This office action supersedes the one mailed 7/28/2026 and was necessitated by improper citation of prior art.
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 .
Information Disclosure Statement
The submitted information disclosure statement (IDS) were filed on 06/25/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1-6 and 8-20 are rejected under 35 U.S.C. 101 because the claims are directed to a system for assessing lipid membrane-associated molecules, comprising a molecular scaffold having a tubular shape with open terminal ends; these claims are broad enough to read on the human digestive system: a tube with two openings one or more molecules, each molecule of the one or more molecules reversibly tethered to the molecular scaffold within a lumen of the molecular scaffold. Especially, claims 1-12 describe human cell membranes that line digestive track and a plurality of hydrophobic seeds tethered to the molecular scaffold within a lumen of the molecular scaffold, where fat is absorbed via encapsulation by micelles that move it to the microvilli, then fatty acid binding proteins that bind is tethered.
Claim Rejections - 35 USC § 112
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.
Claims 1-20 are 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.
Claims 1-20 are rejected under 35 U.S.C. 112(a) because as containing 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(s), at the time the application was filed, had possession of the claimed invention. The instant claims are directed to a system for assessing lipid membrane-associated molecules by tubular shape with open terminal ends molecular scaffolds having
one or more molecules reversibly tethered and a plurality of hydrophobic seeds tethered to a lumen. The system is defined only by their components (e. g., hydrophobic seeds interacting moiety), thus the system is based on the use of hydrophobic seeds that are defined only by the functional characteristics of its components.
The Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, Paragraph 1, “Written Description” Requirement, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole cover, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing. This should include the following considerations: (1) actual reduction to practice, (2) disclosure of drawings or structural chemical formulas, (3) sufficient relevant identifying characteristics such as complete structure, partial structure, physical and/or chemical properties and functional characteristics when coupled with a known or disclosed correlation between function and structure, (4) method of making the claimed invention, (5) level of skill and knowledge in the art and (6) predictability of the art. For each claim drawn to a single embodiment or species, each of these factors is to be considered with regard to that embodiment or species. For each claim drawn to a genus, each of these factors is to be considered to determine whether there is disclosure of a representative number of species that would lead one skilled in the art to conclude that applicant was in possession of the claimed invention. Where skill and knowledge in the art is high adequate written description would require fewer species to be disclosed than in an art where little is known; further, more species would need to be disclosed to provide adequate written description for a highly variable genus.
First, what do the claims as a whole cover?
Claims 1-20 are directed to the system the plurality of hydrophobic seeds tethered to the molecular scaffold are patterned in a manner such that it can allow a molecule to pass thereby via a lipid membrane of a liposome formed by the plurality of hydrophobic seeds. Especially Claim 7, clearly defines the molecular scaffold comprises DNA origami. And each molecular scaffold is conjoined with another molecular in an end-to-end manner.
Second, how does the scope of the claims compare to the scope of the disclosure?
The claims are similar in scope to the disclosure.
Third, the factors need to be considered.
(1) What was actually reduced to practice?
The functional characteristics of the scaffolds are disclosed, of a DNA origami barrel, . S. F. J. Wickham, et al., Nat Commun. 2020, 11 (1 ):5768.
(2) Is there disclosure of drawings or structural chemical formulas?
The tubular with opened end structure is given for the scaffold that was reduced to practice. No chemical structure is provided for each scaffold, each scaffold is defined by with lumen of the scaffold that one or more molecules and hydrophobic seeds interact. There is no disclosure of how any particular structure gives rise to the function of assessing lipid membrane-associated molecules or how scaffolds are connected to each other.
(3) Are there sufficient relevant identifying characteristics disclosed?
The only identifying characteristics shown are the composition molecular scaffolds with one or more molecules and hydrophobic seeds tethered. The functional characteristics of the scaffolds are disclosed, of a DNA origami barrel, . S. F. J. Wickham, et al., Nat Commun. 2020, 11 (1 ):5768, but they are not coupled with a known or disclosed correlation between function and structure. The specification discloses the structure of the scaffold molecules with which the one or more molecules and hydrophobic seeds tethered but nothing about how they are tethered.
(4) Is there at least one method of making the claimed invention disclosed?
Given the identity of the molecular scaffolds having one or more molecules reversibly tethered and a plurality of hydrophobic seeds tethered to a lumen, one of skill in the art could easily tether one or more molecules and hydrophobic seeds to the scaffold since only basic organic chemical synthesis skills (3) would be needed.
(5) What is the level of skill in the art and what knowledge is present in the art?
The level of skill in the art of 3D DNA-barrel pegboard and elucidation of information from the crystal structure is high, about that of a PhD scientist with several years’ experience with molecular biology, DNA structures and digital technologies.
Wickham et al. and Maingi et al. teach the importance of preparing 3D DNA scaffolds and Digital nanoreactors for control over absolute stoichiometry and spatiotemporal behavior of receptors within lipid bilayers.
(6) What is the level of predictability of the art?
The level of predictability in this art is very low since, until the scaffold is examined, there is no information upon which to base a prediction of what molecule might be suitable as, say, a region interacting moiety.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species which would lead one skilled in the art to conclude that applicant was in possession of the claimed invention.
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 non-obviousness.
Claim(s) 1-20 is/are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Wickham et al. (Wickham et al., Complex multicomponent patterns rendered on a 3D DNA-barrel pegboard. Nature Communications. 11:5768. 2020), in view of Maingi et al. (Maingi et al., Digital nanoreactors for control over absolute stoichiometry and spatiotemporal behavior of receptors within lipid bilayers. bioRxiv preprint doi: https://doi.org/10.1101/2022.10.04.509789. this version posted October 7, 2022).
Claim(s) 1-3, 5-7, 9-14, and 18-20,
Wickham et al. teach coaxially stacked dimer of DNA-origami barrels. Barrels consist of three layers of circular double helices arranged with honeycomb-lattice spacing, (Fig. 1, pg. 4), which form a tubular shape with open terminal ends and the system of claim 1 further comprising two or more molecular scaffolds, wherein each molecular scaffold has a tubular shape and is conjoined with another molecular scaffold in an end-to-end manner such that the lumen of each molecular scaffold is conjoined.
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This demonstrates that barrels can be used to scaffold large lipid nanotubes within their interior cavity. (pg. 7, left col., 3rd par.). Lipid nanotubes can be templated inside and scaffolding of large lipid nanodiscs inside of DNA-origami barrels. (pg. 7, left par., last par.).
Wickham et al. teach molecular scaffolds, but do not teach the applications of the system, and additional development on the scaffold.
Maingi et al. teach digital nanoreactors that can control interactions between lipid-bound molecular receptors along three key dimensions: stoichiometric, spatial, and temporal. Each nanoreactor is based on a DNA origami ring, which both templates the synthesis of a liposome and provides tethering sites for DNA-based receptors. (pg. 1, lines 12-16). A hybrid DNA-lipid
instrument, a DNA Origami-templated Liposome (DOL), which provides a generic assay platform to orchestrate and measure the interactions between reacting species in a single lipid bilayer. (pg. 3, lines 100-103). Liposomes of well-defined size can be templated within DNA origami cages, with discrete numbers (e.g. two or four) of DNA receptors at precise distances (e.g. 45 nm) along the circumference of a liposome-filled cage to create a well-defined initial state (Figure 1A and B, Step 1). Cholesterol on the DNA receptors bound them to the liposome, and tethers between the receptors and the cage served to protect them and keep them from reacting until desired, (pg. 3, lines 108-114), and cholesterol is the hydrophobic domain. Membrane-anchored DNA complexes, which are called DNA receptors, as models for membrane proteins Oligonucleotide conjugated lipid molecules are site-specifically placed onto the interior surface of the 90 nm DNA-origami nanotube, which nucleate the formation of an enclosed lipid nanotube (Fig. 3g and Supplementary Figs. 80–82), so oligonucleotides can be hydrophobic seeds tethered to the lumen of the nanotube. Receptors are tethered and cholesterol modifications served as seeds for the formation of a liposome on each ring, creating DOL. (pg. 4, lines 148-153). See Fig. 1: Step A: Linkers are in the lumen; Step B: cholesterol (hydrophobic) (red ovals) tethered to the ring.
Intermediate states formed by either receptor individually with the reporter complex (i.e. states Ai and Bi in Supplementary Figure S2) are thermodynamically less favorable than the reactants, and thus sequester very little of either receptor.68 Further, formation of intermediate states, which are kinetically reversible. (pg. 5, line 199-203), so they can be untethered.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to prepare molecular scaffolds having tubular shape with open terminal ends, conjoined with several others, in an end to end, taught by Wickham et al., and the scaffold comprising molecules tethered to its lumen, and some parts or some molecules can be hydrophobic, comprising a liposome formed within the lumen of the scaffold, with receptors tethered to lipid membranes, they can be reversible taught by Maingi et al. and since they have shown it would be feasible to do so.
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With regard to claim 4,
Wickham et al. teach Fig. 1 Schematic of coaxially stacked dimer of DNA-origami barrels, 1d Zoom-in detail of the staple strands that mediate coaxial stacking between monomers, rendered as orange pipes. Staple-strand extensions (plugs) on the top of the interface hybridize to connector strands (dark orange), leaving single-stranded regions (sockets), which plugs from the second barrel hybridize to. In zoom-out view a, b two orthogonal sets of connector strands are rendered in yellow and orange. (pg. 4), where molecular scaffold conjoined such that gaps between the conjoined molecular scaffold are mitigated or absent.
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With regard to claim 8,
Maingi et al. teach about Inter-DOL receptor interactions. The main purpose of the DOL platform is to control and quantify single-molecule isolated interactions between receptors on the same lipid bilayer surface (intra-DOL) with minimal cross-talk among the DOLs in bulk solution. (pg. 6, lines 280-283). Liposomes of well-defined size can be templated within DNA origami cages, with discrete numbers (e.g. two or four) of DNA receptors at precise distances (e.g. 45 nm) along the circumference of a liposome-filled cage to create a well-defined initial state (Figure 1A and B, Step 1). Cholesterol on the DNA receptors bound them to the liposome, and tethers between the receptors and the cage served to protect them and keep them from reacting until desired. (pg. 3, lines 108-114).
With regard to claims 14-17,
Maingi et al. teach receptors were detethered (Step 2) by adding release strands complementary to the linkers; domains T* and S* provided toeholds for this reaction. Released receptors diffuse freely within the bilayer but do not interact. (Fig. 1, lines 916-918). Intermediate states formed by either receptor individually with the reporter complex (i.e. states Ai and Bi in Supplementary Figure S2) are thermodynamically less favorable than the reactants, and thus sequester very little of either receptor.68 Further, formation of intermediate states, which are kinetically reversible, does not result in dequenching of the fluorophore (Figure 4 discussed). Successful dequenching of the reporter complex (and resulting fluorescence) is only possible when both the receptors are present to cooperatively displace the BHQ-containing top strand. P1 and P2 domains of the ternary complex remain unpaired, acting as flexible hinges. (pg. 5, lines 100-207).
Figure 4: Determining tethering efficiency. Tethering efficiency of receptors to the DOL1A1B platform was determined by comparing the extent of receptor reaction when both receptors were released and reacted normally within the DOL, and when one or the other receptor was reacted with a receptor complex in the presence of a stimulant strand in solution. (A) shows a modified logic circuit in which only receptor Receptor A was released; a stimulant strand (anchor B without a cholesterol modification) was supplied in excess to make up for any missing Receptor B. A reciprocal experiment using anchor A without a cholesterol modification is not shown. (B) Fluorescence curves (as in Figure 2) where either both the receptors were released with a normal reporter complex (cyan), only Receptor A was released (red), or only Receptor B was released (blue). Analogous curves are shown for a ring-only system (without a liposome), in which both the receptors were released (grey), only Receptor A was released (orange, two repeats averaged), or only Receptor B was released (green, two repeats averaged). As in Figure 2, reporter complexes were quenched after ~36 hours with an excess of both stimulant strands, or whichever was missing. (pg. 23).
Conclusion
No claim is allowed.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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