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 .
Status of the Claims
Claims 1-20 are pending and examined on their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application claims domestic benefit from U.S. provisional application 63/249892 filed on September 29, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 14, 2023 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of numerous terms relating to embodiments of specific fluorophores listed on pages 14-15 of the specification, including but not limited to Cy5, Alexa Fluor, ATTO-TAG, BOBO, BO-PRO, BODIPY, Calcium Crimson, Calcium Green-1, Calcium Orange, etc., which are trade names or a marks used in commerce, has been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms 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.
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.
Claim 6 is 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 6 recites the limitation "the amphiphilic compound" in line 2. There is insufficient antecedent basis for this limitation in the claim as there is no previous mention of an amphiphilic compound. Appropriate correction is required.
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.
Claims 1 and 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claims 2-14 and 18-20 are rejected as being dependent on a rejected claim without correcting the deficiency.
MPEP 2106.04 states:
In addition to the terms "laws of nature," "natural phenomena," and "abstract ideas," judicially recognized exceptions have been described using various other terms, including "physical phenomena," "products of nature," "scientific principles," "systems that depend on human intelligence alone," "disembodied concepts," "mental processes," and "disembodied mathematical algorithms and formulas." It should be noted that there are no bright lines between the types of exceptions, and that many of the concepts identified by the courts as exceptions can fall under several exceptions. For example, mathematical formulas are considered to be a judicial exception as they express a scientific truth, but have been labelled by the courts as both abstract ideas and laws of nature. Likewise, "products of nature" are considered to be an exception because they tie up the use of naturally occurring things, but have been labelled as both laws of nature and natural phenomena. Thus, it is sufficient for this analysis for the examiner to identify that the claimed concept (the specific claim limitation(s) that the examiner believes may recite an exception) aligns with at least one judicial exception.
Claim 1 recites a method of identifying a cell uptake modulator of a molecule and claim 15 depends from claim 1. Claims 1 and 15 are drawn to the statutory category of a process and eligible under Step 1.
Claim 1 recites “detecting the presence of the at least one molecule…” in limitation (c). Pg 8, lines 22-23 of the specification indicate that “detecting” can refer to “a method used to discover, determine, or confirm the existence or presence of a compound and/or substance”. The broadest reasonable interpretation of “detecting” includes an observation and decision as to the presence or absence of any visually identifiable signal, such as fluorescence. Thus, claim 1 recites a concept that falls into the mental processes group of abstract ideas.
Claim 15 recites the method of claim 1 further comprising “selecting a molecule uptake-deficient cell” and “profiling the isolated sgRNA fragment”. The specification provides various embodiments which “can” function as selecting or profiling which are not considered to be limiting. As such, the broadest reasonable interpretation of “selecting” and “profiling” includes mental processes such as making a decision or determination based on an observable characteristic and therefore recites a concept that fall into the grouping of abstract ideas. Thus claims 1 and 15 are drawn to the judicial exception of abstract ideas under Step 2A, Prong One.
This judicial exception is not integrated into a practical application because the additional method steps are no more than insignificant extra-solution activity. Claim 1 recites additional steps of (a) contacting a plurality of cells in a cell-containing biological sample with a plurality of gene-editing agents and (b) contacting the plurality of cells with a plurality of molecules. Claim 15 recites additional steps of isolating an sgRNA fragment. These additional method steps are performed in order to generate conditions required for the use of the recited judicial exception of detecting the presence of the at least one molecule in the plurality of cells (the mental process of claim 1) and selecting a molecule uptake-deficient cell and profiling the isolated sgRNA fragment (the mental processes of claim 15). Thus, the judicial exceptions are not integrated into a practical application under Step 2A, Prong Two.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception under Step 2B because the instant disclosure teaches well-understood, routine, and conventional methods which are implemented for the steps of contacting a plurality of cells with a plurality of gene-editing agents, contacting the plurality of cells with a plurality of molecules, and isolating an sgRNA fragment which are known in the art as evidenced by the teachings of Park et al., detailed below in the 102 rejections. Thus, the additional elements recited in the claims are no more than well-understood, routine, and conventional activities commonly known in the art under Step 2B.
MPEP 2106.04 states:
In addition to the terms "laws of nature," "natural phenomena," and "abstract ideas," judicially recognized exceptions have been described using various other terms, including "physical phenomena," "products of nature," "scientific principles," "systems that depend on human intelligence alone," "disembodied concepts," "mental processes," and "disembodied mathematical algorithms and formulas." It should be noted that there are no bright lines between the types of exceptions, and that many of the concepts identified by the courts as exceptions can fall under several exceptions. For example, mathematical formulas are considered to be a judicial exception as they express a scientific truth, but have been labelled by the courts as both abstract ideas and laws of nature. Likewise, "products of nature" are considered to be an exception because they tie up the use of naturally occurring things, but have been labelled as both laws of nature and natural phenomena. Thus, it is sufficient for this analysis for the examiner to identify that the claimed concept (the specific claim limitation(s) that the examiner believes may recite an exception) aligns with at least one judicial exception.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 and 15-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park et al. (2019, Imaging inflammation using an activated macrophage probe with Slc18b1 as the activation-selective gating target. Nature Communications, 10(1), 1111, hereafter “Park”).
With regard to claim 1, Park teaches wherein macrophages (which are considered to read on a plurality of cells of a cell-containing biological sample) were exposed to a small molecule probe (which is considered to read on a plurality of molecules) in order to visualize inflammatory atherosclerotic plaques (which is considered to read on detecting the presence of the molecules) and wherein subsequent use of a transporter screen using a CRISPR library (which is considered to read on contacting the plurality of cells with a plurality of gene editing agents) identified the transporter SLC18B1 as the “gating target” (which is considered to read on identifying a cell uptake modulator) of the small molecule probe (Abstract). Additionally, Park teaches a fluorescently labeled small molecule (Pg. 2, left column, Results, 1st para.) (i.e., the plurality of molecules) which is detected intracellularly in lysosomal vesicles of live cells (Pg. 4, right column, lines 7-8), which lends support for detecting at least one molecule which has been transported into at least one cell.
With regard to claims 2-4, Park teaches use of a sgRNA library design (Methods, sgRNA library design) comprising use of a lentivirus and CRISPR/Cas9 components to generate solute carrier (SLC)-CRISPRa pools (Methods, Lentiviral production and Generation of SLC-CRISPRa pools) in order to identify the cell uptake modulator of the fluorescently-labeled small molecule (Pg. 4, Slc18b1-mediated uptake of CDg16 in activated macrophages).
With regard to claims 15-17, Park teaches wherein detection of the fluorescently labeled small molecule is used as a selection marker for cells from the SLC-CRISPRa library and wherein marker-containing cells are sorted and processed for identification of the particular sgRNA associated with cellular uptake of the small molecule. Further, Park teaches wherein next-generation sequencing analysis of SLC-CRISPRa small molecule-containing cells is used to determine enriched sequences corresponding to the sorted SLC-CRISPRa small molecule-containing cells (Pg. 4, right column, 1st full para., lines 25-33) and wherein sgRNA containing regions from the sorted SLC-CRISPRa small molecule-containing cells were amplified and sequenced using an Illumina HiSeq 400 (Methods, Analysis of integrated sgRNA) , which is considered to reasonably read on high-throughput sequencing of the isolated sgRNA fragment. While Park teaches wherein cells having indicators of efficient cellular uptake (i.e., increased or presence of fluorescent signal) are selected for further profiling using high-throughput sequencing, one having ordinary skill in the art would recognize that the same steps as taught by Park could be applied to cells having indicators of impaired cellular uptake (i.e., low or absent fluorescent signal).
With regard to claim 18, teaches that by the combination of the techniques detailed above with over-expression studies of SLC18B1 sgRNA-transduced cells (Pg. 4, right column, 1st full para., lines 35-37) and fluorescent co-localization studies of the small molecule and fluorescently tagged SLC18B1 (Pg. 4, right column, 1st full para., lines 39-42), SLC18B1 is identified as the cell uptake modulator for the small molecule.
With regard to claims 19 and 20, Park teaches wherein the fluorescently labeled small molecule which is present only in live cells (Pg. 4, right column, lines 7-8) is detected in cells in culture and in animals, which is considered to read on a tissue sample including cultured macrophage cells (i.e., Raw264.7) (Pg. 2, right column, Detecting atherosclerotic plaques using CDg16), ApoE knockout mice (Pg. 3, left column, line 7), live isolated aorta cells (Pg. 3, right column, line 21), in vivo aorta cells and liver cells, and in vitro endothelial, smooth muscle, and human cancer cell lines (Pg. 4, right column, lines 6-12).
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Park as applied to claims 1-4 and 15-20 above, and further in view of Rush et al. (2013, Nuclease-resistant DNA via high-density packing in polymeric micellar nanoparticle coronas. ACS nano, 7(2), 1379-1387, hereafter “Rush 2013”) in further view of Rush et al. (2014, Intracellular mRNA regulation with self-assembled locked nucleic acid polymer nanoparticles. J. of the American Chem Society, 136(21), 7615-7618, hereafter “Rush 2014”) and Mao et al. (US 20160331845 A1, hereafter “Mao”).
With regard to claims 5-7 and 9, as detailed above in the 102 rejections, Park teaches wherein a plurality of macrophage cells are contacted with a plurality of fluorescently labeled small molecule probes and a plurality of gene editing agents (i.e., an sgRNA CRISPR library) is used to identify the cell uptake modulator (Abstract) responsible for intracellular uptake of the small molecule (Pg. 4, right column, lines 7-8).
Park does not teach wherein the plurality of molecules is a DNA polymer micelle.
Rush 2013 teaches a polymeric micellar nanoparticle comprising DNA-polymer amphiphiles (Abstract) wherein the DNA polymer micelles comprise a hydrophobic polymer and an oligonucleotide, which form a DNA-polymer conjugate (Pg. 1380, left column, 1st para.), and wherein the DNA can comprise a fluorescein at the 3’ terminus (Pg. 1380, right column, 1st para., lines 9-10). Additionally, Rush teaches that the DNA polymer micelles render nucleic acids resistant to digestion by nucleases (Abstract) and have potential use for in vivo delivery of nucleic acids (Pg. 1384, left column, 1st full para.), which is considered to reasonably read on cellular uptake of the DNA polymer micelle.
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the fluorescently labeled small molecule probe in the method of identifying a cell uptake modulator by contacting a plurality of cells with the small molecule probe and using a gene-editing library to identify the cellular uptake modulator as taught by Park with the molecule of a fluorescently labeled DNA polymer micelle as taught by Rush 2013. Since Rush 2013 teaches that DNA polymer micelles have potential use for in vivo delivery of nucleic acids (Pg. 1384, left column, 1st full para.) and that nucleic acids complexed into nanostructures have utility as in vivo therapeutic agents (Pg. 1379, left column, 1st para., lines 1-6), one having ordinary skill in the art would have been motivated to combine the method of Park wherein an sgRNA library design was used to identify the cell uptake modulator of a small molecule with the DNA polymer micelle as taught by Rush 2013 in order to identify the cell uptake modulator of the DNA polymer micelle. A skilled artisan would have recognized that identifying the cell uptake modulator of the DNA polymer micelle, which Rush 2013 teaches have potential use for the delivery of nucleic acids which have use as therapeutic agents, could aid in the ability to deliver DNA polymer micelles carrying therapeutics to targeted cells or to increase cellular delivery of DNA polymer micelles carrying therapeutics. One having ordinary skill in the art would have had a reasonable expectation of success as both Park and Rush 2013 teach molecules which can be delivered to cells via cellular uptake.
With regard to claim 8, as detailed above, the combined teachings of Park and Rush 2013 teach a method of identifying a cell uptake modulator comprising contacting a plurality of cells with a plurality of molecules (i.e., fluorescently-labeled DNA polymer micelles) and use of a plurality of gene-editing agents (i.e., sgRNA CRISPR library) in order to identify the modulator of molecule uptake.
While Rush 2013 does teach fluorescent labeling of the DNA polymer micelles, Rush 2013 does not teach wherein the fluorophore is Cy5.
Rush 2014 teaches an antisense oligonucleotide delivery system for intracellular delivery comprising locked nucleic acid (LNA)-polymer conjugates which assemble into micelles (Abstract) and which can be labeled with Cy5 (Fig. 2).
Therefore it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the fluorescently-labeled DNA polymer micelle wherein the label is fluorescein as taught by Rush 2013 with a Cy5 label as taught by Rush 2014. One having ordinary skill in the art would have recognized that the fluorescent labels could be substituted with the predictable result of yielding a Cy5 labeled DNA polymer micelle. A skilled artisan would have had a reasonable expectation of success as both Rush 2013 and Rush 2014 teach oligonucleotide-based polymer micelles which are fluorescently labeled.
With regard to claim 10, Rush 2013 teaches wherein the DNA sequence comprises about 30 nucleotides (Supporting information, Figure S4).
With regard to claim 11, per the instant specification, the instantly claimed DNA sequence comprises a spacer sequence comprising T and/or A nucleotides (Pg. 13, lines 13-15) which are present at the polymer interface (Pg. 34, line 2). This is shown in Fig. 6A of the instant specification where the DNA sequence comprises a T nucleotide at the 3’ end which is attached to the hydrophobic polymer. Rush 2013 teaches a DNA sequence comprising a T nucleotide at the 3’ end which is attached to the hydrophobic polymer which is considered to reasonable read on a spacer sequence (Supporting Information, Fig. S4).
With regard to claim 12, as detailed above, Rush 2013 teaches wherein the DNA polymer micelle comprises approximately 200 DNA strands (i.e., amphiphilic compounds) per particle (Pg. 1380, left column, line 21) which is interpreted to read on comprising about 20 amphiphilic compounds.
With regard to claims 13 and 14, as detailed above, the combined teachings of Park and Rush 2013 teach a method of identifying a cell uptake modulator comprising contacting a plurality of cells with a plurality of molecules (i.e., fluorescently-labeled DNA polymer micelles) and use of a plurality of gene-editing agents (i.e., sgRNA CRISPR library) in order to identify the modulator of molecule uptake. Rush 2013 teaches a polymeric micellar nanoparticle comprising DNA-polymer amphiphiles which is able to render nucleic acids resistant to digestion by nucleases (Abstract) and which have potential use for in vivo delivery of nucleic acids (Pg. 1384, left column, 1st full para.).
Rush 2013 does not teach wherein the DNA polymer micelle further comprises therapeutic cargo or wherein the therapeutic cargo comprises a nucleic acid.
Mao teaches a polymeric micellar nanoparticle comprising at least one nucleic acid (Mao Claim 1) and wherein the micellar nanoparticle can further comprise a at least one nucleic acid encoding a therapeutic gene, which is considered to read on therapeutic cargo. (Para. [0026], line 3).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the combined teachings of Park and Rush 2013 wherein a contacting a plurality of cells with a plurality of molecules (i.e., fluorescently-labeled DNA polymer micelles) combined with use of a plurality of gene-editing agents (i.e., sgRNA CRISPR library) can be used in order to identify the cellular uptake modulator of a DNA-polymer micelle with Mao’s polymeric micellar nanoparticle comprising at least one nucleic acid and further comprising a therapeutic gene. A skilled artisan would have been motivated to make this combination as they would have recognized that identification of the specific cellular uptake modulator for a DNA polymer micelle as taught by the combination of Park and Rush 2013 wherein the DNA polymer micelle can comprise a therapeutic agent as taught by Mao could be used to increase, modify, or target cellular delivery of a DNA polymer micelle comprising a therapeutic compound thereby providing increased or targeted cellular delivery of a therapeutic compound and thereby better treatment. One having ordinary skill in the art would have had a reasonable expectation of success as Park, Rush 2013, and Mao all teach intracellular delivery of molecules and Rush 2013 and Mao both teach polymeric micelles containing DNA for use in intracellular delivery.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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, Doug Schultz can be reached at 571-272-0763. 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.
/ERIN V PAULUS/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631