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 .
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.
Subject Matter Eligibility - Step 1:
Claims 1, 3-4, 7-8, 11, 16, 21, 25-26, 28, 31, 33, 35, 39-40, 42, 45-46 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more. The claim(s) recite(s) a method of quantifying a concentration of extracellular vesicles in a sample. Accordingly, claim is directed to statutory subject matter under Step 1.
Subject Matter Eligibility - Step 2A, Prong 1:
Regarding claim 1, the recitation of "correlating the cholesterol content of the sample with the concentration of extracellular vesicles" is considered a consequence of a natural correlation (law of nature) of cholesterol content and the concentration of extracellular vesicles, and the "correlating" could be performed by a human using mental steps or basic critical thinking (Abstract idea).
Regarding claims 3-4, 7-8, 11, 16, 21, 25-26, 28, 31, 33, 35, 39-40, 42, 45-46, the limitations merely modify the type of extracellular vesicles in the sample and processing the sample and does not modify the law of nature or the abstract idea.
Subject Matter Eligibility - Step 2A, Prong 2:
This judicial exception is not integrated into a practical application because the concentration of extracellular vesicles is merely linking the abstract idea to the field of endeavor and would not be considered a particular practical application (MPEP 2106.05(h)). Accordingly, the claim is directed to an abstract idea.
Regarding claims 3-4, 7-8, 11, 16, 21, 25-26, 28, 31, 33, 35, 39-40, 42, 45-46, the limitations merely modify the type of extracellular vesicles in the sample and processing the sample and does not modify the law of nature or the abstract idea.
Subject Matter Eligibility - Step 2B:
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the sample and the analyzing steps are the other elements. Analyzing a cholesterol content of a sample suspected of comprising one or more extracellular vesicles are well understood and conventional as evidenced by He et al, "Direct Exosome Quantification via Bivalent-Cholesterol-Labeled DNA Anchor for Signal Amplification" Anal. Chem. 2017, 89, 12968−12975. Therefore these steps are considered an insignificant extra solution activity and would not amount to significantly more. The claim is therefore not patent eligible.
Regarding claims 3-4, 7-8, 11, 16, 21, 25-26, 28, 31, 33, 35, 39-40, 42, 45-46, the limitations merely modify the type of extracellular vesicles in the sample and processing the sample and does not amount to significantly more than the judicial exception as evidenced by the rejections below.
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(s) 1, 3-4, 11, 16, 21, 25, 40, 45-46 is/are rejected under 35 U.S.C. 102a1 as being anticipated by He et al, "Direct Exosome Quantification via Bivalent-Cholesterol-Labeled DNA Anchor for Signal Amplification" Anal. Chem. 2017, 89, 12968−12975.
Regarding claim 1, He et al teach a method of quantifying a concentration of extracellular vesicles in a sample (Abstract), comprising: preparing providing a sample suspected of comprising one or more extracellular vesicles (Scheme 1: exosome in tube), the method comprising quantifying the concentration of extracellular vesicles in a sample by analyzing a cholesterol content of the sample (Scheme 1: cholesterol bound anchor is analyzed), and correlating the cholesterol content of the sample with the concentration of extracellular vesicles (p. 12971, col. 2 para. 1: concentration of the exosome).
Regarding claims 3 and 11, He et al teach processing the sample using filtration, ultracentrifugation, or polyethylene glycol (PEG) precipitation (p. 12970, col. 1 para. 4: filtered through 0.22 um filter, reads on "filtration").
Regarding claim 4, He et al teach the sample is prepared prior to the analysis (i) the sample is prepared from a bioreactor; and/or (ii) the extracellular vesicles are produced in a mixture comprising a cell. (p. 12970, col. 1 para. 4: cell culture supernatant made from mixture comprising HepG2 cells)
Regarding claim 16, He et al teach the cholesterol content is analyzed using a fluorometric method to detect the cholesterol (p. 12972, col. 1, para 1, fluorescence detection of the exosomes)
Regarding claim 21, He et al teach the cholesterol content is analyzed in cell culture, and wherein the cholesterol content is analyzed by collecting cellular supernatant (p. 12970, col. 1 para. 4: cell culture supernatant)
Regarding claim 25, He et al teach the extracellular vesicles are engineered extracellular vesicles. (p. 12974: lipid membrane modification)
Regarding claim 40, He et al teach the extracellular vesicles comprise (i) a protein, a peptide, a small molecule, a nucleotide, a polynucleotide, an oligonucleotide, a virus or any combination thereof; or (ii) an antibody or an antigen binding fragment thereof, a fusion protein, an oligonucleotide, a dinucleotide, an mRNA, a virus, or any combination thereof (p. 12971, col. 1 para. 1: exosomal marker CD9).
Regarding claim 45, He et al teach comparing qNano concentration as the exosome standard (p. 12970, col. 1 para. 5, Fig. 7 and S1: reads on nanoparticle tracking analysis particle count curve) to the cholesterol concentration.
Regarding claim 46, He et al teach the extracellular vesicles are exosomes (Abstract).
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.
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.
Claim(s) 26, 28, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over He et al in view of Yu et al, "Pancreatic cancer-derived exosomes promote tumor metastasis and liver pre-metastatic niche formation", Oncotarget. 2017 Jun 28;8(38):63461–63483.
Regarding claims 26, 28, and 31, He et al teach modifying lipid membranes of the exosomes, but is silent the extracellular vesicles comprise a scaffold protein, optionally wherein the scaffold protein is a Scaffold X protein or a Scaffold Y protein; the Scaffold X protein comprises prostaglandin F2 receptor negative regulator (PTGFRN); basigin (BSG); immunoglobulin superfamily member 2 (IGSF2); immunoglobulin superfamily member 3 (IGSF3); immunoglobulin superfamily member 8 (IGSF8); integrin beta-1 ([[the]] ITGB1 protein); integrin alpha-4 ([[the]] ITGA4 protein); 4F2 cell-surface antigen heavy chain ([[the]] SLC3A2 protein); a class of ATP transporter proteins (theATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B3, ATP2B1, ATP2B2, ATP2B3, ATP2B4 proteins); a functional fragment thereof; [[and]]or any combination thereof; the Scaffold X protein comprises an amino acid sequence at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% identical to SEQ ID NO: 1.
Yu et al teach exosomes having prostaglandin F2 receptor negative regulator (PTGFRN) integrin subunits that are associated with pancreatic cancer metastasis to multiple organs. It is advantageous to study the effects of exosome accumulation in pre-metastatic organs and to determine whether or not such accumulation could prime the liver microenvironment for metastatic tumor cell colonization (Table 3, p. 63467 col. 1 para. 1: it is noted that PTGFRN is SEQ ID NO:1). Combining prior art elements according to known methods to yield predictable results is known. Therefore it would have been obvious to one of ordinary skill in the art to combine the prostaglandin F2 receptor negative regulator (PTGFRN) scaffold protein to provide the above advantage of studying the effects of exosome accumulation in pre-metastatic organs and to determine whether or not such accumulation could prime the liver microenvironment for metastatic tumor cell colonization.
Claim(s) 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over He et al in view of Kim et al, "Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes", Biochemical and Biophysical Research Communications 499 (2018) 803-808.
Regarding claims 7-8, He teaches HepG2 cells for exosomes, but is silent to the cell comprises a HEK293 cell, a Chinese hamster ovary (CHO) cell, a mesenchymal stem cell (MSC), a fibroblast cell, a s9f cell, a fHDF fibroblast cell, an AGE.HN neuronal precursor cell, a CAP amniocyte cell, a HT1080 cell, a C2C12 cell, a SIM-A9 cell, an adipose mesenchymal stem cell, an RPTEC/TERT1 cell, or any combination thereof; wherein the viability of the cells is at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.
Kim et al teach exosomes from HEK 293 cells for therapeutic applications. The HEK 293 cells with the exosomes maintain cell viability of almost 100%. It is desirable to provide cells at 100% viability upon genetic modifications of the exosomes to ensure efficient manufacturing of the therapies. Simple substitution of one known element for another to obtain predictable results is held to be obvious. Therefore, it would have been obvious to one of ordinary skill in the art to substitute the HepG2 cells for exosome with the HEK293 cells having about 100% viability of Kim to provide the above advantage of cells that ensure efficient manufacturing of the therapies.
Claim(s) 33, 35, 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over He et al in view of Yu et al, "Pancreatic cancer-derived exosomes promote tumor metastasis and liver pre-metastatic niche formation", Oncotarget. 2017 Jun 28;8(38):63461–63483 and further in view of Morton et al, "MARCKS-ED Peptide as a Curvature and Lipid Sensor", ACS Chem. Biol. 2013, 8, 1, 218–225.
He/Yu teach the limitations of claim 26 supra.
Regarding claim 33, 35, and 39, He/Yu are silent to the Scaffold Y protein is selected from the group consisting of comprises myristoylated alanine rich Protein Kinase C substrate (MARCKS), myristoylated alanine rich Protein Kinase C substrate like 1 (MARCKSL1), brain acid soluble protein 1 (BASP1), a functional fragment thereof, or any combination thereof; the Scaffold Y comprises an N terminus domain (ND) and an effector domain (ED), wherein:(i) the ND and/or the ED are associated with the luminal surface of the EV; (ii) the ND is associated with the luminal surface of the extracellular vesicles via myristoylation; (iii) the ED is associated with the luminal surface of the extracellular vesicles by an ionic interaction; (iv) the ED comprises at least one basic amino acid in sequence, wherein the basic amino acid is selected from the group consisting of Lys, Arg, His, and any combination thereof; or (v) any combination thereof; the basic amino acid is (Lys)n, wherein n is an integer between 1 and 10.
Morton et al teach the ED region of MARCKS protein to extracellular vesicles based on the effector domain sequence of the intracellular membrane protein myristoylated alanine-rich C-kinase substrate that can recognize PS. The ED region has Lys(5) (Table 1). It is well known for extracellular vesicles to have the scaffold Y protein MARCKS for membrane binding in the ED peptide region having Lys residues for electrostatic to provide curvature of the extracellular vesicles. Combining prior art elements according to known methods to yield predictable results is known. Therefore it would have been obvious to one of ordinary skill in the art to combine the MARCKS scaffold protein to provide the above advantage of providing curvature of the extracellular vesicle.
Claim(s) 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over He et al in view of Yang et al (US 20180371418)
Regarding claim 42, He is silent to the extracellular vesicles comprises (i)IL-2, IL-7, IL-12, CD40L, FLT3L, or any combination thereof; (ii) an oligonucleotide targeting STAT3, STAT6, NRas, KRas, or CEBP/3;(iii) a dinucleotide comprising a STING agonist; or (iv) any combination of (i) to (iii). Yang et al teach extracellular vesicles having helper molecules like IL-2 (Para. 0104-0105). The helper molecules, such as interleukin IL-2 and IL-12 are advantageous to enhance the therapeutic effect of the active agent. Combining prior art elements according to known methods to yield predictable results is known. Therefore it would have been obvious to one of ordinary skill in the art to combine the helper molecules, such as IL-2 and IL-12, to provide the above advantage of enhancing the therapeutic effect of the active agent.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS MICHAEL WHITE whose telephone number is (571)270-3747. The examiner can normally be reached M-F 8:30am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris R. Kessel can be reached at (571) 270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Dennis White/Primary Examiner, Art Unit 1758