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
The listing of claims filed 05 February 2026, have been examined. In response to the Requirement for Restriction/Election, dated 05 December 2025, the applicant has elected Group 1, Species A (claims 1, 12, 14-16, and 50-52), for prosecution without traverse in the reply filed 05 February 2026. The election without traverse is therefore made final and cannot be further petitioned under 37 CFR 1.144.
Claims 2-11, 13, 17-31, 33-49, and 53-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention (see also MPEP § 821.03). Claim 32 is canceled and no new claims have been added. Claims 1, 12, 14-16, and 50-52 are pending. Preliminary Specification amendment filed 01 April 2024, is also acknowledged.
Claim Objections
Claims 1, 12, 50 and 51 are objected to because of the following informalities:
Claim 1 is objected to for the phrase "delivering ultrasound pulses to the microbial biofilm which cause the cavitation enhancing agent to cavitate" which contains a potential ambiguity. The relative clause "which cause" grammatically could refer to "the microbial biofilm" immediately preceding it or "ultrasound pulses" , which seems to be the intent. This could be clarified by adding a comma (i.e., "delivering ultrasound pulses to the microbial biofilm, which cause the cavitation enhancing agent to cavitate."). In addition, the claim recites 37 C°, in which the degree symbol improperly follows the notation for Celsius (C) and should be corrected to 37° C.
Claim 12 is objected to as being of improper dependent form. Claim 12 depends from claim 8, however, claim 8 is not present in the current claim set. Accordingly, claim 12 fails to comply with 37 CFR 1.75(c) because it does not further limit a preceding claim. Correction is required by amending the dependency to refer to an existing claim.
Claim 50 is objected to for minor grammatical inconsistency in parallel structure. The claim mixes verb forms by reciting "comprises" (present tense, active) for the first element, but "having" (present participle) for the second element. This lack of parallel structure renders the claim unclear as to whether the particle limitation is positively recited. The structure should be parallel. The applicant is advised to amend claim 50 to provide proper parallel grammatical structure by using consistent verb forms to clearly define the claimed subject matter (e.g., "wherein the cavitation enhancing agent comprises a plurality of particles smaller than one micron in diameter, and each particle comprises a core that comprises a liquid in a metastable state prior to administration to the biofilm.").
Claim 51 is objected to for a punctuation error. Claim 51 lacks a comma after “claim 1” and before “wherein”, which is required for proper grammatical form. The applicant is advised to amend the claim to include a comma (i.e., “claim 1, wherein”).
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 and 50-52 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.
Claim 1 introduces "a microbial biofilm" and uses both "the microbial biofilm" and "the biofilm" interchangeably. Consistent terminology establishing clear and proper antecedent basis is required. The applicant is advised to amend the claim to change the last reference in the claim of "the biofilm" to "the microbial biofilm".
In addition, claim 1 is rejected for the limitation “a material that has a boiling point less than 37 C° at atmospheric pressure”, which renders the scope unclear when read in light of the recitation that the material forms a “core” of a “phase change contrast agent”. It is unclear whether the claimed boiling point refers to the bulk material, the encapsulated state, or the effective boiling point under nanoscale confinement. The metes and bounds of the claim are therefore uncertain. In addition, it would be unclear to one of skill in the art which materials across the entire genus that have a boiling point < 37 C° at atmospheric pressure are encompassed and would result in consistent cavitation behavior. The material is ambiguous without disclosure of representative species or guidance in the specification. In particular, the claim encompasses a wide range of volatile compounds and without guidance as to which materials across the entire genus are appropriate, one of ordinary skill in the art would not understand which materials are encompassed.
Further, the functional limitation “which cause the cavitation enhancing agent to cavitate and increase penetration” in claim 1 lacks objective boundaries, as the degree of “increase penetration” is not quantified or otherwise bounded. Dependent claims 14-16 and 50-52 are included with the rejection of claim 1 because they do not cure the defect noted above (presumably also claim 12 if it depends from claim 1).
Claim 12 recites “the microbubble,” which lacks antecedent basis in claim 8, from which it depends (as presented in the record), nor has “a microbubble” been introduced in any claim proceeding claim 8 within the claim set (i.e., claim 1). Without a prior recitation of a microbubble, it is uncertain as to the structure to which the limitation refers. It is also unclear whether “the microbubble” refers to the cavitation enhancing agent recited in the base claim, the phase change contrast agent, or another structure, rendering the scope ambiguous. To overcome this rejection, the applicant is advised to recast claim 12 to depend from claim 1 and introduce microbubble as “a microbubble” in the claim (e.g., “wherein the cavitation enhancing agent comprises a microbubble”).
Claims 12, 15, 16, and 50, which depend from claim 1 (assuming claim 12 now depends from claim 1 as well), recite “a core”, however “a core” has been introduced previously in claim 1. Therefore, it is unclear if the “a core” of the claims refer to the same “a core” as claim 1 or a different “a core”. The applicant is advised to amend the claims to state “the core”, rather than “a core” to establish proper antecedent basis.
Likewise, claim 14 depends from claim 1 and recites, “a phase change agent”, however “a phase change agent” has been previously introduced in claim 1, thus the claim should recite “the phase change agent” since it has already been established in claim 1. In addition, the phrase “exceeding a threshold” is indefinite in claim 14 because the claim fails to specify the threshold value or provide objective criteria for determining when the threshold is exceeded. The scope of the claim is therefore dependent on an undefined parameter.
Claim 16 recites the limitation “a material that would normally be a gas in bulk state at 37° C and standard atmospheric pressure” this is indefinite because the phrase “would normally be” introduces ambiguity and lacks objective boundaries. It is unclear whether this refers to standard thermodynamic properties or to behavior under specific formulation conditions. In addition, it would be unclear to one of ordinary skill in the art which materials “that would normally be a gas in bulk state at 37° C” would result in consistent cavitation behavior across the entire genus without disclosure of representative species or guidance in the specification. The claim encompasses a wide range of phase change volatile compounds and without further guidance as to which materials are intended, the scope of the claim is uncertain.
Claims 50 and 51 depend from claim 1 and recite “the biofilm” (recited twice in claim 51), however “a microbial biofilm” is introduce previously in claim 1, thus “the biofilm” lacks proper antecedent basis and should be corrected to “the microbial biofilm” to be consistent with antecedent basis in claim 1.
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, 14-16 and 50-52 are rejected under 35 U.S.C. § 103 as being unpatentable over Chen et al. (US-10322178-B2; published 18 June 2019, hereinafter referred to as “Chen”) in view of Lattwein (Lattwein et al., Sonobactericide: An Emerging Treatment Strategy for Bacterial Infections. Ultrasound Med Biol. 2020 Feb;46(2):193-215; Epub 2019 Nov 5) and in further view of Zhou (Zhou Y. Application of acoustic droplet vaporization in ultrasound therapy. J Ther Ultrasound. 2015 Nov 11;3:20).
Chen teaches administering a phase-change nanodroplet cavitation enhancing agent and applying ultrasound to induce cavitation for delivering a therapeutic agent (claim 1) to enhance drug delivery (claim 17, column 6, lines 10-35; col. 8, lines 5-24). Chen teaches wherein the ultrasound is delivered in pulses (claim 20), wherein the applying an ultrasound beam cause the nanodroplets vaporize, or cavitate, or convert to microbubbles that cavitate, thereby causing the blood brain barrier to open and allowing the therapeutic agent to diffuse out of the blood vessel through the open blood brain barrier and to the target location in the brain (i.e., increase therapeutic agent penetration; claim 1 and column 7, lines 19-52). Chen discloses that such cavitation enhances permeability and penetration of therapeutic agents into biological tissues (column 6, lines 24-34 and column 13, lines 55-60).
Chen also teaches nanodroplets and microbubbles formulated using a perfluorocarbon gas perfluorobutane (boiling point -1.7° C, significantly below 37° C) core for the ultrasound contrast agent (column 7, lines 19-28 and Example 1, column 6, lines 47-48). The perfluorocarbon nanodroplets (phase changing microbubble condensation liquid) taught by Chen exists as liquid at room temperature and can be vaporized back to gas or convert to microbubbles that cavitate (claim 1), meeting the metastable liquid limitation of instant claim 16 and the microbubble limitation of instant claim 51.
Chen teaches wherein the nanodroplets each have a diameter between 100-300 nm (claim 3) and may contain a plurality of nanodroplets (column 4, line 67-column 5, line 2, claim 1 and column 18, lines 53-65), meeting the particle diameter limitation of instant claim 50 and strongly overlapping with the claimed particle size range of 100-400 nm in diameter of instant claim 52. In Drawing FIG 5A, Chen illustrates representative size distributions of nanodroplets, which primarily fall within the 100-300 nm diameter range however encompass some nanodroplets over 400 nm, thus fully teaching the upper range of the limitation of instant claim 52.
Chen does not explicitly disclose application to microbial biofilms, wherein the perfluorocarbon is specifically decafluorobutane, perfluoropropane, or perfluoropentane or explicitly recite a boiling point limitation.
Lattwein teaches ultrasound-mediated cavitation for enhancing antibiotic efficacy in the treatment of bacterial infections and biofilms (Abstract). Lattwein teaches nanodroplets having an average diameter of ~300 nm with a perfluoropentane perfluorocarbon core loaded with an antibiotic therapeutic agent that can be phase-transitioning into microbubbles using ultrasound acoustic droplet vaporization (page 12 last paragraph). The nanodroplets enhanced the effect beyond antibiotics alone (page 14, first 2 lines of Experimental Outcomes) and ultrasound-mediated microbubbles aid in the penetration of antibiotic through biofilms (page 16, lines 4-10). Thus, Lattwein explicitly teaches ultrasound-mediated nanodroplet cavitation with therapeutic antibiotic agents in the microbial biofilm context, enhanced penetration into biofilm via cavitation, and nanodroplet diameter size consistent with the range of from 100-400 nm.
Lattwein does not explicitly teach a boiling point limitation.
Zhou teaches the physics of acoustic droplet vaporization and material selection (page 1, Abstract). Zhou discloses phase-change contrast agents converting from liquid droplets to gas microbubbles under ultrasound energy exceeding a threshold (page 6, paragraphs 1 and 2 and page 8, right column, second paragraph), thus teaching threshold-triggered phase transition. Perfluorocarbons taught include decafluorobutane, pefluoropentane, and perfluorobutane (page 8, Manufacture, first paragraph). Zhou further teaches selection of perfluorocarbons based on boiling point, ideally with materials near or below physiological temperature (page 3-4, Physics, first 4 paragraphs; page 4, Fig.2; and summarized on page 16, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teachings of Chen, Lattwein, and Zhou. It would have been obvious to substitute or apply the phase-change nanodroplets of Chen within the biofilm treatment context of Lattwein because both references rely on the same underlying physical mechanism of ultrasound-induced cavitation. Lattwein explicitly identifies cavitation as the operative mechanism for enhancing antibiotic penetration and Chen provides an improved cavitation modality (i.e., nanodroplets capable of in situ vaporization). This constitutes a simple substitution of one known cavitation agent for another, yielding predictable results, consistent with KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
Zhou teaches that boiling point is a result-effective variable governing vaporization threshold and cavitation efficiency. Selection of perfluorocarbons with boiling points below 37°C would have been obvious to lower the acoustic energy required for vaporization and enable efficient cavitation under clinically relevant ultrasound conditions. Thus, it would have been obvious to one of skill in the art at the time of the invention to select perfluorocarbons with boiling points below 37°C to lower vaporization threshold and improve responsiveness to ultrasound. Optimizing a result-effective variable of known workable values is prima facie obvious (see In re Aller, 220 F.2d 454 (CCPA 1955)). In addition, the prior art also specifically identifies a finite set of perfluorocarbon candidates (e.g., perfluoropentane, decafluorobutane, perfluoropropane). Selection among these constitutes routine experimentation and predictable selection from a known genus (see In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009)).
Chen and Lattwein both teach particle diameter sizes overlapping with the instant claimed range (<1 µm and 100-400 nm). The optimization of particle size diameter is motivated by the recognized advantage that nanodroplets (~300 nm) penetrate dense biological structures (e.g., biofilms) more effectively than microbubbles, explicitly supported by Lattwein. Optimization of size for penetration is routine and predictable optimization of a known parameter impacting biofilm penetration (see In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003)).
A person of ordinary skill in the art would have had a reasonable expectation of success because cavitation-enhanced drug delivery was well established, as evidence by Chen and Lattwein, and the acoustic droplet vaporization behavior and physics related to selection of perfluorocarbons based on boiling point was characterized by Zhou. The biofilm environment does not alter the fundamental physics of cavitation, only the delivery context. Thus, applying known nanodroplet phase-change agents and cavitation system of Chen to a known application such as cavitation enhanced drug penetration into biofilms, as taught by Lattwein, represents routine application of established technology. The resulting method represents no more than the predictable use of prior art elements according to their established functions.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L. SCOTLAND whose telephone number is (571) 272-2979. The examiner can normally be reached M-F 9:00 am to 5:00 pm EST.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615