Notice of Pre-AIA or AIA Status
The present application, filed on or after July 18, 2023, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 07/18/2023 in the matter of Application N° 18/261,891. Said documents are entered on the record. The Examiner further acknowledges the following:
Thus, claims 1-15, and 19-23, represent all claims currently under consideration.
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.
Claims 1-15 and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (Intradermal delivery of Stat3 siRNA to treat melanoma via dissolving microneedles), in view of Troiano et al. (US8420123B2) and Tan et al. (WO2020050779A1), and Wang et al. (Upconversion Nanoparticle Powered Microneedle Patches for Transdermal Delivery of siRNA).
Regarding claims 1,2, 3, 4, 5, 6, 15, 19, and 23, Pan et al. discloses a topical microneedle patch that dissolves to deliver STAT3 siRNA intradermally to treat melanoma (a skin ailment or disorder). The dissolvable microneedle patch consists of a substrate portion made of dextran 40, polyvinylpyrrolidone 17, and hyaluronic acid (i.e. biocompatible materials); and a number of microneedle structures that extend from the substrate portion. Each microneedle structure (height=650 µm) consists of a base portion made of dextran 40, polyvinylpyrrolidone 17, and hyaluronic acid; the tip portion is made of a nanoplex (diameter=135.1±5.2 nm; potential =34.6±2.2mV) that encapsulates STAT3 siRNA through attractive electrostatic interactions (See pgs. 1, 2, 6, and 8)
Pan et al. don’t reveal that the nanoplex will be made from a positively charged biopolymer that combines siRNA with a cell targeting moiety. To increase the therapeutic drug’s effectiveness, it is typical in the art to combine a cell targeting moiety with the therapeutic agent. In order to improve the treatment outcome, it is also common practice in the art to investigate better alternative carriers for a therapeutic agent, such as a positively charged biopolymer that is both biodegradable and biocompatible. In this sense, a person of ordinary skill in the art could have taken into consideration a nanoplex made from a positively charged biopolymer that includes a cell targeting moiety in addition to the siRNA.
However, Pan et al. do not teach a heterobifunctional polymer comprising a first set of functional groups that are positively charged and a second set of functional groups that are negatively charged in an aqueous environment; etc.
Regarding claims 7, and 10, a heterobifunctional polymer comprising a first set of functional groups that are positively charged and a second set of functional groups that are negatively charged in an aqueous environment. This description is pointing to a zwitterionic heterobifunctional polymer. A heterobifunctional polymer is a polymer that has two different types of functional groups. The first set of functional groups becomes positively charged in water (e.g. amines, and ammonia). The second set of functional groups becomes negatively charger in water (e.g., carboxylates). The polymer is classified as a zwitterionic polymer.
Regarding claims 7, and 10, Troiano et al. disclose amphiphilic polymers having cationic and/or anionic functional groups, including zwitterionic (inner salt) polymers, acrylic copolymers with quaternary ammonium groups, and negatively charged substituents (e.g., phosphate, carboxylate), as well as therapeutic agents bearing negatively charged functional groups (e.g., phosphate esters) that are combined with or associated with polymeric systems for delivery. It would have been obvious to one of ordinary skill in the art to covalently conjugate such negatively charged molecules to the negatively charged functional groups of a heterobifunctional polymer, thereby reducing the number of negatively charged groups and shifting the net charge of the polymer to be positively charged, as claimed.
Troiano et al. disclose polymeric delivery systems suitable for solid dosage forms and nanoparticle based therapeutic delivery, which are routinely adapted for dissolvable microneedle patches as a known, predictable delivery format for polymeric drug delivery systems. The use of a dissolvable microneedle patch represents a known delivery format and does not impart patentable distinction over the polymer compositions disclosed by Troiano et al. (See MPEP 2144.04, “obvious use of a known technique”). “Positively charged biopolymer formed from a heterobifunctional polymer comprising a first set of positively charged functional groups and a second set of negatively charged functional groups in an aqueous environment”. Troiano et al. expressly disclose amphiphilic compounds wherein the polar portion may have a formal positive charge, a formal negative charge, or both, including zwitterion or inner salts. Acrylic polymers and copolymers comprising quaternary ammonium groups (positively charged). Polymers comprising negatively charged groups, including phosphate and carboxylate substituents. Thus, Troiano et al. disclose a heterobifunctional polymer (polyampholyte) comprising both cationic and anionic functional groups that are ionized in aqueous environments, as claimed. Troiano et al. disclose, therapeutic agents combined with polymeric systems. Therapeutic agents bearing reactive negatively charged functional groups, including phosphate esters (e.g., etoposide phosphate) and carboxylate-substituted aromatic rings. Such molecules are well known to be conjugated to polymers via amide, ester, or phosphate-based linkages, particularly in polymer-drug conjugate systems. Wherein the molecule is conjugated by a functional group that forms a bond with the second set of functional groups so as to reduce the number of the second functional groups, thereby providing the positively charged biopolymer. Troiano et al. disclose polymers containing negatively charged functional groups. Molecules containing phosphate, carboxylate or thiocarboxylate substituents. Quaternary ammonium-containing polymers used in solid dosage forms (See pg. 34, column 10, lines 35-45, pg. 35, column 12, lines 29-32, pg. 32, column 6, line 47, pg. 31, column 3, lines 27-34, pg. 32 lines 33-36, pg. 41, column 23, lines 62-66, pg. 41, column 24, line 7, pg. 41, column).
It would have been obvious to one of ordinary skill in the art to covalently conjugate a molecule bearing a phosphate or carboxylate functional group to the negatively charged functional groups of a polymer, thereby neutralizing or consuming a portion of the anionic groups, and shifting the net charge balance of the polymer toward positive charge, resulting in a positively charged biopolymer. This modification represents routine optimization of polymer charge properties to improve interaction with biological tissues, loading efficiency or delivery performance, and would have yielded predictable results (MPEP 2144, 2143).
One of ordinary skill in the art would have been motivated to perform such conjugation in in view of Troiano et al.’s teachings to control polymer charge density, improve stability, delivery efficiency, and bioavailability, optimize polymer-therapeutic interactions, Tailor electrostatic interactions with biological membranes or tissues. Charge modulation of amphiphilic and zwitterionic polymers via conjugation is a well-established design principle in polymeric drug delivery systems.
Therefore, claim 7 is obvious over Troiano et al. as the reference teaches or suggests each claimed limitation, and any differences amount to routine chemical modification and predictable optimization that would have been obvious to one of ordinary skill in the art at the time of the invention.
However, Troiano et al. do not teach, the dissolvable microneedle patch, wherein the heterobifunctional polymer is selected from one or more of gelatin, collagen, silk fibroin, elastin and H2N-PEG-CO2H.
Regarding claims 8, 9, 11, and 12, Tan et al. teach a sustained release composition that consists of an active agent that, when in an aqueous environment, has either a positive or a negative charge, and a crosslinked hydrogel that is tuned to have an overall charge that promotes electrostatic interaction between the crosslinked hydrogel and the active agent. The crosslinked hydrogel is made of a heterobifunctional polymer, such as gelatin, and a heterobifunctional crosslinking agent, such as tyramine or hydroxyphenyl propionic acid. Gelatin is frequently utilized in the pharmaceutical and culinary sectors. Gelatin’s biocompatibility, biodegradability, and ease of processing are widely established. Phenolic molecules with amine groups are selected from one or more of 4-hydroxybenzylamine, dopamine, and tyramine (See abstract, and pg. 4, paragraph 30, and claim 9).
Regarding claim 10, Tan et al. disclose wherein at least one functional group from one or more amide and amino groups is appropriate for forming a connection with the second set of functional groups (See claim 8 B).
Regarding claims 13, and 14, Tan et al. teach wherein the siRNA is selected from one or more of 5’-AACAAGACCUUCGACUCUUCC-3’ (See claim 3).
Regarding claim 20, Tan et al. teach use of a sustained release composition in the preparation of a medication for the treatment and/or prevention of scarring, where the active ingredient is an anti-scarring agent (e.g. the anti-scarring agent is a siRNA, such as 5’AACAAGACCUUCGACUCUUCC-3’) optionally, where the use relates to the treatment and/or prevention of scarring in a subject who has undergone surgery (e.g., glaucoma eye surgery) (See claim 14).
However, Tan et al. do not teach wherein the skin condition or disorder is hypertrophic scarring.
Regarding claim 21, Wang et al. disclose wherein the cell internalization of UCNPs@mSiO2 was studied with normal dermal fibroblast (NDF) and hypertrophic scar fibroblasts (See page 5, cargo loading, cell internalization, and cytotoxicity of UCNPs@mSiO2)).
Regarding claim 22, Wang et al. teach wherein a novel strategy for the transdermal distribution of siRNA using MNs that tackles the aforementioned issues. In particular, dissolvable MNs are used to transport siRNA into multifunctional NPs that are applied to the skin. The multifunctional NPs offer special physical characteristics for imaging and diagnostics while acting as a siRNA storage and cellular uptake booster (See page 2, paragraph 3).
Conclusion
No claim is allowed.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615