DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 08 September 2026, in response to the Office Correspondence dated 07 April 2026, are acknowledged.
The listing of Claims filed 08 September 2026, have been examined. Claims 1, 12, 14-16, 50-52, and 57-59 are presently treated as claims under examination based on the claim-status identifiers supplied with the amendment. Claims 1, 12, 14-16, 50, and 51 are amended, claims 8, 32, 41, and 44 are canceled, and claims 57-59 are newly added. Claims 2-7, 9-11, 13, 17-31, 33-40, 42, 43, 45-49, and 53-56 remain withdrawn from consideration under 37 CFR 1.142(b) (see also MPEP § 821, § 821.04) pursuant to the restriction requirement unless and until rejoined.
Response to Amendment
The applicant argues that the objections previously made to claims 1, 12, 50, and 51 have been overcome by amendment. The argument is persuasive. Claim 1 has been amended to clarify the grammatical relationship between the ultrasound pulses and the resulting cavitation and now consistently recites the microbial biofilm. The temperature notation has also been corrected. Claim 12 has been recast to depend from claim 1 and affirmatively introduces the gas microbubble. Claim 50 has been rewritten in parallel grammatical form to positively recite the plurality of particles and the liquid contained in each particle. Claim 51 has been corrected to include appropriate punctuation and to use terminology consistent with claim 1. Accordingly, the previously stated objections to claims 1, 12, 50, and 51 are withdrawn.
The previous 35 U.S.C. §112(b) rejection of claim 1 based on alternating use of “the microbial biofilm” and “the biofilm” has been overcome by amendment. The antecedent-basis defect formerly identified in claim 12 has likewise been overcome by amendment. The corresponding terminology objections in claims 50 and 51 have also been corrected. Accordingly, those portions of the previous rejection are withdrawn.
Amended claim 1 now expressly recites that the liquid perfluorocarbon core comprises “a perfluorocarbon material having a boiling point less than 37°C at atmospheric pressure.” The amendment sufficiently identifies the boiling-point property as a property of the perfluorocarbon material under stated atmospheric-pressure conditions. Accordingly, the previous §112(b) rejection directed to uncertainty concerning whether the claimed boiling point referred to the bulk material or to an encapsulated effective boiling point is withdrawn. To the extent the previous action suggested that the breadth of the genus of materials having a boiling point below the recited value, standing alone, rendered the claim indefinite, that reasoning is also withdrawn.
Amended claim 1 now recites, in relevant part, that ultrasound pulses are configured to induce acoustic droplet vaporization “by releasing the dissolved or encapsulated oxygen from the phase-change contrast agent at the microbial biofilm site during or after the acoustic droplet vaporization”; the ADV increases penetration of the therapeutic agent relative to ADV in the absence of oxygen release; and oxygen release and ADV produce greater antimicrobial activity than ADV in the absence of oxygen release. The applicant’s amendment supplies substantially more objective comparative context than the prior recitation merely requiring an unspecified “increase” in penetration. The previous rejection based simply on the absence of a quantified magnitude of increased penetration is therefore withdrawn.
However, the wording “configured to induce acoustic droplet vaporization by releasing the dissolved or encapsulated oxygen … during or after the acoustic droplet vaporization” introduces internal ambiguity. As presently drafted, the phrase may grammatically indicate that oxygen release causes ADV, while simultaneously specifying that the oxygen is released during or after the ADV event. Those temporal propositions are not necessarily equivalent and accordingly, a new rejection under 35 U.S.C. §112(b) is made, as detailed below.
The previous rejection of claim 14 based on an unspecified “threshold” has been overcome because amended claim 14 now supplies numerical frequency and acoustic-pressure threshold ranges. The previous rejection of claim 16 based upon the phrase “would normally be a gas” has likewise been overcome. Claim 16 now recites a metastable liquid PFC core comprising material that exists as a liquid in a metastable state at 37°C and standard atmospheric pressure. The amended language more directly defines the physical state relied upon. The previously identified “a core”/“the core” antecedent-basis concerns have also been materially clarified by the amendments. Accordingly, except for any separately identified ambiguity arising from dependency or inconsistent characterization of the same cavitation-enhancing agent in a particular dependent claim, the foregoing prior §112(b) grounds are withdrawn.
The applicant’s argument, to the limited extent that the prior rejection fails to account for all limitations of amended claim 1, is persuasive. This conclusion is not based on applicant’s broader proposition that Chen, Lattwein, and Zhou provide no reason to combine PCCAs with biofilm therapy. The record provides substantial technical reasons for that combination, as detailed in the Response to Arguments section below. Instead, the deficiency arises because the applicant has added further oxygen-loading/release limitation and comparative oxygen-dependent therapeutic results not established by the presently applied combination. Accordingly, the prior rejection of amended claims 1, 12, 14-16, and 50-52 under 35 U.S.C. §103 over Chen in view of Lattwein and Zhou, as previously formulated, is withdrawn.
New rejections for claims 1, 12, 14-16, 50-52, and 57-59 under 35 U.S.C. §103, claims 1, 12, 14-16, 50-52, and 57-59 under 35 U.S.C. §112(a) as failing to comply with the written-description requirement, claims 1, 12, 14-16, 50-52, and 57-59 under 35 U.S.C. §112(b) as indefinite, are outlined below in addition to objections to claims 16 and 59 for minor informalities.
New Objections and Rejections
The following new rejections are made from the previous Office Correspondence dated 07 April 2026, as the applicant's amendment necessitated the new grounds of rejection presented below based on the amended/newly cited limitations.
Claim Objections
Claims 16 and 59 objected to because of the following informalities:
Claim 16 recites, “comprising liquid perfluorocarbon core” and should read “comprising a liquid perfluorocarbon core.”
Claim 59 recites the phrase “due to the plurality of microbubbles’ cyclic diameter increase and decrease period”, which is grammatically awkward. A clearer formulation would be “due to cyclic increases and decreases in the diameters of the plurality of microbubbles.” For consistency of antecedent terminology, claim 59 preferably should refer to “the at least one therapeutic agent” rather than “the therapeutic agent.”
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, 12, 14-16, 50-52, and 57-59 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.
To satisfy 35 U.S.C. § 112(a), the application as originally filed, must reasonably convey to a person of ordinary skill in the art that the inventor had possession of the claimed subject matter as of the filing date (see Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351-52 (Fed. Cir. 2010) (en banc)). Where subject matter is newly added to a claim, the appropriate treatment is a rejection under 35 U.S.C. § 112(a) for lack of written description (see In re Rasmussen, 650 F.2d 1212, 1214 (CCPA 1981); MPEP § 2163.01, § 2163.06).
Claim 1 has been amended to require, inter alia, a phase-change contrast agent comprising a liquid perfluorocarbon core and dissolved or encapsulated oxygen and further requires ultrasound pulses configured to induce acoustic droplet vaporization by releasing the dissolved or encapsulated oxygen from the phase-change contrast agent at the microbial biofilm site during or after the acoustic droplet vaporization, with the additional requirements that acoustic droplet vaporization increase penetration of the therapeutic agent compared to acoustic droplet vaporization in the absence of oxygen release; and oxygen release and acoustic droplet vaporization produce greater antimicrobial activity than acoustic droplet vaporization in the absence of oxygen release.
The original disclosure provides substantial support for the more general PCCA/ADV mechanism. In particular, the specification teaches that PCCA generally comprise a liquid perfluorocarbon droplet, that ultrasound converts the liquid phase to gas by acoustic droplet vaporization, and that the resulting microbubbles undergo cavitation and microstreaming capable of enhancing penetration into the biofilm (¶[0036]-[0037]; ¶[0066]-[0067]). The disclosure also contemplates oxygen-containing cavitation-enhancing agents. The Abstract states that cavitation-enhancing agents may be “loaded with oxygen gas” or combined with oxygen-carrying microbubbles, and ¶[0105] states that the cavitation-enhancing agent may comprise oxygen in the core.
The original disclosure, however, does not reasonably convey possession of the more specific oxygen-release mechanism and oxygen-specific comparative relationships now required by amended claim 1. First, the disclosure does not describe ultrasound-induced ADV occurring “by releasing” oxygen from the phase-change contrast agent, nor does it disclose oxygen being released from the agent during or after ADV. The disclosed ADV mechanism instead concerns vaporization of the perfluorocarbon core from liquid to gas and subsequent oscillation/cavitation of the resulting microbubble (¶[0037], ¶[0067]). The original specification contains no express teaching that oxygen must leave the PCCA or resulting microbubble during or after that transformation. A disclosure that oxygen is “in the core” does not, without more, demonstrate possession of the presently claimed temporal release step.
Second, the disclosure does not demonstrate possession of the requirement that oxygen release causes or contributes to greater penetration of the therapeutic agent relative to ADV conducted without oxygen release. Specification ¶[0067] attributes improved penetration to physical mechanisms produced by the converted microbubbles (i.e., mechanical disruption and microstreaming) and not to release of oxygen.
Third, the disclosure does not demonstrate possession of the claimed comparison in antimicrobial activity, namely that oxygen release plus ADV produces greater antimicrobial activity than ADV in the absence of oxygen release. Specification ¶[0068] and Figure 9 describe treatment of an MRSA biofilm with an oxygen-nanodroplet PCCA plus tobramycin and state that addition of the oxygen nanodroplets increased treatment effectiveness relative to tobramycin without the oxygen nanodroplets. That is not the comparison now claimed. The disclosed control does not establish antimicrobial activity of oxygen-containing ADV against an otherwise comparable ADV treatment in which oxygen release is absent.
The distinction is material. The amended claim does not merely recite oxygen-containing PCCA or improved antibiotic activity. It affirmatively defines the claimed method by an oxygen-release event and by the performance of that event relative to a specific no-oxygen-release ADV comparator. The disclosure of PCCA-mediated mechanical drug penetration and a separate oxygen-nanodroplet experiment cannot, without an express, implicit, or inherent disclosure linking those teachings in the claimed manner, establish possession of the newly claimed causal and comparative relationship (see MPEP § 2163).
Specification ¶[0055]-[0056] do not cure this deficiency. Those paragraphs explain that mechanical disruption of the biofilm may create holes that allow oxygen penetration into an otherwise hypoxic biofilm. That teaching concerns environmental oxygen gaining access through a mechanically disrupted matrix, it does not teach release of oxygen from an oxygen-bearing phase-change contrast agent during or after ADV. Accordingly, the original disclosure does not reasonably convey to a person of ordinary skill in the art that the inventors possessed the full method now defined by claim 1. Claims 12, 14-16, 50-52, and 57-59 incorporate the limitations of claim 1 directly or indirectly and are rejected for the same reason.
Claim 14 is additionally rejected under 35 U.S.C. § 112(a). The specification discloses a PCCA that converts from a liquid droplet to a gas microbubble when acoustic or thermal energy exceeds a threshold (¶[0102]), ultrasound operation within a frequency range of 0.5-1.5 MHz (¶[0108]); and ultrasound operation within an acoustic-pressure range of 300-1200 kPa (¶[0109]). The disclosure does not, however, identify the entire 0.5-1.5 MHz operating range as a “frequency threshold,” nor does it identify the entire 300-1200 kPa operating range as an “acoustic threshold.”
The specification instead distinguishes the generic threshold concept from disclosed operating ranges. It further reports that an octofluoropropane PCCA may vaporize at peak negative pressures as low as 300 kPa at 1 MHz, illustrating that activation threshold depends on the acoustic conditions rather than establishing the two operating ranges themselves as interchangeable threshold ranges (¶[0037]). The disclosure therefore supports the disclosed operating ranges and a generic activation threshold, but it does not reasonably convey possession of the newly claimed combination in which those ranges themselves constitute the recited “frequency threshold” and “acoustic threshold.”
Claim 57 is additionally rejected under 35 U.S.C. § 112(a). Claim 57 further requires that the dissolved or encapsulated oxygen released from the phase-change contrast agent elevates local oxygen concentration within the microbial biofilm. The specification recognizes that biofilms can be hypoxic and states that mechanically creating holes in the biofilm may permit oxygen penetration. It also discloses oxygen in the cavitation-enhancing-agent core and reports an oxygen-nanodroplet experiment.
The disclosure does not, however, describe oxygen being released from a PCCA into the biofilm or state that such release elevates the local oxygen concentration within the biofilm. Thus, to the extent claim 57 is intended to require this particular source-and-effect relationship rather than merely the presence of oxygen, the relationship is not described in the application as originally filed. Claim 57 is therefore additionally rejected.
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 Applicant regards as his invention.
Claims 1, 12, 14-16, 50-52, and 57-59 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Particular claim language that is ambiguous, vague, incoherent, or otherwise unclear wherein the metes and bounds of the claim cannot be determined with reasonable precision are indefinite (see In re Packard, 751 F.3d 1307, 1311–13 (Fed. Cir. 2014); MPEP § 2173, § 2173.02).
Claim 1 recites ultrasound pulses configured to induce acoustic droplet vaporization by releasing the dissolved or encapsulated oxygen from the phase-change contrast agent at the microbial biofilm site during or after the acoustic droplet vaporization. The limitation is internally unclear. The phrase “induce acoustic droplet vaporization by releasing” grammatically identifies oxygen release as the mechanism by which ADV is induced. The same limitation then states that the oxygen may be released “during or after” that ADV.
In particular, under the claimed “after” alternative, the event said to induce ADV would occur only after the ADV that it purportedly induces. It is consequently unclear whether the claim requires release of oxygen to initiate/cause ADV, oxygen release as a consequence of ADV, oxygen release contemporaneously with ADV without a required causal relationship, or oxygen release after ADV from the resulting microbubble. These interpretations impose materially different temporal and mechanistic requirements. The specification’s conventional description of ADV does not resolve the ambiguity because it states that ultrasound changes the PFC nanodroplet core from liquid to gas and thereafter the resulting microbubble oscillates, wherein it does not define oxygen release as the mechanism that induces vaporization (¶[0037], ¶[0067]).
Thus, claim 1 therefore fails to define the required relationship between ultrasound, ADV, and oxygen release with the clarity required by 35 U.S.C. § 112(b). Claims 12, 14-16, 50-52, and 57-59 incorporate this limitation and are rejected for the same reason. A possible clarification would be to recite the events sequentially if that is what the applicant intends, for example, by separately specifying that ultrasound induces ADV and that oxygen is released as a result of, during, or following ADV, rather than stating that ADV is induced “by” an event that may occur after it.
Claim 1 additionally employs the undefined oxygen-free ADV comparator as
acoustic droplet vaporization in the absence of oxygen release, both for therapeutic-agent penetration and antimicrobial activity. The concern is not merely the use of the relative expressions “increase” or “greater”, yet the specification does not identify what constitutes the claimed comparison condition. It is unclear whether “ADV in the absence of oxygen release” means ADV of an otherwise identical oxygen-free PCCA, ADV of an oxygen-containing PCCA under conditions in which the oxygen remains confined, ADV using a conventional PCCA lacking oxygen while all other treatment conditions remain unchanged, or any ADV treatment for which no oxygen release is detected.
The distinction affects the metes and bounds of both functional limitations. Figure 9 does not provide the missing definition because its stated comparison is oxygen nanodroplet treatment versus tobramycin treatment without the oxygen nanodroplets, not oxygen-releasing ADV versus otherwise corresponding ADV without oxygen release. The applicant should clarify the reference/control condition if these comparative limitations are to define patentable scope.
Claim 14 is additional rejected as indefinite for “threshold” ranges. The following language does not define the claimed ultrasound condition with reasonable clarity exceeding a frequency threshold of 0.5 MHz to 1.5 MHz, an acoustic threshold of 300 kPa to 1200 kPa, or both. A “threshold” ordinarily denotes a boundary that must be crossed. The claim instead recites each threshold as a numerical range, without explaining whether the threshold may be any selected value within 0.5-1.5 MHz or 300-1200 kPa and the applied ultrasound must exceed that selected value, the ultrasound itself must be operated within the stated range, the lower endpoint is the threshold and the upper endpoint is an operating limit, or the claimed PCCA has a variable threshold anywhere within the stated interval. The specification reinforces rather than resolves this distinction. Specification ¶[0102] refers generically to energy “exceeding a threshold,” whereas ¶[0108]-[0109] separately characterize 0.5-1.5 MHz and 300-1200 kPa as operating ranges. Accordingly, claim 14 should be amended either to recite an actual threshold criterion or, if intended, to recite that the ultrasound pulses are delivered within the specified frequency and/or acoustic-pressure ranges.
In addition, claim 14 presently depends from claim 10, while claim 10 states that the cavitation-enhancing agent “is a gas microbubble,” and claim 14 characterizes the phase-change contrast agent as converting “from a liquid droplet to the gas microbubble.” The amended listing identifies claim 10 as withdrawn while claim 14 is identified as currently amended. This differs from the originally published claim structure. Original claim 14 depended directly from claim 1 and recited conversion of the PCCA from a liquid droplet to a gas microbubble. Original claim 10 instead depended from original claim 8, the gas-microbubble embodiment.
The present dependency therefore creates avoidable uncertainty as to whether claim 14 is intended to require an agent that is already a gas microbubble under inherited claim 10, or an initially liquid PCCA that subsequently converts to a gas microbubble under claim 14. In the absence of a clear temporal qualification in claim 10, the dependency should be corrected. If the applicant’s intent is the latter embodiment, dependence directly from claim 1 appears consistent with the originally disclosed claim architecture.
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.
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.
Claims 1, 12, 15, 16, 50-52, and 57-59 are rejected under 35 U.S.C. § 103 as being unpatentable over Chen et al. (US20150045724A1; published 12 February 2015, hereinafter “Chen”), in view of Lattwein et al. (Sonobactericide: An Emerging Treatment Strategy for Bacterial Infections. Ultrasound Med Biol. 2020 Feb;46(2):193-215; Epub 2019 Nov 5; hereinafter “Lattwein”), Zhou (Application of acoustic droplet vaporization in ultrasound therapy. J Ther Ultrasound. 2015 Nov 11;3:20), Jandhyala and Luke (Optically Activated Oxygen-Loaded Perfluorocarbon Nanoparticles for Ultrasound-guided Radiation Therapy, OSA Technical Digest, Paper OmW3D.7, April 2017; hereinafter “Jandhyala”), and Kolpen et al. (Sensitizes Anoxic Pseudomonas aeruginosa Biofilm to Ciprofloxacin. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01024-17; hereinafter “Kolpen”).
Each cited reference was publicly available before 01 June 2020.
Chen teaches administering phase-change nanodroplets and a therapeutic agent to a target region and applying ultrasound such that the nanodroplets “vaporize, or cavitate, or convert to microbubbles that cavitate,” thereby opening a biological barrier and permitting the therapeutic agent to diffuse to a target location (claim 1). Chen therefore teaches the basic sequence of administering a phase-change cavitation-enhancing agent, exposing the target to a therapeutic agent, and delivering ultrasound to cause phase transition/cavitation and thereby enhance therapeutic-agent delivery (claim 1).
Chen additionally teaches phase-change nanodroplets produced from highly volatile perfluorocarbons. Chen explains that highly volatile perfluorocarbon microbubbles may be pressurized and condensed into liquid nanodroplets having peak diameters of approximately 200-300 nm, which subsequently vaporize at clinically relevant acoustic pressures (¶[0045]).
Chen specifically uses perfluorobutane (PFB) as the perfluorocarbon core material for contrast-agent generation (Example 1, ¶[0046] “perfluorobutane gas (PFB, 99 wt % purity)”). Chen further teaches that microbubbles and nanodroplets were formulated using the same lipid composition (Example 1,¶[0044]). Chen also claims nanodroplets having diameters of 100-300 nm (claim 2).
Thus, Chen teaches a phase-change perfluorocarbon nanodroplet, administration with a therapeutic agent, ultrasound-induced vaporization/conversion to a microbubble, cavitation, and resulting enhancement of therapeutic-agent delivery. Chen does not expressly teach treatment of a microbial biofilm, intentional loading of the phase-change droplet with oxygen, or the oxygen-dependent comparative results newly recited in instant claim 1. Lattwein supplies the microbial-biofilm application and expressly connects ultrasound-activated droplets/microbubbles with enhanced antibiotic treatment.
Lattwein states that exposure of “microbubbles or droplets” to ultrasound can directly affect bacteria and enhance antibiotic or other therapeutic efficacy and reviews ultrasound-activated microbubble or droplet treatment of “bacteria and biofilm”. Lattwein further recognizes that biofilm architecture interferes with antibiotic penetration and efficacy and explains that cavitation-mediated mechanical effects can enhance therapeutic delivery through biofilms (p. 1, Abstract).
Most significantly, in discussing future sonobactericide approaches, Lattwein explicitly proposes nanoscale cavitation nuclei such as nanodroplets because such particles could penetrate the biofilm and nucleate cavitation throughout the biofilm, with subsequent droplet vaporization exerting mechanical effects upon the biofilm (Conclusions and Future Perspectives, p. 20, ¶2). This directly provides a reason for using phase-change nanodroplets rather than relying exclusively upon preformed micron-scale bubbles.
Accordingly, Lattwein teaches or suggests application of ultrasound-activated droplets to microbial biofilm, therapeutic/antibiotic treatment of the biofilm, use of nanoscale cavitation nuclei to penetrate the biofilm before activation, nucleation of cavitation throughout the biofilm, and enhancement of antibiotic penetration/effect through ultrasound-mediated cavitation.
Zhou teaches the physical principles governing acoustic droplet vaporization (ADV), including conversion of a liquid perfluorocarbon droplet to a gaseous bubble when sufficient acoustic energy is supplied (p. 4, last ¶-p. 8, last ¶ before “Manufacture” heading). Zhou explains that the vaporization threshold is affected by perfluorocarbon properties, including boiling point, and specifically discusses low-boiling perfluorocarbons such as perfluoropentane in connection with reducing the acoustic amplitude required for vaporization (p. 3, “Physics” section ¶’s).
Thus, the prior art recognized before the effective filing date that PFC boiling point is a parameter affecting acoustic vaporization behavior. Selection of an identified PFC having a boiling point at or below physiological temperature for the known purpose of facilitating ADV therefore constitutes optimization of a known result-effective parameter, rather than discovery of an unrecognized variable. Optimization of a parameter known to affect a desired result ordinarily falls within the skill of the art (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); MPEP § 2144.05).
However, neither Chen, Lattwein, nor Zhou expressly teaches the newly added requirement that the phase-change PFC agent contain dissolved or encapsulated oxygen. Jandhyala remedies this deficiency. Jandhyala discloses “Perfluoropentane nanodroplet ultrasound and photoacoustic contrast agents” loaded with “oxygen” for image-guided oxygen delivery, with oxygen release being triggered by application of energy (p. 1, Abstract). Jandhyala therefore establishes that, well before 01 June 2020, persons of ordinary skill knew how to provide an oxygen-loaded liquid perfluorocarbon nanodroplet contrast agent and to employ that nanodroplet for localized triggered oxygen delivery. Jandhyala uses photoacoustic laser pulses to trigger oxygen release. Jandhyala therefore does not itself disclose oxygen release specifically as a result of ultrasound-induced ADV within a microbial biofilm. Chen and Zhou supply the independently known ultrasound-induced phase-transition mechanism.
Kolpen supplies an express biological reason to deliver oxygen to a microbial biofilm in combination with antibiotic treatment. Kolpen teaches that Pseudomonas aeruginosa biofilms can be strongly oxygen depleted and investigated whether restoration of oxygen would sensitize such biofilms to antibiotics (p. 1, Abstract and the introduction ¶1). Kolpen experimentally found that application of hyperbaric oxygen significantly enhanced ciprofloxacin killing of Pseudomonas aeruginosa biofilm and reports that maximum enhancement of bacterial killing exceeded two log units under the tested conditions (pp. 2-3, Results, Effect of HBOT on P. aeruginosa biofilm during ciprofloxacin treatment, ¶1-4).
Kolpen concludes that oxygenation improves ciprofloxacin bactericidal activity against Pseudomonas aeruginosa biofilm and that biofilms may be sensitized to antibiotic treatment by supplying oxygen (p. 1, Abstract). Accordingly, Kolpen teaches a specific therapeutic benefit, not merely a generalized biological role for oxygen, arising from increasing oxygen availability in an antibiotic-treated microbial biofilm.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to employ the phase-change PFC nanodroplets taught by Chen and Zhou in the microbial-biofilm treatment expressly contemplated by Lattwein and to provide such droplets with an oxygen payload as taught by Jandhyala for the purpose of increasing biofilm oxygenation and antibiotic susceptibility as taught by Kolpen.
Lattwein itself identifies the pertinent problem and proposed solution wherein therapeutic penetration through biofilm is limited, and nanoscale cavitation nuclei such as nanodroplets could penetrate the biofilm and nucleate cavitation throughout it. Chen teaches a known PFC nanodroplet system specifically adapted to phase transition and cavitation under ultrasound. Applying Chen’s known phase-change nanodroplet technology to Lattwein’s expressly identified biofilm application therefore represents application of a known technique to a known method ready for improvement, with the nanodroplet serving its established function of ultrasound-responsive phase transition and cavitation.
KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417-18 (2007), explains that a claimed combination may be obvious when a known technique is used to improve a known device or method in the same way and when the combination produces no more than a predictable result. In addition, MPEP §2143 identifies, inter alia, applying a known technique to a known method ready for improvement and combining known elements according to known methods to obtain predictable results as appropriate obviousness rationales. Once a skilled artisan selected a nanodroplet approach for delivery into biofilm, Jandhyala supplied a known oxygen-loaded PFC nanodroplet technology, while Kolpen supplied a concrete therapeutic reason to employ that oxygen payload: oxygenation increased antibiotic killing of hypoxic/anoxic Pseudomonas aeruginosa biofilm.
The proposed combination therefore does not rest on knowledge of the applicant’s disclosure, rather the prior art itself supplies the biofilm penetration problem (Lattwein), nanoscale intrabiofilm cavitation as a proposed solution (Lattwein), an operable ultrasound-responsive PFC nanodroplet platform (Chen/Zhou), an operable oxygen-loaded PFC nanodroplet (Jandhyala), and a known therapeutic benefit of oxygenating antibiotic-treated biofilm (Kolpen). The required reasoning thus has a rational underpinning and is not merely a conclusory assertion that the individual limitations were independently known.
A person of ordinary skill would also have possessed a reasonable expectation of success in doing so because Chen demonstrates that highly volatile PFC material can be condensed into nanodroplets of approximately 200-300 nm that subsequently vaporize under clinically relevant ultrasound conditions. Lattwein expressly proposes that nanoscale cavitation agents could penetrate biofilm and nucleate cavitation throughout it. Jandhyala demonstrates that PFC nanodroplets, specifically perfluoropentane nanodroplets, can be loaded with oxygen and used for triggered oxygen release. Kolpen experimentally demonstrates that oxygenating Pseudomonas aeruginosa biofilm enhances antibiotic bactericidal activity. Thus, each functional step of the proposed modification was established independently before the effective filing date of the instant application, providing more than a mere hope that the combination would work. A reasonable expectation of success is sufficient (see MPEP §2143.02; In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)).
Regarding the newly recited comparative functional results, amended claim 1 additionally requires that ADV causes the cavitation-enhancing agent to cavitate and increase therapeutic-agent penetration compared with ADV in the absence of oxygen release, and oxygen release together with ADV produces greater antimicrobial activity than ADV in the absence of oxygen release.
As to antimicrobial activity, Kolpen provides direct experimental evidence that oxygenation of Pseudomonas aeruginosa biofilm increases antibiotic-mediated bacterial killing relative to oxygen-deprived conditions. Lattwein independently teaches cavitation-assisted biofilm treatment. A skilled artisan combining the known oxygen-delivery function of Jandhyala with Lattwein’s sonobactericide system for the purpose expressly taught by Kolpen would therefore have reasonably expected greater antimicrobial activity from oxygen delivery plus the cavitation-assisted antibiotic treatment than from the corresponding oxygen-deprived treatment. This limitation is therefore a predictable consequence of the combination.
Instant claim 12 further recites that the cavitation-enhancing agent comprises a gas microbubble having a core comprising a perfluorocarbon gas. Chen eteaches phase-change nanodroplets that convert to microbubbles that cavitate (claim 1) and teaches use of perfluorobutane gas as the perfluorocarbon contrast-agent core material, as discussed above. Accordingly, instant claim 12 would have been obvious for the reasons set forth for instant claim 1.
Instant claim 15 further recites that the PFC material comprises one or more of decafluorobutane, perfluoropropane, perfluoropentane, or combinations thereof. Jandhyala teaches perfluoropentane nanodroplet ultrasound/photoacoustic contrast agents loaded with oxygen (p. 1, Abstract). Thus, perfluoropentane is directly taught by the prior art. Accordingly, instant claim 15 would have been obvious for the reasons set forth for instant claim 1.
Instant claim 16 further requires a metastable phase-change contrast agent comprising a liquid PFC core, wherein the PFC exists as a liquid in a metastable state at 37°C and atmospheric pressure. Chen teaches nanodroplets formed by condensing a highly volatile PFC gas core into a liquid phase and subsequently vaporizing the resulting liquid nanodroplets with ultrasound (¶[0045]). Zhou further teaches the thermodynamic basis of ADV, including the influence of Laplace pressure, droplet size, vapor pressure, and normal boiling point on maintenance of a liquid droplet and its subsequent ultrasound-induced transition to gas (p. 3, “Physics” section ¶’s and p. 4, last ¶-p. 8, last ¶ before “Manufacture” heading). The combined Chen/Zhou teachings therefore disclosed the known metastable/superheated liquid-PFC droplet state underlying ADV, based upon the combined teachings concerning low-boiling liquid PFC nanodroplets maintained in liquid form until ultrasound-induced vaporization.
Instant claim 50 further recites a plurality of particles smaller than one micron in diameter, each comprising liquid in a metastable state before administration. Chen recites nanodroplets having diameters of 100-300 nm (claim 2), all of which are below one micron. Chen further teaches preparation of those nanodroplets by condensation of highly volatile PFC gas into a liquid phase (¶[0045]) followed by ultrasound-induced vaporization (¶[0059]). Thus, the particle-size limitation is met.
Instant claim 51 further requires the cavitation-enhancing agent to be liquid before administration and to convert into microbubbles after penetrating the microbial biofilm. Chen teaches liquid phase-change nanodroplets that convert into gaseous/cavitating microbubbles upon ultrasound activation (claim 1; (¶[0045]; ¶[0059]). Lattwein proposes use of nanoscale cavitation nuclei such as nanodroplets because such particles could penetrate the biofilm and nucleate cavitation throughout the biofilm (p. 20, ¶2). Thus, the combination directly supplies both portions of the limitations including penetration into the biofilm while in nanoscale droplet form; and subsequent phase transition/cavitation after ultrasound activation. Accordingly, instant claim 51 would have been obvious for the reasons set forth above.
Instant claim 52 further requires particles ranging from 100-400 nm in diameter. Chen claims nanodroplets having diameters of 100-300 nm (claim 2), a range lying entirely within and overlapping the instant claimed 100-400 nm range. A prima facie case of obviousness ordinarily exists where the claimed range overlaps or encompasses a range disclosed by the prior art (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)). Chen expressly teaches example embodiment values within the instant claimed range wherein the averaged number-weighted mean, median and mode diameters across all samples were 204±10 nm, 209±29 nm and 180±25 nm, respectively (¶[0057]; see MPEP § 2123). Accordingly, instant claim 52 would have been obvious.
Instant claim 57 further requires that released dissolved or encapsulated oxygen elevate the local oxygen concentration within the microbial biofilm. Jandhyala expressly teaches oxygen-loaded perfluoropentane nanodroplets for localized oxygen delivery and triggered oxygen release (p.1, Abstract). Kolpen teaches deliberate oxygenation of anoxic Pseudomonas aeruginosa biofilm and demonstrates increased antibiotic efficacy resulting from supplying oxygen (p. 1, Abstract). Lattwein provides the motivation to deliver nanoscale cavitation agents into the biofilm before activation.
Thus, a person of ordinary skill combining Jandhyala’s oxygen-delivery nanodroplet with Lattwein’s intrabiofilm nanodroplet treatment for the antibiotic-sensitizing purpose taught by Kolpen would have intended and reasonably expected release of the oxygen payload within the biofilm to increase local oxygen availability. This conclusion is based on the expressly intended oxygen-delivery function of the Jandhyala agent, not upon an assertion that ordinary PFC nanodroplets inherently contain oxygen. Accordingly, instant claim 57 would have been obvious for the reasons stated above.
Instant claim 58 further recites applying a plurality of phase-change nanodroplets, controlling the cores to change from liquid to gas, converting the droplets to microbubbles, and having the resulting microbubbles oscillate in diameter. Chen teaches phase-change liquid nanodroplets converted under ultrasound to gaseous microbubbles that cavitate (claim 1). Lattwein explains that stable cavitation involves sustained oscillation of microbubbles under an ultrasound field and describes the mechanical and fluid-flow effects generated by such oscillation (p. 14, ¶3). Thus, microbubble oscillation was an expressly recognized acoustic behavior of ultrasound-exposed microbubbles. Accordingly, instant claim 58 would have been obvious.
Instant claim 59 further requires that oscillation improves penetration through mechanical disruption of the biofilm matrix and through microstreaming, with microstreaming constituting local flow generated around cyclically expanding and contracting microbubbles. Lattwein teaches that ultrasound-driven bubble oscillation generates fluid motion and discusses microstreaming as a mechanism by which oscillating cavitation nuclei create mechanical effects and enhance mass transport (p. 14, ¶3-4). Lattwein also teaches that cavitation can create defects in biofilm matrix that aid antibiotic penetration and proposes intrabiofilm cavitation using nanoscale agents (p. 16, ¶2). Accordingly, the mechanical-disruption and microstreaming limitations represent known consequences of the ultrasound-driven microbubble oscillation already taught by the combination, and instant claim 59 would have been obvious.
Claims 1 and 14 are rejected under 35 U.S.C. § 103 as being unpatentable over Chen et al. (US20150045724A1; published 12 February 2015, hereinafter “Chen”), in view of Lattwein et al. (Sonobactericide: An Emerging Treatment Strategy for Bacterial Infections. Ultrasound Med Biol. 2020 Feb;46(2):193-215; Epub 2019 Nov 5; hereinafter “Lattwein”), Zhou (Application of acoustic droplet vaporization in ultrasound therapy. J Ther Ultrasound. 2015 Nov 11;3:20), Jandhyala and Luke (Optically Activated Oxygen-Loaded Perfluorocarbon Nanoparticles for Ultrasound-guided Radiation Therapy, OSA Technical Digest, Paper OmW3D.7, April 2017; hereinafter “Jandhyala”), and Kolpen et al. (Sensitizes Anoxic Pseudomonas aeruginosa Biofilm to Ciprofloxacin. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01024-17; hereinafter “Kolpen”), as applied to claim 1, in further view of Xu et al. (Biosurfactants for microbubble preparation and application. Int J Mol Sci. 2011 Jan 17;12(1):462-75; hereinafter “Xu”).
Each cited reference was publicly available before 01 June 2020.
Instant claim 14 depends from instant claim 10, which requires that the cavitation-enhancing agent be a gas microbubble and that the microbubble be encapsulated within a rhamnolipid. Given instant claim 10 remains withdrawn, instant claim 14 has been examined to depend from instant claim 1, as previously indicated.
Chen, in view of Lattwein, Zhou, Jandhyala, and Kolpen teach the limitations of instant claim 1, as described above, from which instant claim 14 is examined to depend from, however do not explicitly teach the specific limitations of instant claim 14.
Xu teaches preparation and stabilization of microbubbles using biosurfactants and expressly discusses rhamnolipid-stabilized microbubble dispersions. Xu explains that rhamnolipid concentration affects microbubble stability because rhamnolipid is present at the bubble interface and alters interfacial-film properties, including viscoelasticity, mechanical strength, and electrostatic repulsion (p. 469, ¶2). Under the broadest reasonable interpretation consistent with the specification, a gas microbubble stabilized by an interfacial rhamnolipid layer corresponds to a gas microbubble “encapsulated within a rhamnolipid.”
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to use the known rhamnolipid microbubble stabilization taught by Xu for a microbubble employed in Lattwein’s microbial-biofilm environment because rhamnolipid was an established biosurfactant capable of forming/stabilizing microbubble interfaces. This represents use of a known surfactant coating for its established microbubble-stabilization function (see KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417-18 (2007)).
Instant claim 14 further requires conversion from liquid droplet to gas microbubble upon exposure to ultrasound exceeding a frequency threshold of 0.5-1.5 MHz, an acoustic-pressure threshold of 300-1200 kPa, or both. The sonobactericide literature surveyed by Lattwein includes use of approximately 1 MHz ultrasound (p. 7, last ¶-p. 8, last ¶, and pp. 37-39, Table 1), which falls squarely within the claimed 0.5-1.5 MHz interval, and acoustic pressures in the several-hundred-kPa range (p. 7, last ¶-p. 8, last ¶, and pp. 37-39, Table 1; 400 kPa, 1 MPa [1000 kPa], 0.44 MPa [440 kPa], 0.24 MPa [240 kPa], 0.23 MPa [230 kPa], 1.1 MPa [1100 kPa], 0.5 MPa [500 kPa], 1.2 MPa [1200 kPa]), encompassing and falling within the instant claimed 300-1200 kPa interval.
Zhou independently teaches that ADV occurs once an acoustic vaporization threshold is exceeded and identifies ultrasound amplitude, droplet characteristics, and PFC properties as parameters affecting that threshold, as described above. Where the prior art discloses a range overlapping the claimed range, a prima facie case of obviousness ordinarily exists (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
Moreover, because Zhou teaches that acoustic conditions affect whether and when vaporization occurs, acoustic pressure and frequency were recognized operative parameters, routine selection of workable operating values within the known region therefore falls within the optimization principle of In re Aller, 220 F.2d 454, 456 (CCPA 1955). Accordingly, instant claim 14 would have been obvious over the cited combination further in view of Xu.
The proposed combinations would not have required changing the cited components so extensively that they ceased to operate according to their known principles. Chen’s droplets remain ultrasound-responsive PFC phase-change agents. Lattwein’s biofilm remains treated by cavitation-assisted therapeutic delivery. Jandhyala’s oxygen-loaded PFC nanodroplet continues to perform its known oxygen-delivery function. Kolpen provides a known biofilm-specific therapeutic reason for supplying oxygen. Xu’s rhamnolipid continues to perform its known microbubble-interface/stabilization function. Accordingly, the references provide both an articulated reason to make the proposed modifications and a reasonable expectation that the resulting agents would perform their respective known functions.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 08 September 2026, have been fully considered.
The applicant traverses the rejection of claims 1, 12, 14-16, and 50-52 as obvious over Chen in view of Lattwein and Zhou. The applicant correctly states that an obviousness rejection must account for the claim as a whole and that merely establishing that individual claim elements were separately known, wherein a rejection based on a combination of references must contain an articulated reason, having rational underpinning, why a person of ordinary skill would have combined or modified the cited teachings.
The applicant’s reliance on In re Royka should, however, is imprecise. In re Royka, 490 F.2d 981, 984 (C.C.P.A. 1974) directly states the all-elements requirement in the anticipation context (i.e., an anticipation rejection made under 35 U.S.C. § 102, rather than an obviousness rejection made under 35 U.S.C. § 103, as here). The Federal Circuit has recognized application of that principle in the obviousness context (i.e., rejections made under 35 U.S.C. § 103; see also In re Miller, 21-1599, slip op. at 10 (Fed. Cir. Feb. 28, 2022)). Yet, KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-21 (2007) makes clear that an obviousness rejection is not restricted to finding an express teaching, suggestion, or motivation stated verbatim in the references. A reason to combine prior art references may arise from the interrelated teachings of the prior art, known design incentives, known problems, and the background knowledge and ordinary creativity of a person of skill. Thus, the applicant is correct that all limitations must be accounted for, but it is not necessary for every limitation or motivation to appear in a single reference or in an express statement using the language of the claim.
The applicant further argues that Lattwein is principally limited to microbubble treatment and does not teach the use of nanodroplets or phase-change droplets in the biofilm context. That characterization is not persuasive. Lattwein expressly describes “ultrasound-activated microbubble or droplet treatment of bacteria and biofilm” and identifies microbubbles, droplets, nanodroplets, cavitation, antibiotics, and biofilm as part of the sonobactericide field. Its abstract expressly states that exposure of “microbubbles or droplets” to ultrasound can directly affect bacteria and enhance antibiotic or therapeutic efficacy.
Thus, Lattwein is not properly characterized as teaching only conventional micron-scale microbubbles acting externally upon the biofilm. The prior rationale also did not depend upon Lattwein alone supplying every structural property of the PCCA. Rather, Chen was relied upon for highly volatile PFC nanodroplets and ultrasound-induced phase transition, Lattwein for the bacterial/biofilm therapeutic context and sonobactericide mechanism, and Zhou for established ADV physics and PFC-selection principles.
The applicant also argues that the cited combination improperly treats microbubbles and PCCAs as interchangeable and overlooks the ability of PCCAs to penetrate a biological structure before being converted to bubbles. The examiner agrees that a PCCA nanodroplet and a preexisting gas microbubble are structurally different before activation. Applicant is also correct that nanoscale phase-change droplets may possess transport characteristics unavailable to micron-scale gas bubbles. That distinction, however, does not by itself defeat the previous rationale.
Chen teaches nanodroplets produced from highly volatile perfluorocarbon material, including perfluorobutane, with peak droplet sizes around 200-300 nm, and teaches vaporization under ultrasound into gaseous bubbles for enhanced delivery. Zhou independently explains that submicron droplets can overcome limitations associated with conventional microbubbles and can undergo localized conversion to gas microbubbles following ultrasound exposure. Moreover, the concept that smaller PCCA droplets may access regions inaccessible to larger preformed microbubbles is consistent with, rather than contrary to, the rationale for substituting a phase-change nanodroplet for a conventional cavitation nucleus where improved penetration is desired. Accordingly, Applicant has not shown that the Chen, in view of Lattwein and Zhou combination was technically incompatible or that a skilled artisan would have lacked any reason to employ ultrasound-responsive phase-change droplets in a biofilm-treatment context.
The applicant argues that the cited art fails to teach the claimed low-boiling-point PFC core. That argument is not persuasive with respect to the material-selection limitation considered independently. Chen teaches nanodroplets formed from highly volatile perfluorobutane, while Zhou expressly explains that ADV may be practiced with liquids having a normal boiling point near or below body temperature and specifically discusses perfluorocarbons as suitable materials. Zhou further explains that a lower-boiling PFC such as perfluoropentane facilitates vaporization at lower acoustic amplitude.
Consequently, the record supports the proposition that boiling point was recognized as affecting ADV behavior and acoustic vaporization requirements. The general principle that optimization of a parameter recognized in the art as affecting the relevant result may support obviousness remains applicable (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); MPEP §2144.05). Likewise, where the prior art discloses overlapping numerical ranges or sufficiently close ranges (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)). Establishing that the variable and its relationship to the result were recognized in the prior art is more clearly articulated in the new rejections, as stated above.
The newly added oxygen-containing PCCA and oxygen-release limitations introduced by the amendments changes the dispositive issue. Amended claim 1 no longer merely requires a low-boiling PFC PCCA used with ultrasound to improve therapeutic penetration into a microbial biofilm. Claim 1 now additionally requires the phase-change contrast agent to comprise a liquid perfluorocarbon core and dissolved or encapsulated oxygen, release of that oxygen at the microbial biofilm site during or after ADV, increased penetration relative specifically to ADV conducted in the absence of oxygen release, and greater antimicrobial activity from oxygen release plus ADV than from ADV without oxygen release. The previously applied Chen, in view of Lattwein and Zhou combination does not adequately establish those newly added limitations.
Chen teaches volatile PFC nanodroplets and ultrasound-mediated vaporization for delivery, but the relied-upon disclosure does not establish a PCCA comprising the claimed dissolved or encapsulated oxygen or oxygen release at a microbial biofilm. Lattwein establishes sonobactericide, including ultrasound-activated droplets or bubbles for bacteria and biofilm, but the presently cited portions do not establish an oxygen-bearing PCCA releasing oxygen during or after ADV and producing the claimed oxygen-dependent comparative therapeutic effect. Zhou establishes general ADV physics, phase transition of liquid PFC droplets to gaseous microbubbles, and the relationship between PFC properties and vaporization, but does not disclose the presently claimed oxygen-delivery limitation in a microbial biofilm.
The examiner therefore agrees with the applicant, to the limited extent that the prior rejection fails to account for all limitations of amended claim 1. This conclusion is not based on the applicant’s broader proposition that Chen, Lattwein, and Zhou provide no reason to combine PCCAs with biofilm therapy. As explained above, the record provides substantial technical reason for that combination. Instead, the deficiency arises because the applicant has added a further oxygen-loading/release limitation and comparative oxygen-dependent therapeutic results not established by the presently applied combination.
Accordingly, the rejection of amended claims 1, 12, 14-16, and 50-52 under 35 U.S.C. §103 over Chen in view of Lattwein and Zhou, as previously formulated, has been withdrawn and the newly added limitations necessitate further consideration of the prior art and a new rejection under 35 U.S.C. §103 is outlined as detailed above. Claims 1, 12, 15, 16, 50-52, and 57-59 are rejected under 35 U.S.C. §103 over Chen in view of Lattwein and Zhou, and further in view of Jandhyala and Kolpen. Claim 14 is rejected under the same combination and further in view of Xu to account expressly for the rhamnolipid-encapsulated microbubble limitation. The new rejections expressly identify where each newly added limitation is taught or suggested, articulate why a skilled artisan would have combined the teachings in the manner claimed, and establish a reasonable expectation of success rather than merely asserting that all individual components were independently known.
The principal technical features added by claims 58 and 59 are supported by the original disclosure. With respect to claim 57, the specification teaches that deep portions of bacterial biofilms can be hypoxic or oxygen-depleted, discusses delivery using oxygen-containing nanodroplets, and reports increased efficacy when oxygen nanodroplets were combined with antibiotic treatment. It also explains that improving oxygen access may stimulate metabolically dormant persisted cells. Nevertheless, the precise amended formulation that “the dissolved or encapsulated oxygen released from the phase-change contrast agent elevates local oxygen concentration within the microbial biofilm” is not sufficiently supported by the originally filed disclosure and accordingly, a §112(a) written description rejection has been made, as outlined above.
The applicant requests rejoinder of the withdrawn claims pursuant to MPEP §821.04. The applicant’s request is premature at this stage. MPEP §821.04 provides that the propriety of the restriction requirement is reconsidered when all claims directed to the elected invention are in condition for allowance. A nonelected claim is eligible for rejoinder where it depends from or otherwise requires all the limitations of an allowable claim. Because the elected claims have not yet been determined to be in condition for allowance, the prerequisite for rejoinder has not been satisfied. Accordingly, the request for rejoinder is denied as premature, without prejudice to reconsideration if and when the elected claims are found allowable.
The applicant’s request for allowance of all pending claims has been considered but is not persuasive on the present record. The amendments overcome the specific informalities identified in the prior action and overcome several of the previously stated §112(b) issues, but do not overcome the new rejections, as outline above. Accordingly, the applicant’s request for immediate allowance of all pending claims is respectfully declined.
In conclusion, the previous objections to claims 1, 12, 50, and 51 are withdrawn; the prior §112(b) rejections concerning inconsistent “biofilm” terminology, the stated bulk boiling-point limitation, the former unspecified threshold language of claim 14, the former “would normally be” terminology of claim 16, and the identified antecedent-basis defects are withdrawn in view of the amendments; the amended causal phrase requiring ultrasound to induce ADV “by releasing” oxygen “during or after” ADV are rejected under §112(b); the applicant’s contention that Lattwein is essentially limited to conventional microbubbles is not persuasive, wherein Lattwein expressly encompasses ultrasound-activated droplets and microbubbles in bacterial and biofilm treatment; the applicant’s contention that Chen/Lattwein/Zhou provide no basis for applying phase-change droplets to biofilm treatment is not persuasive; the applicant is persuasive that the presently formulated Chen/Lattwein/Zhou rejection does not account for the newly added oxygen-containing PCCA, oxygen-release, and oxygen-dependent comparative efficacy limitations, thus, the prior §103 rejection has been withdrawn and new grounds of rejection have been made supported by appropriate prior art; new claims 57-59 have been examined on the merits, wherein claims 58-59 have substantial express support in the original disclosure and claim 57 lacks sufficient written-description support for the specific “elevates local oxygen concentration” limitation; the applicant’s request for rejoinder under MPEP §821.04 is premature because the elected invention has not yet been found allowable. No claims are allowable at this time.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 (87 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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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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