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 .
Response to Amendment
Applicant’s response of 08/17/2026 has been received and entered into the application file. Claims 1-23 are pending in this application.
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 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Maxwell et al. (US 2022/0073534 A1, Published 03/10/2022), Singh et al. (Stimuli-responsive Drug Delivery Systems, The Royal Society of Chemistry, 2018) Zhang et al. (Biosynthetic Gas Vesicles Combined with Focused Ultrasound for Blood-Brain Barrier Opening, International Journal of Nanomedicine, 2022)
Maxwell discloses a mechanophore platform that efficiently releases a cargo molecule via a mechanically triggered cascade reaction. The mechanophore platform comprises a stable Diels-Alder adduct mechanophore wherein a 2-furylcarbinol derivative is pre-loaded with a covalently attached cargo molecule, and wherein the Diels-Alder adduct mechanophore is embedded into a polymer chain or polymer network, wherein the cargo molecule is released (Abstract). Maxwell discloses a method for mechanochemically-gating release of molecular cargo ([0022]). Maxwell discloses that the use of fluid-filled microcapsules is used to release their payload after being ruptured. The use of mechanical force as an external stimulus to drive covalent chemical transformations leading to a payload release is an attractive strategy. In these recent developments, force is typically transduced via polymer chains attached to mechanically sensitive molecules (i.e., mechanophores) that respond in a chemoselective fashion, resulting in a productive chemical reaction. Such platforms could be useful, for example, in drug delivery applications, wherein, in the context of such applications, the activating force can be applied via ultrasound, which, in turn, is capable of penetrating deep within biological tissues to stimulate mechanochemical transformations noninvasively and with spatial and temporal precision ([0069]). In many embodiments, application of mechanical force, such as, for example, produced by ultrasonication of a solution comprising the mechanophore platform of the instant disclosure, induces mechanochemical activation of the mechanophore platform to reveal the unstable furan moiety, which, next, easily decomposes with the release of its covalently pre-installed cargo molecule. (ultrasonication parameter was 1 s on/2 s off, 0 degrees Celsius, 20 kHz, 8.2 W/cm2) ([0099]).
Maxwell discloses rupture of microcapsules that release payloads but does not explicitly mention gas-filled structures.
Singh discloses stimuli-responsive drug delivery systems. Microbubbles may serve as drug carriers, as they perform the dual functions of target-specific delivery by responding to ultrasound and can deliver their payload intracellularly because of membrane permeabilization under the action of ultrasound. PTX and siRNA co-loaded ultrasound-responsive nanobubbles have also been developed to treat hepatocellular carcinoma (HCC) by heteroassembly of polymeric micelles and liposomes with nanobubbles. Such complexes have been given intravenously to nude mice bearing human HepG2 xerografts and an external low-frequency ultrasound was applied at the tumor site providing effective codelivery of the active component to the tumor (pages 12-13).
Above references do not explicitly mention focused ultrasound.
Zhang discloses that extensive studies have demonstrated the outstanding capability of focused ultrasound combined with systemically circulating microbubbles (FUS/MBs) to enhance macromolecular delivery to the brain. This approach has tremendous potential for enhancing the delivery of chemotherapeutic drugs, antibodies, genes, and cells. Gas vesicles (GVs) are nanoscale biconical cylinders with a width of 45-250 nm and a length of 100-600 nm. GVs exclude water but make gas exchanges through the protein shell, endowing them with robust physical stability (pages 6759-6760). Zhang discloses that ultrasound collapses gas-filled structures (See Figure 1).
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Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at a method for activating a mechanochemical reaction comprising: applying ultrasound to a solution containing a polymer functionalized with mechanophore and gas-filled structures to deliver drugs or other agents. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, the mechanophore with a cargo molecule is discussed above.
Regarding claim 3, releasing the cargo molecule from a mechanophore is taught above.
Regarding claim 4, a Diels-Alder adduct is taught above.
Regrading claim 5, Maxwell discloses that the Diels-Alder adduct is covalently embedded into a polymer ([0094]).
Regarding claims 6-7, Maxwell discloses that mechanophore platforms can release various cargo molecules with diverse functionalities ([0100]).
Regarding claim 8, focused ultrasound is discussed above.
Regarding claim 9, Maxwell discloses in various embodiments, the at least one substituent is at least one position selected from a group consisting of 3-position, 4-position, 5-position, a-position, and any combination thereof; and wherein the at least one substituent is, each, independently selected from a group consisting of: alkyl, alkenyl, aryl, heteroaryl, any other aromatic or heteroaromatic functional group, alkoxy, aryloxy, amine, sulfide, any other heteroatom-containing group, including silane, a polymer chain of any composition, and any combination thereof ([0015]). Maxwell also teaches that the furan is a 2-furylcarbinol derivative ([0007]). One of ordinary skill in the art would envisage that the furan includes at least one substituent at a position of the 2-furylcarbinol scaffold and that substituents with polymer chain of any composition would be routinely considered. Furthermore, Maxwell discloses that the polymer is selected from a group consisting of polyacrylate including poly(methyl acrylate) ([0021]).
Regarding claim 10, Maxwell discloses polymer solutions of MeCN/MeOH (FIG. 17C). Additionally, one of ordinary skill in the art would routinely select the ideal solution for ultrasound.
Regarding claim 11, gas-filled structures are taught above.
Regarding claim 12, Zhang discloses that GVs are broken and release the gas contents as nanobubbles (pg 6769). One of ordinary skill in the art would envisage that gas-filled structures would release any and all gas combinations and thus experiment with different gas combinations that would exist within these gas vesicles.
Regarding claims 13-15, gas-filled structure diameters is taught by Zhang above.
Regarding claim 16, Maxwell teaches that cargo molecule release from mechanophore platform proceeds quickly under mild conditions, such as, for example, room temperature ([0068]). One of ordinary skill in the art would carefully consider the temperature ranges for mechanochemical reactions.
Regarding claims 17-19, Maxwell discloses acoustic intensity above. Furthermore, one of ordinary skill in the art would routinely experiment with a range of acoustic intensity to optimize the mechanochemical reaction.
Regarding claim 20, a method of delivering one or more cargo molecules is taught above. Applying ultrasound to polymer functionalized mechanophores and gas-filled structures would, through mechanochemical changes, release cargo molecules attached.
Regarding claim 21, Maxwell discloses that mechanophore platforms are capable of penetrating deep within biological tissues to stimulate mechanochemical transformation noninvasively and with spatial and temporal precision ([0069]).
Regarding claim 22, delivering drugs with a mechanophore is taught above.
Regarding claim 23, Singh discloses liposome-microbubble complexes that deliver paclitaxel by ultrasound (pg 17).
Response to Arguments
Applicant’s arguments filed 08/17/2026 have been fully considered but they are not persuasive.
On page 2 of remarks, applicant argues that Maxwell discloses mechanophore activation using conventional probe sonication and that Maxwell’s procedure relies on cavitation of dissolved gases under high-intensity, low-frequency sonication – conditions that are “highly destructive to tissues, making it incompatible with most biological applications.” (paragraph 61 of instant specification). However, claim 1 does not mention any specific conditions of ultrasound other than the limitation of “ultrasound is configured to collapse”. As currently written, instant claim 1 activates a mechanochemical reaction by simply applying ultrasound to a solution containing at least one polymer and a plurality of gas-filled structures. Applicant argues that none of the references teaches or suggests the claimed synergy in which gas-filled structures collapse to transduce ultrasound into a mechanical force. Robb discloses a mechanophore covalently attached with a carbo molecule, wherein the mechanophore is embedded into a polymer chain of polymer network (Abstract). Robb discloses that mechanical to chemical transduction is a powerful strategy for achieving materials with stimuli-responsive properties, including a variety of techniques such as high intensity focused ultrasound ([0003]). Robb teaches that applying a mechanical force to the mechanophore platform for a period of time, such that the polymer transduces the mechanical force to the mechanophore platform and activates the mechanophore platform to reveal the furan, such that the furan further decomposes to release the cargo molecule ([0031]). Applying the mechanical force includes deforming the polymer – application of tension, compression, shearing, stretching, grinding, and any combination thereof ([0041-0042]). Robb discloses that ultrasound collapses mechanophores.
On page 3 of remarks, applicant argues that the combination of prior arts would not have led a skilled artisan to arrive at present invention. As mentioned above, Robb teaches that activating a mechanochemical reaction using ultrasound is nothing new in the art.
On page 4 of remarks, applicant argues that ultrasound collapsing the gas-filled structures is absent from cited reference. However, Robb teaches that ultrasound is routinely used as a mechanical force to collapse a mechanophore. Therefore, claims remain rejected.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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