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 .
Application Status
This action is written in response to the claims filed on 9/7/2023. Claims 1-20 are currently under examination on the merits.
Priority
This application claims foreign priority to application to EP21162290.7, filed on 3/12/2021. This priority is acknowledged in the Certified Copy of Foreign Priority submitted with the instant application on 9/7/2023.
Claim Rejections – Improper Markush Groups
Claims 1, 7, and 18 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 1, 7, and 18 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Regarding claim 1, applicant claims a photoresponsive organic particle, wherein the photoresponsive organic particle is selected from the group consisting of a polymer-based particle, a protein-based particle, a lipid-based particle, and a combination thereof. The listed particles of claim 1 are structurally distinct as a polymer, protein, and lipid share no common structure.
Regarding claim 7, applicant claims a polymer-based particle which share no structural similarities. Even though the particles may share a polymer base as a feature, the listed particles such as poly(DL-lactic-co-glycolic acid), polyvinyl alcohol, cellulose, gelatine, collagen, silk, etc. do have share a single structural similarity as an alcohol has a different structure compared to an acid, cellulose, or silk.
Regarding claim 18, applicant claims a compound which coats the photoresponsive organic particle. The listed compounds include albumin, polyethylene glycol, gelatin, polyethylene glycol, dextran, silica, a cationic lipid, etc., which share no structural similarities.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
Written Description
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.
Regarding the breadth of claim 1, applicant claims an in vivo or ex vivo method of delivering a cargo into a cell, the method comprising contacting a cell with one or more photoresponsive organic particles and a cargo. Based off the claim language, a photoresponsive organic particle can be any photoresponsive organic particle provided it is polymer, protein, or lipid-based, as well as any cargo known in the art to be delivered by electro- or photoporation.
Regarding the number of species that are described by complete structure or that have been reduced to practice, applicant provides working examples for at least one protein, lipid, and polymer-based photoresponsive organic particles including polydopamine-BSA nanoparticles (PD-BSA NPs), polyvinyl alcohol (PVA)-coated polypyrrole NPs, human serum albumin ICG NPs, and trypan blue-loaded lipid NPs. Applicant does acknowledge that there were additional experiments carried out with different polymer, protein, and lipid-based nanoparticles, and/or a combination there of, this information was not added to the specification or instant application.
Claim 1 recites a method in which applicant presents photoporation of polymer based nanoparticles using laser-induced electromagnetic radiation and a method of delivery for lipid and protein-based nanoparticles through the generation of vapor nanobubbles. Mechanistically, vapor nanobubble photoporation and traditional photoporation differ as disclosed in Ramon et al. (Vapor nanobubble-mediated photoporation constitutes a versatile intracellular delivery technology, Current Opinion in Colloid & Interface Science, Volume 54, all pages, 2021). Applicant does not provide evidence for protein-based particle delivery of a cargo, only that human serum albumin ICG nanoparticles demonstrate the ability to form vapor nanobubbles upon excitation by a pulsed laser (see instant specification).
As disclosed by Ramon et al. , vapor nanobubbles can emerge from laser-irradiated photothermal nanomaterials in a hydrated environment, and when they collapse, induce transient membrane pores through which exogenous effector molecules can be delivered into the cells (see abstract and introduction). Mitragotri et al. (Organic nanoparticles for drug delivery and imaging, MRS Bulletin, Volume 39, Issue 3, all pages, 2014) discloses a large number of organic nanoparticles have been developed to encapsulate and delivery therapeutic and imaging agents. Selection of nanoparticles is important for delivering drugs in a sustained manner (see introduction). Furthermore, one skilled in the art would determine that structurally, polymer, lipid, and protein based particles share no common structure, and to apply a method to such numerous types of particles would be inconsistent.
Given that the specification does not provide guidance on protein-based particles used to deliver a cargo (only that these protein-based particles generated vapor nanobubbles), presents inconsistencies in the mechanism of delivery (laser-photoporation without vapor nanobubbles and vapor nanobubbles), and with prior art describing that more research is needed to investigate to systematically demonstrate actual vapor nanobubble formation rather than a phenomenon based on applied laser conditions (Ramon et al., see conclusion), as well as the large number of nanoparticles that one can select from, it is determined that the specification does not describe a representative number of species within the claimed genus. One skilled in the art would not be able to extrapolate the results in the specification and prior art to determine that the instant claim recites species representative of the entire broad genus of organic photoresponsive particles. Subsequent claims 2-20 are dependent on claim 1.
Taken together, it is clear the applicant does not have possession of all embodiments of the invention as claimed. In view of the foregoing, it is concluded that the instant specification fails to adequately describe the claimed method in such a way as to reasonably convey to one skilled in the relevant art that the instant co-inventors had possession of the claimed invention at the time the application was filed.
Claim Interpretation
In the instant application, claim 1 recites two alternatives, being an in vitro or ex vivo method for delivering cargo into a cell where in the first embodiment, the cargo is not bound to one or more photoresponsive organic particles, and in the second embodiment, the cargo is bound to one or more photoresponsive organic particles. Currently, the first embodiment is under examination.
Furthermore, regarding claim 1, applicant recites any polymer, protein, and lipid-based photoresponsive organic particle. However, applicant does not define whether the entire composition of the particle needs to be organic. The use of an inorganic nanoparticle core coated in an organic photoresponsive particle shell can be broadly interpreted as a photoresponsive organic particle.
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 1-8 and 11-13, 16-18, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (Surface Functionalization with Polyethylene Glycol and Polyethyleneimine Improves the Performance of Graphene-Based Materials for Safe and Efficient Intracellular Delivery by Laser-Induced Photoporation, Internation Journal of Molecular Sciences, Volume 21, Issue 4, all pages, 2/24/2020).
Regarding claim 1, Liu teaches an in vitro or ex vivo method of delivering extrinsic molecules, or a cargo, into living cells through nanoparticle (graphene quantum dots (CQD)- and reduced graphene oxide (rGO)) mediated laser-induced photoporation (see abstract). Liu teaches rGOs functionalized with polyethylene glycol (PEG) and polyethyleneimine (PEI) are suitable for photoporation using a near-infrared laser to allow cell permeability (see introduction). Furthermore, Liu teaches a method where FD10 is delivered into cells, first by incubating cells with nanoparticles, absent of the cargo, washing away unbound nanoparticles, adding fresh cell medium supplemented with the cargo, and then applying laser treatment (see section 2.2)
Regarding claim 2, Liu teaches that prior to functionalization with PEG or PEI, the average size of rGO was around 348 ± 104 nm in size. Post functionalization, rGO nanoparticles ranged from 207 ± 60 nm and 282 ± 87 nm, respectively (see section 2.1 and Fig. 2G).
Regarding claim 3, Liu teaches where the cargo can range from smaller nucleic acids such as siRNA, as well as larger cargos representative of proteins and larger nucleic acids like mRNA (see section 2.4).
Regarding claims 4, 5, and 6 Liu teaches where the photoresponsive organic particle is polymer-based PEI (see introduction).
Regarding claims 7 and 8, Liu discloses the functionalization of GQD and rGO nanoparticles on the surface with polyethylene glycol (PEG) and polyethyleneimine (PEI) (see section 2.1, paragraph 2, and Fig. 2).
Regarding claim 11, Liu discloses delivery of a photoresponsive organic particle (rGO) into HeLa and Jurkat (See Fig. 3 and 4).
Regarding claim 12, Liu discloses the use of Jurkat cells, which is an art recognized human T-lymphocyte cell line (see Fig. 4).
Regarding claim 13, Liu teaches where in the presence of rGO-PEI, laser treatment markedly increased cell transfection efficiency, reaching 80% with cell viability of 80% for a 1.28 x 109 nsp/mL and a laser fluence of 0.89 J/cm2 (see section 2.5).
Regarding claim 16, Liu teaches
Regarding claim 17, Liu teaches the evaluation of their method includes FITC-dextran of 10 kDa, which is representative of small nucleic acids such as siRNAs and FITC-dextran of 70 kDa and 500 kDa, representative of proteins and larger nucleic acids like mRNA (see section 2.4).
Regarding claim 18, Liu teaches the modification of graphene-based nanoparticles with PEG and especially PEI to provide better colloidal stability in cell medium, resulting in more uniform transfection and overall increased efficiency (see abstract).
Regarding claim 20, Liu teaches wherein the method of delivering cargo is delivered in Jurkat cells (see Fig. 4). Jurkat cells are human T cell leukemia cell line that is commonly used as a model for hard-to-transfect primary T cells (see section 2.3).
Thus, Liu clearly anticipates claims 1-9, 11-13, 17-18, and 20.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 9, 10, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Surface Functionalization with Polyethylene Glycol and Polyethyleneimine Improves the Performance of Graphene-Based Materials for Safe and Efficient Intracellular Delivery by Laser-Induced Photoporation, Internation Journal of Molecular Sciences, Volume 21, Issue 4, all pages, 2/24/2020), in view of Xiong et al. (Polydopamine-Based Nanocarriers for Photosensitizer Delivery, Frontiers in Chemistry, Volume 7, All pages, 7/11/2019).
Regarding claims 9, 10, and 14-16, the method according to claim 1, which recites an in vitro or ex vivo method for delivering a cargo into a cell, is described above in Liu.
Regarding claim 15, Liu teaches wherein the largest distance between two points of the one or more photoresponsive organic particles is about 348 nm, as described above.
Regarding claim 16, Liu teaches the method of delivering cargo is delivered in Jurkat cells (see Fig. 4). Furthermore, Liu teaches laser induced photoporation (see section 2.5), as described above.
Liu does not teach where the photoresponsive organic particle is biodegradable (claim 9), is polydopamine (claim 10), or wherein delivery of a cargo to a cell is used in a method of therapy (claim 14).
Regarding claims 9 and 10, Xiong teaches where a melanin-like biopolymer, polydopamine (PDA), is used to make PDA-based nanocarriers to overcome the inherent shortcomings of free photosensitizer (PS) in photodynamic therapy (PDT) (see abstract), as polydopamine has prominent properties, including favorable biocompatibility, easy preparation, and versatile functionality (see introduction). Furthermore, bio-inspired PDA possess excellent biocompatibility and biodegradation, which provide a prerequisite for biological application (introduction).
Regarding claim 14, Xiong teaches where PDT can be used as an alternative emerging treatment for cancer therapies (see introduction). Xiong discloses that compared with existing treatment modalities, PDT possess numerous incomparable superiorities including non-/minimal invasiveness, low side effects, and controllability (see introduction). Xiong teaches where modified graphene with PDA reacted with nucleophilic amine groups of folic acid-C60 to form C60-PDA-graphene nanohybrids which exhibited synergistic PDT effect against Hela cancer cells (see section titled ‘chemical conjugation strategy’). Xiong also teaches where another nanoparticle was developed to achieve PDT combination therapy of tumors with Ce6 covalently conjugated onto the surface of PDA. PDA-Ce6 nanoparticles exhibited higher photo-stability and PDT efficacy. Under the irradiation of two different lasers (670 and 808 nm), the PDA-Ce6 nanoparticles demonstrated potent antitumor efficacy both in vitro and in vivo (see section titled ‘chemical conjugation strategy’).-
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to combine the teachings above in order to create an in vitro or ex vivo method for delivering a cargo into a cell, wherein the cell is contacted with one or more photoresponsive organic particles, and where said photoresponsive organic particle is a polydopamine particle. It would have been obvious to combine prior art elements according to known methods to yield predictable results as Xiong teaches PDA-Ce6 nanoparticles have demonstrated potent antitumor efficacy both in vitro and in vivo. Liu teaches a method of delivering cargo to a cell using photoporation and a reduced oxide graphene nanoparticle to target hard-to-transfect primary cells (see introduction of Liu). Xiong teaches where polydopamine can help overcome the issues of photosensitizer molecules which include low light stability, fast body clearance, and poor water solubility (see introduction of Xiong). Xiong teaches many active groups in PDA are able to react with a variety of drug molecules and that PDA is an excellent coating material that can easily form a multifunctional core-shell nanostructure through facile dip coating of nanoparticles in an aqueous solution of dopamine (see introduction of Xiong). Furthermore, Xiong teaches PDA possess excellent biocompatibility and biodegradation, which provides a prerequisite for biological application (see introduction of Xiong).
One would be motivated to combine the teachings of these prior arts in order to use photoporation with a polydopamine coated nanoparticle in order to deliver a cargo to a cell, especially as a method of therapy, with low side effects and high controllability. Using biodegradable PDA particles for photoporation avoids the drug tolerance, non-specificity, and unavoidable side effects of current cancer therapies (see introduction of Xiong).
In view of the foregoing, claims 10, 14, 15 and 16 are rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Surface Functionalization with Polyethylene Glycol and Polyethyleneimine Improves the Performance of Graphene-Based Materials for Safe and Efficient Intracellular Delivery by Laser-Induced Photoporation, Internation Journal of Molecular Sciences, Volume 21, Issue 4, all pages, 2/24/2020), in view of Xiong et al. (Polydopamine-Based Nanocarriers for Photosensitizer Delivery, Frontiers in Chemistry, Volume 7, All pages, 7/11/2019) and Sy et al. (Morphological Diversity, Protein Adsorption, and Cellular Uptake of Polydopamine-Coated Gold Nanoparticles, Langmuir, Volume 34, Issue 46, Pgs. 14033-14045, 10/25/2018).
With regards to claim 19, Liu and Xiong teach the method of delivering a cargo using one or more photoresponsive organic particles, wherein one of the organic particles is polydopamine.
Liu and Xiong does not teach where the photoresponsive organic particle is a polydopamine coated with albumin.
Sy teaches polydopamine coated nanoparticles and there interactions with serum proteins (albumin and hemoglobin) and mammalian cells, wherein serum stabilized gold-polydopamine nanoparticles enter Neuro-2a and HeLa cancer cells more abundantly than those prepared without (see abstract). Sy concludes that gold-coated polydopamine nanoparticles in serum-containing medium are more stable than in serum-free medium, only becoming slightly larger than their original, noncoated forms (see conclusion). Serum-stabilized polydopamine nanoparticles can more effectively enter the cell and preserve their original nanoparticle morphologies inside the cell (see conclusion).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to combine the teachings above to arrive at a method of delivering a cargo in a cell using polydopamine photoresponsive organic particles, wherein the particles are coated in albumin. One would expect a reasonable expectation of success and be motivated to do so as Sy has shown gold-polydopamine nanoparticles interacts with serums, such as albumin, to allow nanoparticles to more effectively enter the cell and preserve their original nanoparticle morphologies once inside (see conclusion of Sy). One would be further motivated to use the organic graphene based nanoparticles conjugated with polydopamine as taught by Liu and Xiong as polydopamine increases biocompatibility and hydrophilicity (see section titled ‘chemical conjugation strategy’ in Xiong) and graphene, which has better physiochemical properties compared to gold (see introduction of Liu).
In view of the foregoing, claim 19 is rejected under 35 U.S.C. 103 as being prima facie obvious before the effective filing date.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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