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 .
Election/Restrictions
Applicant’s election without traverse of Group I and the species has-miR-4669 from claim 3, TREM1 from claim 5 (which does not appear to be an option), CD9 from claim 7, HLA-ABC from claim 13, LPS from claim 22 and peak amplitude from claim 43, in the reply filed on 04/24/2026 is acknowledged.
Claim 95 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/24/2026.
Claims 1, 3, 5, 7, 10, 12-14, 18-20, 22-24, 28, 31, 33, 38, 40, 42-43 and 46 are being examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/25/2024 is being considered by the examiner. The signed IDS form is attached with the instant office action.
Drawings
The drawings filed on 05/03/2024 are acceptable subject to correction of the informalities indicated below. In order to avoid abandonment of this application, correction is required in reply to the Office action. The correction will not be held in abeyance. The drawings are objected to for not having proper page numbers. All sheets of drawings must be numbered in the center of either the top or the bottom of each sheet but not in the margin in numbers larger than those used as reference signs in order to avoid confusion with the latter. For drawings, a separate series of page numbers is to be used. The number of each sheet of the drawings must consist of two Arabic numerals separated by an oblique stroke, the first being the sheet number and the second being the total number of sheets of drawings.
For example “2/5” would be used for the second sheet of drawings where there are five in all (see MPEP 37 C.F.R. 1.437); 1825 The Drawings [R-08.2017].
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13, 23, and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 recites “essentially no” and it is unclear to the metes and bounds to what is considered essentially no making the limitation confusing.
Claim 23 recites the limitation "conditioned media" in line 1. There is insufficient antecedent basis for this limitation in the claim as claim 1 does not require conditioned media.
Claim 24 recites the limitation "conditioned media" in line 2. There is insufficient antecedent basis for this limitation in the claim as claim 1 does not require conditioned media.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 1, 7 and 46 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Deok-ho Kim et. al. (US20230075630A1).
Kim discloses a composition comprising a glial-derived extracellular vesicle (see claim 1) and wherein the EVs are derived from stem cells from induced pluripotent stem cells (see claim 5).
Kim discloses the Ev’s express CD9 (see claim 8).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, 20, 2224, 31, 38, 40, 42-43 and 46 are rejected under 35 U.S.C. 103 as being unpatentable Anna Mallach et. al. (Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons, Cells 24, October 2021, 10, 2866) and Sijie Jiang et. al. (Exosomes Derived has-miR-4669 as a Novel Biomarker for Early Predicting the Response of Subcutaneous Immunotherapy in Pediatric Allergic Rhinitis, Journal of Inflammation Research, September 3, 2022: I 5, 5063-5074).
Regarding claims 1 and 46, Mallach teaches creating exosomes from microglia-derived iPSC’s (see page 2, materials and methods 2.2.1-2.2.2).
Regarding claim 5, Mallach teaches iPS-neurons were exposed to basal exosomes derived from untreated iPS-Mg carrying either the Cv (common variant) or R47Hhet TREM2 variant (see 2.6, page 4).
Regarding claim 20, Mallach teaches creating iPSc’s from patient cells (see 2.1-2.2.2, page 2).
Regarding claim 22, Mallach teaches Exosomal protein content changed according to how the iPS-Mg were stimulated (see abstract) and does not require LPS stimulation.
Mallach does not specifically teach that the enriched secretome comprises of has-mir-4669.
Jiang teaches wherein serum exosomes derived miRNA were associated with has-miR-4669 which might serve as a novel biomarker for early predicting the response of SCIT in AR children (see results in abstract) and that exosomal miRNAs possess a fruitful area for further exploring and lays the groundwork for future molecularly targeted therapy research (see conclusion).
Therefore it would have been obvious to persons having ordinary skill in the art before the effective filing date to enrich the extracellular vesicles with of Mallach’s composition to create assays for testing miR-4669’s ability to be a predictive biomarker in the lab, either in vitro or in vivo. One could create a population of EV’s containing miR-4669 for testing its ability to influence other cell types and genetic pathways. Regarding claim 20, Mallach does not require them to be and it would have been obvious to use fresh microglia as opposed to cryopreserved ones as preservation techniques can reduce viability of the cells. The extracellular vesicles as being singlets, doublets, etc. are typical when screening EVs and would be ones in which any person could select given the prior art.
Regarding claim 23, pertaining to the different ways of separating or isolating the exosomes using ultracentrifugation, this limitation would have been prima facie obvious to persons having ordinary skill in the art as it is common and conventional to the art. Also the examination is to the product and not a method for obtaining the product.
Regarding claims 38, 40, 42-43, pertaining to the activities being claimed and depending from claim 1, the prior art appears to be identical in nature to instant claim 1 and thus the activities being claimed from those same EVs would be an inherent property as there was nothing done to those EVs to impart any additional activity or function to the EVs being claimed.
Claims 7, 14, 18-19, 28 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Anna Mallach et. al. (Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons, Cells 24, October 2021, 10, 2866) and Sijie Jiang et. al. (Exosomes Derived has-miR-4669 as a Novel Biomarker for Early Predicting the Response of Subcutaneous Immunotherapy in Pediatric Allergic Rhinitis, Journal of Inflammation Research, September 3, 2022: I 5, 5063-5074) as applied to claims 1, 3, 5, 20, 22,24, 31, 38, 40, 42-43 and 46 above, and further in view of Springer Nature (https://link.springer.com/protocol/10.1007/978-1-4939-7253-1_12).
Mallach teaches the instant composition however is silent on the extracellular vesicles being positive for CD9.
Springer Nature teaches “EVs can be characterized by a wide variety of techniques, including profiling the proteins they contain. Tetraspanins are a group of proteins that contain four transmembrane domains and certain characteristic features. The tetraspanins CD9 , CD63 and CD81 are transmembrane proteins that are commonly found in extracellular vesicles across cell types” (see page 3, Introduction).
Springer teaches that “we define an exosome as any EV between 30 and ~200 nanometers (nm). The upper limit is imposed by using a 0.22 μ m filter” (see introduction).
Therefore it would have been obvious to persons having ordinary skill in the art to make sure the extracellular vesicles expressed CD9, CD63 and CD81 as these are common markers found on EVs and this tetraspanin could help identify EVs from the composition taught by Mallach. Selecting the EVs which express protein levels of these markers which are at the amounts claimed would have been a matter of mere judicious selection. The amounts also do not appear to be critical to the invention. As discussed in MPEP section 2144.05(II)(A), “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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).” It would have also been obvious to have a median D50 value of 110-130 nm because Springer teaches sizes to fall within this range.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Anna Mallach et. al. (Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons, Cells 24, October 2021, 10, 2866) and Sijie Jiang et. al. (Exosomes Derived has-miR-4669 as a Novel Biomarker for Early Predicting the Response of Subcutaneous Immunotherapy in Pediatric Allergic Rhinitis, Journal of Inflammation Research, September 3, 2022: I 5, 5063-5074) as applied to claims 1, 3, 5, 20, 22,24, 31, 38, 40, 42-43 and 46 above, and further in view of Filippo Ugolini et. al. (Differential HLA class I subunit (A, B, C heavy chain and β2-microglobulin) expression levels in normal tissues, Springer, Virchows Arch, 2022 Nov 27; 482(2): 359-368).
Mallach teaches the instant composition however is silent on the extracellular vesicles having essentially no HLA-ABC experession.
“The immunologically relevant molecules analyzed in malignant cells include the β2-microglobulin-HLA class I heavy chain complexes since they mediate interactions between cancer cells and the host’s immune system by presenting tumor antigen-derived peptide to cognate cytotoxic T cells.
The analysis of changes in HLA class I subunit expression levels associated with the malignant transformation of cells has suffered from the limited available information about the HLA class I subunit expression levels in normal tissues [13–15]” (see Introduction).
Therefore it would have been obvious persons having ordinary skill in the art before the effective filing date to make sure the EVs in Mallach’s composition do not express any HLA-A, HLA-B or HLA-C complexes in order to reduce the level T-cell engagement and immunity activity.
Claims 23 is rejected under 35 U.S.C. 103 as being unpatentable over Anna Mallach et. al. (Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons, Cells 24, October 2021, 10, 2866) and Sijie Jiang et. al. (Exosomes Derived has-miR-4669 as a Novel Biomarker for Early Predicting the Response of Subcutaneous Immunotherapy in Pediatric Allergic Rhinitis, Journal of Inflammation Research, September 3, 2022: I 5, 5063-5074) as applied to claims 1, 3, 5, 20, 22-, 31, 38, 40, 42-43 and 46 above, and further in view of Deepika Rajesh et. al. (WO2022235911A1).
Mallach teaches the instant invention however is silent on the limitations of claims 23-24.
Rajesh teaches of an isolated induced pluripotent stem cell (iPSC)-derived microglia cell line comprising a CD33 rsl2459419T allele or CD33 rsl2459419C allele (see claim 1) and it would be appreciated that the microglia would also include an extracellular vesicle-enriched secretome because Rajesh also discloses that cryopreserved iPSC-derived microglia (iMGL) retain purity, secrete immunomodulatory cytokines and phagocytose pHrodo Red labelled bacterial BioParticles and Amyloid Peta aggregates (see 00129). Rajesh teaches that the cell line express TREM2 (see claim 6, claim 7, claim 50). Rajesh teaches differentiation of HPCs to microglia and discloses using fresh HPCs (see 00129-00130). Rajesh also does not require LPS stimulation as Rajesh teaches other components such as IFN-g or GM-CSF can be used.
Regarding claim 23, Rajesh teaches of conditioned medias: “Generally, a defined medium comprises a basal media (e.g., Dulbecco’ s Modified Eagle’ s Medium (DMEM), F12, or Roswell Park Memorial Institute Medium (RPMI) 1640, containing amino acids, vitamins, inorganic salts, buffers, antioxidants, and energy sources) which is supplemented with recombinant albumin, chemically defined lipids, and recombinant insulin. An example of a fully defined medium is Essential 8™ medium.
For a medium, extracellular matrix, or culture system used with human cells, the term “Xeno-Free (XF)” refers to a condition in which the materials used are not of non-human animal-origin” (see 0056-0057) and teaches harvesting cells with cold PBS and diluting through feeding of cells every 48 hrs (see 00130), or through supplementing different basal media components (see 0069).
Therefore it would have been obvious to persons having ordinary skill in the art to use the culturing methods and techniques taught by Rajesh because Rajesh teaches that these techniques of diluting with PBS and passaging are generally done in the art when culturing iPSC derived microglia cells.
Conclusion
Currently no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACOB ANDREW BOECKELMAN whose telephone number is (571)272-0043. The examiner can normally be reached Monday-Friday 8am-5pm.
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JACOB A BOECKELMAN Examiner, Art Unit 1655
/ANAND U DESAI/ Supervisory Patent Examiner, Art Unit 1655
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