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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Japan on March 5th, 2021. It is noted, however, that applicant has not filed a certified copy of the JP2021-035161 application as required by 37 CFR 1.55. Please file a certified copy in order to perfect priority.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/15/2025 and 09/05/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosures are being considered by the examiner, except where lined through because the NPL source was not placed in the application file.
Claim Objections
There is a typo in Claim 4. Please correct to: “…according to claim…”
Claim Rejections - 35 USC § 112(b)
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 and 3-10 are rejected as indefinite because the step numbering is confusing. Step II-1 and II-2 are both optional (aren’t required to dissemble the molecule using these methods) and mutually exclusive (only would choose one method or the other), but the numbering makes it seem like these steps happen sequentially. Furthermore, Steps II-1 and II-2 would occur prior to the reassembly step (Step I), but are numerically the second stage. Applicant needs to amend claim language to improve clarity. Instead of numerical ordering, Examiner recommends that “a reassembly step” replace “Step I” and “a disassembly step” replace II-1 and “an alternate disassembly step” replace II-2.
Furthermore, claim 1 is rejected because it is unclear whether the claim language means that the subunit of the protein or the protein itself forms the supramolecular structure. For the purposes of claim interpretation, it will be interpreted that the protein has the supramolecular structure.
Claims 1, 4, 5, 7, and 9 are rejected as indefinite because they all refer to a solution and it is confusing whether the applicant intends for these to be the same solution. Examiner recommends amending claim language to refer to them as “a first solution”, a “second solution” etc.
Claim 2 is rejected as indefinite because the specification’s definition of “ferritin” (pg. 1) makes no mention of the iron core, and therefore aligns more closely with apoferritin, which is the ferritin structure without the iron core. Presumably, if the goal is to encapsulate another substance within the core, applicant desires the core to be empty. For the purposes of examination, ferritin will be interpreted to be empty.
Claim 11 is rejected as indefinite because it is unclear if “combination of these” is referring to the different bioactive substances or molecular weights. For the purposes of examination, it will be interpreted to mean combination of the bioactive substance options. Furthermore, “mass average molecular weight” is confusing because it seems to be a blend of “average molecular weight” and “molar mass”. For the purposes of examination, “mass average molecular weight” will be interpreted as “average molecular weight” in Daltons.
Claim Rejections - 35 USC § 112(a)
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 and 3-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ferritin as the supramolecular structure used for encapsulation, does not reasonably provide enablement for every supramolecular structure. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The disclosure does not provide enablement for implementing a micro flow mixer to encapsulate a protein within every supramolecular structure. The specification defines a supramolecular structure as a “high-order structure in which multiple molecules or ions are assembled by interaction” (pg. 4). Many supramolecular structures fall under this definition, including DNA, which uses hydrogen bonds for structural integrity. However, the working examples in the instant application are only directed to ferritin. At the time of filing of the instant application, supramolecular molecules, including DNA based structures, were known for their ability to load cargo and were being explored as protentional therapeutic solutions for things like drug delivery. However, using a flow micro mixer to achieve encapsulation of a bioactive substance with other kinds of supramolecular structures, if even possible, would require significant experimentation. For example, Kim et al, Advanced Materials, 2017, discloses synthesizing protein-encapsulated DNA flowers using rolling circle amplification (pg. 2, right side, line three). In this method, bioactive substances are not encapsulated instantaneously, but rather over time as the DNA flower is built, which does not lend itself to formation within a flow micro mixer. The example of DNA encapsulation is just one embodiment for which “a supramolecular structure” is not enabling. For supramolecular structures that self-assemble on quicker timescale for which implementation of the claimed invention might be possible, such as micelles, the specification has not provided disclosure as to what pH, concentration of subunit, temperature, or flow rate would readily achieve adequate structure formation and encapsulation.
Furthermore, the specification is not enabling for every supramolecular structure to undergo the disassembly steps (Claims 4, 7, and their dependents) prior to the encapsulation step (Claim 1), because it requires that the structure be able to organize reversibly. The disassembly steps of the instant application take a fully formed supramolecular structure, and dissembles it into its subunits in order to load the bioactive substance. This requires that the substance be able to then reassemble with reasonable consistence, and therefore does not apply to supramolecule structures that are obsolete after disassembly. Unlike ferritin which naturally assembles and disassembles based on pH, Examiner could not find evidence to suggest that pH-dependent reversibly assembled DNA cargo-loading structures are commonplace or even exist. For example, Sun et al., American Chemical Society, 2014, teaches a cargo-loaded supramolecular molecule specifically designed to disassemble at a certain pH, but the disassembly is achieved through self-degradation (Figure 1). Reassembly using the claimed invention would not be possible.
The specification has not provided sufficient disclosure to ensure one of ordinary skill in the art could make and use the claimed invention for every supramolecular structure without undue experimentation.
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for siRNAs, DNAs, or oligopeptides, each with a molecular weight of about 1,000 to about 20,000 Daltons, does not reasonably provide enablement for every bioactive substance. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification does not provide a limiting definition of bioactive substance and therefore the definition defers to what is conventional in the art: a substance that has a physiological function. Examiner has found support in the art for ferritin encapsulation of a variety of bioactive substances, such as nutrients or drugs, such that it would be reasonable for one of ordinary skill in the art to implement a variety of substances into ferritin using the method of the instant application, despite the working examples not being drawn to embodiments other than nucleic acids and oligopeptides (Zang et al., Food Science and Nutrition, 2017). However, claims 1-10 make no limitations on the size of the bioactive substance, which must ultimately be constrained by ferritin’s size, as applicant admits on page 12 of the specification. One of ordinary skill in the would not be able to use claimed the invention with bioactive substances that cannot physically fit within ferritin. Therefore, the scope of enablement provided to one skilled in the art is not commensurate with the scope of protection sought by the claim. However, this rejection can be overcome by amending the claim to include size limitations.
Claims 1 and 3-11 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.
While the claims are directed to every supramolecular structure, the disclosure, including the working examples, are only directed to the supramolecular structure ferritin. This genus includes a variety of structurally distinct species, which the working examples are not fully representative of. For example, this genus includes DNA, micelles, and ferritin, but also includes synthetic supramolecular structures. The teachings of the instant disclosure would not have been translatable to all supramolecule structures because their distinct structural elements call for unique considerations for the variables of encapsulation.
MPEP 2163.05 recites: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Because one of ordinary skill in the art would not be able to translate the teachings in the instant disclosure to effectively encapsulate a bioactive substance into every supramolecular structure based on their knowledge and the state of the art at the time of filing, explicit disclosure of those considerations is necessary to show possession. Since the disclosed species of the invention do not constitute the genus, Applicant is not in possession of encapsulating a bioactive substance within every supramolecular structure. However, amending the independent claim to specify that the supramolecular structure is ferritin would overcome this rejection.
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) 1-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over JP 2020556076 in view of Monti et al, Nanomedicine: Nanotechnology, Biology and Medicine, 2019.
Claims 1-3, 6, 9 and 11 are drawn to a method for producing a supramolecular protein, wherein the protein is ferritin, with a bioactive substance encapsulated, wherein the bioactive substance is siRNA, DNA or oligopeptides, using a flow micro mixer. The sum of the flow rate of the subunit of the supramolecular protein and a solution, which is selected from a group including a Tris buffer solution and has a pH of about 5.0 to 9.0, is about 10mL/min or more. Claims 4, 5, 7, 8, and 10 are drawn to two different versions of a disassembly step, both conducted using a flow micro mixer. In one disassembly step, the subunit of the supramolecular protein is obtaining by changing the pH of a solution, wherein the solution has a pH of about 1.5 to about 3.0 or about 10 to 12. In an alternate disassembly step, the subunit of the supramolecular protein is obtained by adding a solvent to the solution containing the protein.
JP 2020556076 teaches a method for reassembling (i.e. refolding) a protein by using a micromixer to mix a denatured (used in the prior art as synonymous with disassembled or dissociated) protein with a buffer (Claim 1). It teaches that this method reduces aggregates (paragraph [0043]). In this method, the buffer flows through a first flow path and the denatured proteins flow through the second flow path (paragraph [0008]), but JP 2020556076 also teaches that the solutions can flow through more than just one or two flow paths [0031]. JP 2020556076 also teaches that the invention can be applied to proteins whose secondary structure is mainly composed of an α – helix. The secondary structure of ferritin is primarily composed of an α – helix (Claim 2). Furthermore, the prior art teaches a total flow rate of the solubilized solution of the denatured protein and buffer is 5mL/min or more (paragraph [0007]) (Claim 3). In one example, JP 2020556076 teaches preparing a denatured protein (i.e. the subunit of the protein in the instant application) by adding a solvent, acetonitrile (paragraph, [0071]) (Claims 7, 8). In another example, the denatured protein is prepared by changing the solution to a basic property with a pH of 9.0 (Claims 4, 5). In JP 2020556076, the solution for forming the reassembled protein is a buffer, wherein the buffer is a Tris buffer solution (paragraph [0025]) (Claims 1 and 9). Lastly, it teaches that the pH of the solution forming the protein having the supramolecular structure is generally between 4.0 and 9.0 (paragraph [0027]) (Claim 6).
JP 2020556076 does not teach encapsulation of a bioactive substance, wherein the bioactive substance is siRNAs, DNAs, or oligopeptides, when the protein is reassembled (Claims 1, 11). It also does not teach that the disassembly steps (i.e. denaturing protein steps) are achieved using the micro mixer (Claim 10).
Monti teaches that ferritin can be reversibly disassembled and reassembled by changing the pH of the reacting solution (pg. 2, right side, third paragraph) and encapsulation of a bioactive substance. Lastly Monti acknowledges that traditional pH assembly/disassembly method can lead to defect formation.
It would have been obvious to one of ordinary skill in the art to combine JP 2020556076 and Monti. Monti demonstrates that ferritin can reversibly assemble or dissemble and that ferritin encapsulation of other molecules is routine in the art. However, Monti also acknowledges that this method is prone to formation of defects. Because ferritin’s qualities make it an ideal carrier for molecules or drug delivery, but there are known issues with traditional encapsulation using pH adjustment, one would have been motivated to determine an optimized method of ferritin encapsulation. JP 2020556076 provides a solution for doing so in the pertinent field of the instant application, namely protein assembly, by using the micro mixer. The instant application claims are drawn to a flow micro mixer, which is defined in the specification as a device that mixes two or more liquids in the space of several tens or several hundreds of microns, which JP 2020556076 reads on (pg. 5). Although JP 2020556076 only explicitly teaches the reassembly step of the instant application, since the reaction is reversible as taught by Monti, it would have obvious to also apply this technique to also accomplish the disassembly to achieve streamlined efficiency and scalability. In fact, JP 2020556076 explicitly states: “…the present invention can be used alone, but the production amount can be increased by connecting a plurality of apparatuses in series or in parallel.” The plurality of micro mixer applications used to achieve ferritin encapsulation reads directly on the inventive concept of the instant application.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over JP 2020556076 and Monti, as applied to claims 1-10, and in further view of Li et al., Biomaterials, 2016.
Claim 11 is drawn to the encapsulated bioactive substance, wherein it is siRNAs, DNAs, or oligopeptides, or a combination of these substances, each having a mass average molecular weight of about 1,000-20,000.
JP 2020556076 and Monti do not teach a bioactive substance, wherein it is siRNAs, DNAs, or oligopeptides, each having a mass average molecular weight of about 1,000-20,000.
Li teaches ferritin encapsulation of siRNA molecules with 20-24 nucleotides.
It would have been obvious to combine Li with Monti and JP 2020556076 in order to effectively implement the bioactive substance of interest into ferritin using a micro mixer. Li teaches that it is possible to encapsulate siRNA in ferritin, albeit by a different method than claimed by the instant application. Because Li shows it was possible to encapsulate siRNA into ferritin, and JP 2020556076 teaches protein reassembly using a micro mixer, it would have been obvious to combine these sources if Applicant was attempting to encapsulate siRNA into ferritin using a micro mixer, since these techniques were known in the pertinent field prior to the time of filing.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE C BUCCINI whose telephone number is (571)272-1352. The examiner can normally be reached M-F 7:30-5 EST.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675