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 gene-editing agent as the imaging agent in the reply filed on October 27, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 112 – New Matter
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 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 20 requires an additional step of “rejecting failed drug delivery vehicles based on the color change” which is not supported by the disclosure as originally filed. The Examiner was unable to locate any information about the determination of the failure or rejection of anything tested using the claimed method in the disclosure as originally filed.
If Applicant is in disagreement with the Examiner regarding support for the amended claim, Applicant is respectfully requested to point to page and line number wherein support may be found for the instant invention.
Claim Rejections - 35 USC § 112 – Indefiniteness
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 1 – 6, 8, 9, 11, 12 and 14 - 20 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 1, from which all other claims depend, requires the presence of “human-based cells” as part of the scaffold matrix material comprising the artificial intestine system and such human-based cells are referenced in multiple dependent claims.
Claim 9 narrows human-based cells to comprise an adenocarcinoma-based cell.
Claims 15 and 16 recite a biologically-based polymer.
In each of these instances, neither the claims nor the specification provides any guidance as to how similar the human cells, adenocarcinoma cells or biological polymer must be to the material it is based on to determine the scope of each of these terms. The use of based suggests that some alterations to the underlying material are permitted while still remaining with the scope of the claims. Different artisans will have different interpretations of the scope and/or type of changes that would fall within the scope of each term. Without any guidance as to how many features and/or what aspects of the material must be retained to still be considered as based on the respective material, the scope of the materials encompassed by each of human-based cells, adenocarcinoma-based cells and biologically based polymers cannot be determined.
For example, does biologically based polymers encompass only polymers that naturally occur in at least one organism? Polypeptides are a large class of biological polymers – would polypeptides made from unnatural amino acids considered biologically based as they use the same amide linkage found in polypeptides from naturally occurring amino acids? Poly(lactic-co-glycolic) acid (PLGA) does not appear to naturally occur in any organism, organisms can produce both the lactic acid and glycolic acid monomers. Does that render PLGA a biologically based polymer? While claim 16 recites silk fibroin, the biologically-based material comprises silk fibroin so this claim is also unclear as some level of modifications to the silk fibroin while still remaining within the scope of this claim appear to be permitted but the metes and bounds cannot be determined.
The dependent claims fall therewith.
Please clarify.
Claims 8 and 11 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.
The scope of “gene-editing agent that activates fluorescence within the human based cells” is not understood. Neither the claims nor the specification provide a clear indication of the scope of these gene-editing agents. There are substances naturally found in cells that have at least some fluorescence whose expression levels could be altered by gene editing – is that the intended target of the gene editing? Or can the gene editing target be something that interacts with a naturally occurring fluorescent material in the cells? Or must the human based cells be altered in some way prior to interaction with the gene editing agent such that the fluorescence of something that is not naturally present in the cells is “activated” when the gene editing occurs? Does activate mean that the fluorescence is no longer quenched after the action of the gene editing agent? Must the gene editing agent target something is capable of becoming fluorescent under the appropriate conditions or simply encode something that is fluorescent such that transcription and translation of the newly inserted genetic materials activates fluorescence within the cell?
Dependent claim 11 falls therewith.
Please clarify.
For the purposes of applying art below, these claims are being interpreted as encompassing a cargo that comprises materials that can edit genetic material and result in the expression of a fluorescent material in the cell or a material that otherwise changes the fluorescence of the cell whose genetic material has been edit.
Claim 17 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.
Section (b) of claim 17 requires that the upper plate is separated from the lower plate by a distance and that the upper plate is spaced from the lower plate by a distance (emphasis added). The phrasing would seem to indicate that these are two distinct, non-identical claim limitations, but two things that are spaced a distance apart are also separated from one another by that same distance. Neither “separated from” nor “spaced from” are defined to determine if Applicant’s intended there to be a distinction between these phrases that means they are not identical. Does the separated from distance need to be different from the spaced from distance? Is there some other structural relationship between the upper and lower plates that is being specified by separated from and spaced from?
The color change referenced in the last two lines of claim 17 is unclear as an imaging agent is added to the two-dimensional culture system that can produce a color change. As claim 17 depends from claim 1, there is also an imaging agent added to the artificial intestinal model system with step (iii) in claim 1 being identical to the last two lines of claim 17 that also results in the determination of a color change. Do what imaging agent in what model system does “a color change” at the end of claim 17 refer to?
Please clarify.
Claim 20 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 20 requires “rejecting failed drug delivery vehicles based on the color change”.
There is an antecedent basis issues as claim 20 depends from claim 17, which requires at least determining the color change induced by the imaging agent from the artificial intestine system of claim 1 and possibly determining the color changed induced by the imaging agent from the two-dimensional culture system in claim 17 (see rejection above).
But when that color change information is determined, no criteria for what is considered a failed drug vehicle is given in either the claims or the specification to determine if a particular drug delivery vehicles system should be rejected. Is only the complete absence of a color change considered a failure? Or is there some threshold level of color change occurring and/or the color change must occur in certain parts of the model systems (e.g., not just the outermost cells directly exposed to the drug delivery vehicle containing solution) that determines failure? Without any such guidance, the scope of the step of claim 20 cannot be determined.
Please clarify.
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) 1, 2, 6, 9, 12, 14 – 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al. (US 2016/0313306) in view of Chen et al. (Sci Reports, 2015) and Simovic et al. (Nanomed Nanotech Biol Med, 2015).
Ingber et al. discloses systems and methods that can be used to grow and differentiate primary cells such as lung or other cells requiring low shear and/also stratified structures or simulation of a microenvironment in living tissues and/or organs that permit co-culture with one or more different cell types (whole document, e.g., abstract). The device can produce artificial tissue layers by being grown under conditions that mimic the appropriate physiological conditions (¶ [0305]). While many examples focus on mimicking the operation of the airway (e.g., ¶ [0078]), that the device can be used for the formation of 3-D gut or intestinal tissue such that the intestinal epithelial grow into folds that resemble the villi are also disclosed (¶¶ [0127] and [0255]). In some embodiments, the devices modeling the function of an intestinal villus structure as described above can be used to assess intestinal absorption, metabolism, and/or excretion of a test agent for the prediction of its bioavailability (¶ [0269]). Amongst the disclosed applications for the organ mimic devices are assessing pharmacokinetics and/or pharmacodynamics of various chemical or biological agents; testing gene therapy vectors; and studies on bioavailability and transport of chemical or biological agents across epithelial or endothelial layers (¶ [0073]). To study the effects of a test agent, one can add these into the desired cell culture medium suitable for growing the cells attached to the membrane in the channel (¶ [0321]). Imaging tools such as fluorescence microscopy can be used for real-time analysis of cellular behavior in the multilayered tissues in the device (¶ [0357]). The movement of fluorescent beads in an airway model is shown in Figures 14A and 14B (¶ [0044]) and fluorescently labeled pathogens can be used to monitor infection of cells with the pathogen with light or fluorescent microscopy (¶ [0301]).
A two-dimensional or three-dimensional model system as in claims 17 and 1 respectively are not disclosed.
Chen et al. discloses an in vitro human intestinal epithelium (whole document, e.g., title). A 2D transwell culture system with the human derived H-MyoFib cell on the bottom of the a 24-well transwell culture system with a pore size of 0.4 µm, reading on the lower plate of claim 17, with the Caco-2 and HT29-MTX cells cultured on the membrane of the transwell cell culture inserts, reading on the upper plate of claim 17, were cultured and maintained routinely in DMEM:SMGM (1:1) for up to 40 days (p 8, ¶ 2), reading on maintaining under physiologically relevant conditions. As shown in this schematic of the transwell system, the upper and lower plates are separated by distance/space as required by claim 17:
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. Caco-2 cells are enterocyte-like cells while HT29-MTX cells are Goblet-like cells routinely used to establish intestinal model systems for nutrient/drug absorption studies while H-InMyoFibs are fibroblasts that secrete cytokines and growth factors to support the growth, differentiation, and expansion of the human intestinal epithelium (p 2, ¶ 3). The same cell types were cultured on a 3D silk scaffold (p 8, ¶ 3) and that scaffold comprises the biologically-based polymer silk fibroin (p 7, ¶ 5) and comprises a porous material with an interconnected network of pores (p 7, ¶ 7). This model reads on the artificial intestine system of claim 1. The 3D model system better mimicked features such as mucus secretion compared to the transwell, 2D system (p 2, ¶ 4). The bioengineered 3D human intestine model using silk protein-based scaffold demonstrated its powerful and enduring strength to reconstitute and sustain both architectural and functional imperatives of human intestine in vitro (p 6, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the intestinal model systems of Chen et al. to carry out studies as disclosed by Ingber et al. on the absorption of materials across the intestinal model system. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because tissue model systems can be used for such studies as taught by Ingber et al. but the 2D and 3D systems disclosed by Chen et al. provide mimicry of intestinal properties including mucus secretion that would reasonably be expected by one of ordinary skill in the art to possibly affect the absorption of the materials being studied. Results obtained from the 3D system would be reasonably expected to be a good mimic of in vivo results without resorting to an in vivo model. A 2D study can be readily carried out in a multi well system to provide initial test results, with the most promising candidates then being tested in the 3D silk fibroin system disclosed by Chen et al. that provides an improved intestinal system compared to the 2D system.
The use of a drug delivery vehicle comprising an imaging agent is not explicitly disclosed.
Simovic et al. discloses that nanoparticles are not generally administered orally mainly because of physiologically obstacles and various strategies have been tried to increase intestinal uptake of such particles (p 1169, col 2, ¶ 2). Model micellar nanoparticles with a hydrophobic phospholipid core, a PEG (polyethylene glycol) corona loaded with the fluorophore coumarin 6 were used in the studies to study in vivo drug delivery characteristics (p 1169, col 2, ¶ 3 and p 1172, col 2). To study the mechanism of endocytosis across healthy intestinal tissues, pieces of rat ileum were incubated with the fluorescently labeled nanoparticles and images as shown in Figure 3 were collected over different times to nanoparticle movement in the tissue (p 1175, col 1, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a fluorescently labeled version of a drug delivery system to study absorption in intestinal cells using the methods and models of Ingber et al. and Chen et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the use of fluorescent materials is generally taught by Ingber et al. but not specifically for studying absorption of nanoparticles that can act as drug delivery systems across the intestine. Simovic et al. discloses using such particles to study intestinal absorption but uses actual tissue samples. The need for such samples is obviated by the use of the model systems of Ingber et al. and Chen et al. that comprise various cells that together create a model of intestinal tissue that is not obtained from an animal.
Claim(s) 3, 4 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al., Chen et al. and Simovic et al. as applied to claims 1, 2, 6, 9, 12, 14 – 18 and 20 above, and further in view of Huang et al. (Molecular Pharmaceutics, 2014).
Ingber et al., Chen et al. and Simovic et al. are discussed above.
Repeated cycles of analysis with different drug delivery vehicles and the same model system is not explicitly disclosed.
Huang et al. discloses a biomimetic colon tissue composed of Matrigel, Caco-2 cells and THP-1 cells for the in vitro evaluation of the delivery efficacy of nanoparticles - quantum dots (QDs), polyetherimide (PEI)/antisense oligonucleotide (ASO) and galactosylated low molecular weight chitosan (G-LMWC)/ASO nanoparticles - as an in vitro test platform which may be applied to select the most effective nanoparticle for further clinical trials (p 2051, col 2, ¶ 1). The image in the abstract shows a 96 well plate format for high throughput screening. Tissue and cellular uptake of three different nanoparticles in the artificial model (see p 2052, ¶ bridging cols 1 and 2 for details) were similar to that in 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitic mice (abstract). Figure 3 shows images with the biodistribution of the fluorescent QD (quantum dots) in normal or inflamed colon tissue (p 2054, col 2, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the same model system to test the performance of different drug delivery vehicle systems. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because as taught by Huang et al., in vitro model systems can be used to screen the behavior of different nanoparticle systems to select those that are most effective. While Huang et al. uses high throughput screening in a 96-well plate format, for a more involved model system particularly the 3D functional model of Chen et al., the preparation of many parallel systems for concurrent screening may not be practical so the used of the same underlying intestinal tissue model system but with different systems, sufficiently spaced out so that the system can ‘reset’ from the previous trial rather than preparing the substrate and allowing the proper layers of cells to grow on numerous separate intestinal tissue models. Parallel high throughput screening and sequential screening using the same model system have their owns pros and cons but the more involved model system that provides a better mimic of the actual tissue can render sequential testing of samples a suitable option. The generation of images, data analysis such as graphs of the performance of the different systems and rating of the performance of the different systems relative to one another would be obvious to one of ordinary skill in the art to analyze each system individually and collectively to determine the most effective nanoparticle under a particular set of conditions in the model system.
Claim(s) 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al., Chen et al. and Simovic et al. as applied to claims 1, 2, 6, 9, 12, 14 – 18 and 20 above, and further in view of Liu et al. (Biomacromolecules, April 2018).
Ingber et al., Chen et al. and Simovic et al. are discussed above. Simovic et al. also discloses the use of various nanoparticle materials as a major tool in intravenous targeted anticancer therapy and the pharmaceutical industry (¶ bridging cols 1 and 2 on p 1169) but are not generally administered orally (p 1169, col 2, ¶ 2).
The presence of a cargo in the drug delivery vehicle that can edit genetic material and result in the expression of a fluorescent material in the cell is not disclosed.
Liu et al. discloses that various vectors are known for the delivery of gene therapy with various advantages and disadvantages that are discussed on p 2957. The aim was to develop a highly efficient vector for large-sized CRISPR-Cas9 plasmids to realize genome editing in targeted tumor cells (p 2958, col 1, ¶ 2). Plasmids with and without the CDK11 knockout but both comprising green fluorescent protein, GFP, were prepared (p 2958, col 2, ¶ 2) and loaded into nanoparticles with and without targeting groups (p 2958, col 2, ¶ 7). GFP expression in cells after plasmid delivery was used to assess plasmid delivery efficacy (p 2961, col 2, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a gene editing cargo comprising the gene for GFP as disclosed by Liu et al. to study the efficacy of different drug vehicles. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Simovic et al. discloses that fluorescence can be used to track intestinal absorption of nanoparticles and the use of a construct as in Liu et al. will demonstrate if the constructs would have orally availability and deliver the gene editing cargo contained therein to a cell and altered the behavior of that cell, in this case the expression of at least a fluorescent protein, that can serve as a proxy for either gene editing as a therapeutic effect or delivery or other cargoes that do not required gene editing to bring about a therapeutic effect.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 6, 8 9, 11, 12, and 14 – 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 21 and 23 of U.S. Patent No. 9,808,557 in view of Chen et al. (Sci Reports, 2015), Ingber et al. (US 2016/0313306) and Simovic et al. (Nanomed Nanotech Biol Med, 2015) optionally further in view of Huang et al. (Molecular Pharmaceutics, 2014) or Liu et al. (Biomacromolecules, April 2018).
The claims of US’557 recite a tubular silk fibroin material with an inner lumen (claim 1) that can have bioactive materials such as cells associated with the silk fibroin material (claims 8 and 9). Methods of making the tubular silk fibroin material are also claimed (claims 18 – 21).
That the tubular material forms an artificial intestine as required by claim 1 is not claimed.
Chen et al. is discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the silk fibroin tubular composition of US’557 to form the robust bioengineered functional human intestinal epithelium disclosed by Chen et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Chen et al. discloses that silk fibroin based tubes can serve as the base material to form a functional human intestinal epithelium.
The use of the functional human intestinal epithelium comprising a silk fibroin material to screen for screening drug delivery vehicles is not disclosed.
Ingber et al. and Simovic et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the intestinal model systems of US’557 and Chen et al. to carry out studies disclosed by Ingber et al. such as the absorption of materials across the intestinal model system. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because tissue model systems can be used for such studies as taught by Ingber et al. but the 2D and 3D systems disclosed by Chen et al. provide mimicry of intestinal properties including mucus secretion that would reasonably be expected by one of ordinary skill in the art to possibly affect the absorption of the materials being studied. Results obtained from the 3D system would be reasonably expected to be a good mimic of in vivo results without resorting to an in vivo model. A 2D study can be readily carried out in a multi well system to provide initial test results, with the most promising candidates then being tested in the 3D silk fibroin system disclosed by Chen et al. that provides an improved intestinal system compared to the 2D system. A fluorescently labeled version of a drug delivery system to studied absorption in intestinal cells can be used in such methods as Simovic et al. discloses using such particles to study intestinal absorption without the need for actual tissue samples.
The repeated use of the same system to evaluate different drug delivery vehicles is not disclosed.
Huang et al. is discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the same model system to test the performance of different drug delivery vehicle systems. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because as taught by Huang et al., in vitro model systems can be used to screen the behavior of different nanoparticle systems to select those that are most effective. While Huang et al. uses high throughput screening in a 96-well plate format, for a more involved model system particularly the 3D functional model of Chen et al., the preparation of many parallel systems for concurrent screening may not be practical so the used of the same underlying intestinal tissue model system but with different systems, sufficiently spaced out so that the system can ‘reset’ from the previous trial rather than preparing the substrate and allowing the proper layers of cells to grow on numerous separate intestinal tissue models. Parallel high throughput screening and sequential screening using the same model system have their owns pros and cons but the more involved model system that provides a better mimic of the actual tissue can render sequential testing of samples a suitable option. The generation of images, data analysis such as graphs of the performance of the different systems and rating of the performance of the different systems relative to one another would be obvious to one of ordinary skill in the art to analyze each system individually and collectively to determine the most effective nanoparticle under a particular set of conditions in the model system.
The presence of a cargo in the drug delivery vehicle that can edit genetic material and result in the expression of a fluorescent material in the cell is not disclosed.
Liu et al. is discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a gene editing cargo comprising the gene for GFP as disclosed by Liu et al. to study the efficacy of different drug vehicles with a model system as taught by US’557 and Chen et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Simovic et al. discloses that a fluorophore can be used to track intestinal absorption of nanoparticles and the use of a construct as in Liu et al. will demonstrate if the constructs would have orally availability and deliver the gene editing cargo contained therein to a cell and altered the behavior of that cell, in this case the expression of at least a fluorescent protein, that can serve as a proxy for either gene editing as a therapeutic effect or delivery or other cargoes that do not required gene editing to bring about a therapeutic effect.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618