides, c. Hormones, d. various DNA and RNA species, e. oligomers of nucleic acids, f. other molecules with a molecular weight higher than 1,000 Daltons; 3. Extracellular vesicles that contain: a. Proteins: growth factors, cytokines, hormones, cell surface receptors, cytosolic and nuclear proteins, metabolic enzymes, receptor ligands, adhesion proteins, endosome associated proteins, tetraspanins, lipid raft associated proteins, antigens, etc. b. RNA species: mRNA, miRNA, tRNA, rRNA, siRNA, and IncRNA and possible other RNA species, c. DNAs: mitochondrial DNA (mtDNA), single stranded DNA (ssDNA), double stranded DNA (dsDNA), d. Lipids: cholesterol, sphingomyelin, hexosylcermides and others, and e. Lectins, glycans, proteoglycans, glycoproteins.”
Figure 11, and tables 2 and 4.
Cell-free
According to some embodiments, the cell-free composition comprises: at least one protein from the group consisting of … lines 17 of page 4 to line 20 of page 5; or at least one microRNA selected from the group consisting of . . . lines 21-30.
Pages 7-10 of the specification elaborate on combinations of proteins and/or microRNAs, along with the method of isolating the secretome.
Working examples:
Applicant isolated hOMSC from oral mucosa biopsies from donors aged 25-80 years of
age. The secretome was generated expanding the cultures of hOMSC in expansion media.
Example 1: Applicant compared stem cell markers of hOMSC to those of other sources, i.e., Foreskin SC. Where hOMSC showed higher expression of pluripotency and neural crest associated markers than the Foreskin SC (figure 1).
Example 2: Applicant analyzed the hOMSC secretome via protein arrays, mass spectrometry, and miRNA characterization. Proteins identified can be found in Figure 11 and Table 1-2. MicroRNA characterized can be found in table 4.
Example 3: Applicant injected mice that had been wounded (full thickness dermal wounds) with i) PBS, ii) human oral mucosa stem cells, or iii) foreskin stem cells (figure 5).
Example 4: Applicant tested the media collected from 1x106 hOMSC (filtering out anything less than 1000Da) on the animals of the above example. “The rate of wound closure is shown in Fig. 10. The results indicate that a one-time administration of hOMSC-secretome confined within the concentrated hOMSC conditioned medium was as effective as hOMSC to enhance diabetic wound healing.”
The specification envisions a cell free pharmaceutical composition with a minimum of either one of the listed proteins or one of the listed microRNA, however, the working examples provide a cell-free composition that contains the secretome of the cells (i.e., proteins, DNA, microRNA), which contains more than one component.
Predictability and state of the art:
Both Zendedel et al (Activation and Regulation of NLRP3 inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model, Molecular Neurobiology, vol 53, pages 3063-3075, published May 14th, 2015) and Olekson et al (SDF-1 liposomes promote sustained cell proliferation in mouse diabetic wounds, Wound Rep Reg, vol 23, pages 711-723, published June 24th, 2015) teach that the SDF-1 protein/peptide providing therapeutic benefit.
More specifically, Zendedel et al teaches, “Using 14-week old male Wistar rats, spinal cord contusion was applied at the thoracic segment 9, and animals were subsequently treated with SDF-1a via intrathecal application through an osmotic pump. SCI temporally increased the expression of the inflammasomes NLRP3, ASC, the inflammatory marker tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1β) and IL-18. SDF-1a significantly reduced the levels of IL-18, IL-1b, TNF-a, NLRP3, ASC, and caspase-1. . . Our data provide clear evidence that SCI stimulates a complex scenario of inflammasome activation at the injured site and that SDF-1a-mediated neuroprotection presumably depends on the attenuation of the inflammasome complex.”, (abstract). Wherein SDF-1a is a protein as taught on p.3065, col 1, para 1.
Olekson et al teaches, “. . . When applied onto an excisional wound model in diabetic mice, acellular dermis spiked with SDF-1 liposomes promoted long-term (4 week) cell proliferation in the dermis, whereby persisting Ki671 cells were concentrated in cells lining luminal structures, which also stained for CD31, suggesting vascular endothelial cells. Furthermore, SDF-1 liposomes resulted in thicker granulation tissue thickness at 4 weeks. . . Furthermore, groups treated with SDF-1 liposomes showed modestly faster closure compared to groups treated with free SDF-1, and groups treated with free SDF-1 showed no such improvement compared to groups treated with empty liposomes, or PBS vehicle.”, (p. 717, col 1, para 2).
Olekson et al teaches that the SDF-1 used in this study is a peptide (see abstract; and p. 718, col 2, para 2)
In both arts, SDF-1 is a peptide/protein and is providing the therapeutic benefit, i.e., Zendedel et al for spinal cord contusion and Olekson et al for diabetic wound healing. The art is silent on microRNA having this ability.
As for the state of the art in regard to microRNAs for therapeutic treatment of any diseases or any disorders, Zhang et al (The risk of miRNA Therapeutics: In a Drug Target Perspective, Drug Design, Development and Therapy, volume 15, pages 721-733, published February 22nd, 2021) teaches, “As expected, Figure 2A showed a flexible complementary ratio of miRNA with target sequence (within the range 20–90%) and none with complete complementation, but all siRNAs had 100% complementary ratio. The less restricted complementary mode may lead to low specificity of target sequence.”, (p.722, col 2, para 2). Moreover, “Beyond our expectation, the targets of the miRNA drug ranged from 30 to 250 in number and almost all miRNA drug* were over 500 and even 1000, but the si0052NA drug generally targets 1–3 genes (Figure 2B). The majority of miRNA targets tens and hundreds of genes, and we named it “too many targets for miRNA effect” (TMTME).”, (p.722, col 2, para 2).
Further, Zhang et al teaches, “TMTME (“too many targets for miRNA effect”) is a typical and inevitable property of miRNA molecules, which is caused by incomplete complementation with the target sequence. TMTME leads to that miRNA could bind to various sequences suitable for the interaction (including protein-coding genes, lncRNA, circRNA, etc), which is different from all approved drugs (including siRNA drugs) with only a few targets… Therefore, both introduction and removal of miRNA in humans can lead to changes of a wide series of pathways and some of them are unknown, even unpredictable, probably triggering disorders of physiological function or the occurrence of additional disease.”, (Page 729, column 1, paragraph 2 to column 2, paragraph 1).
Zhang et al teaches, “Moreover, due to instability of unprotected miRNAs, delivering miRNAs required chemical modifications to avoid rapid degradation in serum, which may impair specificity of miRNAs and lead to off-target effects… Another challenge is that exogenous artificial miRNAs will trigger competition and saturation effect, a competition among exogenous and the endogenous miRNAs for the intracellular machinery, and thus affecting unexpected gene expression and leading to untoward side effects.”, (page 730, column 1, paragraph 1).
Thus, one of skill in the art would appreciate the unpredictability of one microRNA and/or over 30 microRNA in a cell-free composition for the treatment of any disease or any disorder via any route of administration. Zhang et al teaches that (a) the majority of microRNA target tens and hundreds of genes, (b) introduction and remove of miRNA in humans can lead to changes of a wide series of pathways, some unknown and unpredictable, with the possibility of triggering the occurrence of other diseases, and (3) unprotected miRNAs are unstable (delivery).
Amount of experimentation necessary:
The quantity needed to carry out the scope of the invention is large. (1) One would need
to test individual, subcombinations, and the combination of all of the microRNA listed in claim 2/table 4 in art acceptable models that cover the broad genus of “diseases and disorders” for treating diseases associated with tissue remodeling, repair, and regeneration. This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering that any positive results (e.g., successful treatment of any disease or disorder with a combination of microRNAs) would amount to a significant advancement in the state of the art, additional experimentation required is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention.
Therefore, claim(s) 1-2, 5, and 9-20 are not considered to be fully enabled by the instant disclosure.
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.
Claim(s) 1 and 9-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zendedel et al (supra) as evidenced by Uniprot (CXCL12 - Stromal cell-derived factor 1 - Homo sapiens (Human) | UniprotKB; accessed 08/13/2026).
Regarding claim(s) 1, 9, 11-15, and 17-18, Zendedel et al discloses, “Using 14-week old male Wistar rats, spinal cord contusion was applied at the thoracic segment 9, and animals were subsequently treated with SDF-1a via intrathecal application through an osmotic pump. SCI temporally increased the expression of the inflammasomes NLRP3, ASC, the inflammatory marker tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1β) and IL-18. SDF-1a significantly reduced the levels of IL-18, IL-1b, TNF-a, NLRP3, ASC, and caspase-1. . . Our data provide clear evidence that SCI stimulates a complex scenario of inflammasome activation at the injured site and that SDF-1a-mediated neuroprotection presumably depends on the attenuation of the inflammasome complex.”, (abstract). Moreover, Zendedel et al discloses, “Immediately after injury, an infusion pump (Model 2001, ALZET, Cupertino, CA, USA) with a flow rate of 1 μL/h was filled with vehicle solution (PBS/ 1 %BSA) or SDF-1a (500 ng/mL dissolved in 1 % BSA in PBS), connected to the catheter and subcutaneously implanted in to the neck region.”, (p.3065, col 1, para 1).
Wherein SDF-1a reads on a substance secreted from human oral mucosa stem cells (see instant specification page 6, lines 6-8) and a soluble factor (see instant specification page 9, lines 15-19).
Wherein an “a spinal cord contusion was applied” reads on iatrogenic and mechanical.
Wherein “PBS” reads on a diluent.
Regarding claim 10, Zendedel et al does not teach the size of SFD-1a, however this is evidenced by UniProt. Uniprot discloses that the mass of SDF-1 is at least 10,000 Daltons (see page 8).
Regarding claim 16, Zendedel et al teaches, “SDF-1a is up-regulated under pathological conditions such as ischemic stroke, promotes the migration of neural progenitor cells, and participates in the regulation of the neurovascular unit [9]. The administration of SDF-1a ameliorates cell death of cortical neurons induced after stroke most likely by stimulating angiogenesis and neurogenesis and through the modulation of inflammatory responses [10].”, (p. 3064, col 1, para 2).
Accordingly, claim(s) 1 and 9-18 are anticipated by Zendedel et al as evidenced by UniProt.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Olekson et al (supra) as evidenced by Uniprot (supra) disclose the limitations of claim(s) 1, 9-13, 15, and 17-18.
Regarding claim(s) 1, 9, 11, 15, and 17, Olekson et al discloses, “. . . When applied onto an excisional wound model in diabetic mice, acellular dermis spiked with SDF-1 liposomes promoted long-term (4 week) cell proliferation in the dermis, whereby persisting Ki671 cells were concentrated in cells lining luminal structures, which also stained for CD31, suggesting vascular endothelial cells. Furthermore, SDF-1 liposomes resulted in thicker granulation tissue thickness at 4 weeks. . . Furthermore, groups treated with SDF-1 liposomes showed modestly faster closure compared to groups treated with free SDF-1, and groups treated with free SDF-1 showed no such improvement compared to groups treated with empty liposomes, or PBS vehicle.”, (p. 717, col 1, para 2).
Olekson et al teaches that the SDF-1 used in this study is a peptide (see abstract; and p. 718, col 2, para 2)
Regarding claim 10, Olekson et al does not teach the size of SFD-1, however this is evidenced by UniProt. Uniprot discloses that the mass of SDF-1 is at least 10,000 Daltons (see page 8).
Regarding claim(s) 12, 13, and 18, Okelson et al teaches, “The skin was gently lifted up and cut along the marked boundary to generate a full-thickness skin defect on the dorsum. An equivalent area of acellular dermis soaked in treatment (100 lL PBS containing 1 lg SDF-1; 100 lL PBS containing SDF-1 liposomes with 0.88 lg total SDF 1; 100 lL PBS containing empty liposomes; or 100 lL PBS) was applied onto the wound.”, (p. 713, col 1, para 1).
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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