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 .
Claim Status
Claims 1 – 20 are pending.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 – 7 and 9 – 19 are rejected under 35 U.S.C. 103 as being unpatentable over Lang et al. (W.O. Patent Application No. 2022245861 A1; cited on IDS as 2022145861, hereinafter Lang) in view of Ichim et al. (U.S. Patent Application Publication No. 2019/0022147 A1; hereinafter Ichim).
Regarding claims 1 and 3, Lang teaches a method of producing therapeutic exosomes (para. [0030]) that comprises transfecting or transducing MSCs with one or more therapeutic agents (para. [0197]). Thereby, modifying the MSCs, then culturing the MSCs and collecting the modified exosomes from culture. Lang further discloses in some aspects (para. [0008]), the MSCs are from umbilical cord tissue, placental tissue, or a mixture thereof. Lang teaches all of the elements of the current invention as stated above except explicitly disclosing the use of amniotic fluid-derived MSCs to generate exosomes from.
However, Ichim discloses compositions of matter, therapeutic protocols, and cellular reprogramming means to inhibit glioma or other brain neoplasia (Abstract), in which (para. [0086]) exosomes derived from amniotic fluid stem cells serve as an embodiment of the invention.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the amniotic fluid-derived MSCs of Ichim in the method of producing therapeutic exosomes of Lang. Doing so would allow for an additional therapeutic embodiment of the invention for glioma or other brain neoplasia.
Regarding claim 2, Lang discloses purifying the exosomes of claim 1 by differential ultracentrifugation (para [0189]) and filtration through a sucrose gradient.
Regarding claim 4, Lang discloses that the therapeutic agent(s) loaded into the exosomes in certain aspects are exogenous (para. [0194]) in regard to the MSCs.
Regarding claim 5, Lang discloses a method (para. [0047]) for testing a sample for determining one or more characteristics of the exosomes.
Regarding claims 6 and 10, Lang discloses that the therapeutic agents in the rejection for claim 1 are: (para. [0058]) miRNA, siRNA, shRNA, protein, peptides, drugs, etc.
Regarding claims 7 and 9, Lang teaches a method of producing therapeutic exosomes from culturing MSCs (para. [0007]) that comprises culturing the MSCs, collecting the exosomes, and loading one or more therapeutic agents by electroporation. The MSCs can be isolated from different regions (para. [0008]) of the body (e.g. adipose, dental, umbilical cord) and mixed together for exosome production. Lang further discloses electroporation, transfection, using a cationic liposome transfection action (para. [0193]).
Regarding claim 11, Lang discloses that the miRNA can be selected from (para. [0013]) a group of miRNAs that includes miR-942 and miR-657.
Regarding claim 12, Lang discloses the method of claim 7 and the loading efficiency of the therapeutic agents into the electroporated (para. [0012]) exosomes is at least 30% (para. [0013]).
Regarding claims 13 – 15, Lang teaches delivering (para. [0014]) an effective amount of the modified exosomes to an individual in need thereof. The delivery of the exosomes provides neuroprotection against central nervous system toxicities induced by one or more additional therapies. In some aspects, after delivery to an individual in need thereof, the exosomes reduce inflammation. In some aspects, the one or more additional therapies include: chemotherapy, radiotherapy, or a combination. The exosomes (para. [0015]) can also provide a tissue-regenerative effect to a tissue in need of regeneration. Lang further discloses the exosomes cross (para. [0018]) the blood-brain barrier, the blood-tumor barrier, or a combination thereof and can contain miR-124 (Fig. 5).
Regarding claim 16, Lang teaches all of the elements of the current invention as stated above, and that in some aspects, the exosomes cross the blood-tumor barrier in the treatment of cancer (para [018]). Lang further discloses for cancer therapeutic agents (para. [0241]), a drug, small molecule, antibody, inhibitory RNA targeting an oncogene, tumor suppressor protein, or a combination. Lang discloses that the therapeutic agents include: (para. [0058]) miRNA, siRNA, shRNA, protein, peptides, drugs, etc.
Regarding claim 17, Lang discloses that in some embodiments (para. [0028]) of the invention, the MSCs are autologous to the individual and can treat glioblastoma multiforme (para. [0269], ‘home’ efficiently to human gliomas).
Regarding claims 18 and 19, Lang discloses that one of the bioactive (para. [0240]) substances comprises one or more plasmids (para. [0193]). The vector can be ([para. 0201]) a retrovirus or an adeno-associated virus.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Lang and Ichim as applied to claims 1 – 7 and 9 – 19 above, and further in view of Tonkovich et al. (U.S. Patent Application No. 20150336074 A1; cited on IDS, hereinafter Tonkovich)
Regarding claim 8, Lang discloses that the culturing occurs in a bioreactor (para. [0176]) with thousands of semi-permeable hollow fibers and a gas regulator that balances the nitrogen in the chamber. Lang does not explicitly disclose porous microchannels. However, Tonkovich teaches a reactor comprising a plurality of porous microchannels (para. [0006 and 0007]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the bioreactor of Lang with the porous microchannels of Tonkovich in order to provide a large surface area for cell attachment. Lang provides the motivation in paragraph [0174] by stating that the reactor may be of any kind as long as it is suitable for the adherence of cells. Therefore, it would be obvious to optimize the culture reactor for optimal cell attachment, growth, and exosome production.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Lang and Ichim as applied to claims 1 – 7 and 9 – 19 above, and further in view of Brodie et al. (U.S. Patent Application No. 20190367873 A1; cited on IDS, hereinafter Brodie), Ghosh et al. (Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis. J Clin Invest. 2010 Nov;120(11):4141-54; hereinafter Ghosh), and Iacobaeus et al. ((2011) The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis. PLOS ONE 6(5): e19138; hereinafter Iacobaeus).
Regarding claim 20, Lang discloses the composition of claim 18, but does not explicitly disclose a plasmid that promotes expression of one or more VEGF genes. However, Brodie does disclose contacting MSCs (para. [0014]) for exosome production with at least one exogenous miRNA, which includes miR-424. Furthermore, Ghosh discloses that miR-424 (Fig 2D) can induce VEGF expression. Brodie further discloses that contacting (para. [0134 and 0136]) MSCs with mature miRNAs can affect the cells in a number of ways and that the MSCs can be transfected with a vector that encodes the mature miRNA. It is well known that miR-424 targets more genes (Ghosh-Abstract, e.g. CUL2) than VEGF. Therefore, the motivation to include a VEGF plasmid in the MSCs would be to produce exosomes that use VEGF as a therapeutic agent and to affect gene expression (VEGF) in the cell(s) of interest, without the off-target effects of miR-424. Furthermore, Iacobaeus discloses/provides motivation for treating neurological disorder with VEGF by revealing that the expression of VEGF-A is down regulated in peripheral blood mononuclear cells of patients with multiple sclerosis (Abstract, Whole paper).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify one or more of Lang’s therapeutic exosome load agents with VEGF and to reduce off-target effects by substituting the miR-424 plasmid of Brodie with a plasmid to promote VEGF expression. Doing so would reduce off-targeted gene expression, as recognized by Ghosh and potentially treat multiple sclerosis, according to Iacobaeus.
Response to Arguments
Claims 1 – 20 are pending.
Claims 1, 7 – 8, 13 and 16 – 17 are amended.
Claims 1 – 7 and 9 – 19 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lang.
Claim 8 was rejected under 35 U.S.C. 103 as being unpatentable over Lang in view of Tonkovich.
Claim 20 was rejected under 35 U.S.C. 103 as being unpatentable over Lang in view of Brodie and Ghosh.
Applicant’s arguments, see remarks, p. 8, filed 07/20/2026, with respect to the rejection(s) of claim(s) 1 – 7 and 9 – 19 under 35 U.S.C. 102 (a)(1) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection under 35 U.S.C. 103 is made and modified in view of Ichim.
Applicant argues that the rejection of instant claims 1 and 3 do not mention any “modifying” MSCs to introduce “bioactive substances” or “collecting exosomes” from the modified MSCs.
The Examiner has modified the rejection of claim 1 to include para. ([0197]) of Lang. Lang discloses “in one aspect, exosomes may be loaded by transforming or transfecting the MSCs with a nucleic acid construct that expresses the therapeutic agent(s), such that the therapeutic agent(s) are present in the exosomes as the exosomes are produced from the cell.” Also, the rejection of claims 1 – 7 and 9 – 19 has been modified to include Ichim. Ichim discloses the use of exosomes derived from amniotic-fluid derived stem cells.
Applicant argues that the rejection of instant claims 7 and 9 do not mention culturing MSCs to produce a culture, collecting exosomes form the culture, and modifying the collected exosomes to load one or more bioactive substances into the collected exosomes.
The Examiner has modified the rejection of claim 7 to include para. ([0193]) of Lang, which discloses the use of a cationic liposome transfection agent.
Applicant argues that the rejection of claim 16 does not address one or more exosomes derived from one or more types of MSCs and one or more bioactive substances located within the one or more exosomes.
The Examiner had modified the rejection of claim 16 to include para. ([0241]) of Lang, in which cancer therapeutic agents including: a drug, small molecule, antibody, inhibitory RNA targeting an oncogene, tumor suppressor protein, or a combination.
Applicant argues that Lang fails to disclose the claimed “wherein the one or more bioactive substances comprises one or more plasmids” in the rejection of claims 18 – 19. This argument has been fully considered but is not persuasive.
The rejection of claims 18 – 19 are obvious over Lang in view of Ichim, as Lang does disclose modifying the MSCs (para. [0197]) as mentioned above in order to collect the exosomes. The agents used in instant claims 18 – 19 are disclosed by Lang.
Applicant argues that Tonkovich is non-analogous art and should be removed as a reference for the rejection of claim 8. This argument has been fully considered but is not persuasive.
As mentioned in the previous rejection, Lang provides the motivation for a “non-analogous” art reference in para. [0174] by stating that the reactor may be of any kind as long as it is suitable for the adherence of cells. The Examiner took the information from Lang, then searched for “suitable” reactors for culturing conditions balanced with nitrogen, comprising a plurality of porous microchannels.
Applicant’s arguments, see remarks, p. 15, filed 07/20/2026, with respect to the rejection(s) of claim(s) 20 under 35 U.S.C. 103 has been fully considered and is persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection under 35 U.S.C. 103 is made over Lang in view of Ichim, Brodie, Ghoush, and Iacobaeus et al. ((2011) The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis. PLOS ONE 6(5): e19138; hereinafter Iacobaeus).
Applicant argues that a skilled artisan would not have found it obvious to modify the therapeutic exosome load agents of Lang with VEGF and to reduce off-target effects by substituting the miR-424 plasmid of Brodie with a plasmid to promote VEGF expression.
It is well known in the state of the art that miR-424 regulates VEGF and that VEGF-A is down regulated in Peripheral Blood Monocular Cells of patients with multiple sclerosis. Brodie’s disclosure is directed to culturing exosomes after contacting MSCs with at least one exogenous miRNA. Brodie also discloses treating neurological diseases, such as multiple sclerosis (para. [099]).
The Applicant’s amendments of claims 1, 7, 8, 13, 16 and 17 were addressed and the rejections of the claims were modified to encompass the new matter in the office action.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER JACKSON III whose telephone number is (571)272-0247. The examiner can normally be reached M-F 9:00A - 5:00P.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WALTER JACKSON III/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
