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 .
Receipt is acknowledged of Applicant’s Restriction Requirement Response filed on 01/14/2026; and IDS filed on 01/15/2026 and 09/29/2025.
Claims 2-19 are pending in the instant application.
Claims 9, 11, 13, 16 are withdrawn from further consideration.
Election/Restrictions
Applicant's election with traverse of “therapeutic agent provided after the cluster composition (claim 10)”; “cluster composition diameter between 3 to 10 μm (claim 12)”; and “the resonance frequency of the enlarged cluster composition (claim 15)” in the reply filed on 01/14/2026 is acknowledged. The traversal is on the ground(s) that the "physical parameters" are the recited cluster composition diameter between 3 to 10 μm (of Claim 12) or the alleged mutually exclusive recited "circularity of about <0.9 (of Claim 13). However, the Restriction Requirement has not shown that a method including a single cluster composition cannot have both a diameter of 3-10 μm and a circularity of about < 0.9 in an aqueous medium, for example but not limited to Example 2 described in the Specification. The recited diameter does not prohibit the recited circularity; therefore, the features are not mutually exclusive. Accordingly, Applicant respectfully requests reconsideration and withdrawal of at least this species restriction. Similarly, the "application frequencies" are the recited resonance frequency of the enlarged cluster composition (of Claim 15) or about 500 kHz (of Claim 16). Again, the Restriction Requirement has not shown that a single method cannot apply an ultrasound frequency that is both the resonance frequency of the enlarged cluster composition and about 500 kHz. The recited frequencies may overlap, for example but not limited to frequencies as disclosed in the Specification at para. [0060]-[0061]. Therefore, the features are not mutually exclusive. Accordingly, Applicant respectfully requests reconsideration and withdrawal of at least this species restriction.
This is not found persuasive because, as discussed in the restriction requirement, claims to the different species recite the mutually exclusive characteristics of such species.
The requirement is still deemed proper and is therefore made FINAL.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2-8,10,12,14-15 and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 12,478,676; 12,377,146; 12,343,396.
The patents recite a method of high frequency sound wave imaging control of agent delivery to a subject, the method comprising: administering a two-component, bi-phasic formulation and a separate therapeutic agent to the subject, wherein the therapeutic agent is selected from the group consisting of genes, chemotherapeutics and immunotherapeutics; imaging a plurality of gaseous components of the bi-phasic formulation to identify a region of interest within said subject; activating a phase shift of a vaporous component of the bi-phasic formulation by a first high frequency sound wave application of the region of interest, such that individual gaseous components are enlarged by the vaporous component to give enlarged individual gaseous components localised at the region of interest; applying a second high frequency sound wave to the region of interest to oscillate the enlarged gaseous components; and analysing the acoustic signature produced by the enlarged gaseous components to quantify the amount of therapeutic agent delivered, wherein the therapeutic agent is delivered separately from the bi-phasic formulation, and wherein the first high frequency is different from the second high frequency and wherein the second high frequency sound wave comprises a frequency in the range of 0.05 to 1 MHz (see US 12,478,676 at claim 1), wherein the bi-phasic formulation comprises an oil component having an opposite surface charge from the gaseous component (see claim 6).
The patents do not specifically recite the frequency ranges as claimed by Applicant. The frequency ranges in a method that uses frequency ranges to enlarge the gaseous components and to oscillate the enlarged gaseous components are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal frequency ranges to enlarge the gaseous components and to oscillate the enlarged gaseous components in order to best achieve the desired results, such as the desired size of the gaseous components and the rate of drug delivery. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of frequency ranges would have been obvious at the time of Applicant's invention.
Claims 2-8,10,12,14-15 and 17-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/755,221; 17/928,065; 18/553,524; 18/553,535 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-applications recite a method for the treatment of pancreatic cancer with ultrasound in combination with a pharmaceutical composition, the pharmaceutical composition comprising: a cluster composition which comprises a suspension of clusters in an aqueous biocompatible medium, where said clusters have a mean diameter in the range 3 to 10 μm, and a circularity <0.9 and comprise: a first component which comprises a gas microbubble and first stabilizer to stabilize said microbubble, a second component which comprises a microdroplet comprising an oil phase and second stabilizer to stabilize said microdroplet, where the oil comprises a diffusible component capable of diffusing into said gas microbubble so as to at least transiently increase the size thereof, and wherein the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions; and a therapeutic agent selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, and combinations thereof, and wherein the therapeutic agent is not paclitaxel in the free, non-albumin-bound form, provided as a separate composition to (a) (see 17/755,221 at claim 1), further comprising the steps of: administering the pharmaceutical composition to a mammalian subject with pancreatic cancer, wherein at least one therapeutic agent is pre-, and/or co- and/or post administered separate to the cluster composition; activating a phase shift of the diffusible component of the second component of the cluster composition by ultrasound insonation of a region of interest within said subject, facilitating extravasation of the therapeutic agent by further ultrasound irradiation (see claim 13), wherein the step of activating a phase shift is performed with ultrasound insonation at a frequency of 1 to 10 MHz (see claim 15), wherein the step of facilitating extravasation is performed with ultrasound insonation at a frequency of 330 to 650 kHz (see claim 16).
The difference between instant application and the patented claims is that the patent claims include additional limitations. Thus, the invention of the patent is in effect a “species” of the “generic” invention of the application claims. It has been held that the generic invention is “anticipated” by the “species”, and, therefore, the application claims are not patentably distinct from the claims of the patent and are rejected on the ground of nonstatutory obviousness-type double patenting. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112, 4th paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Independent claim 2 recites “a frequency of about 200-1000kHz” and dependent claim 15 recites “the second application comprises a frequency at about the resonance frequency of the enlarged cluster composition”. Applicant’s specification discloses “the resonance frequencies of the large, activated bubbles (i.e. frequency components in the range 0.05 to 2 MHZ, preferably in the range 0.1 to 1.5 MHZ, most preferably in the range of 0.2 to 1 MHZ), can be used to produce mechanical and/or thermal bio-effect mechanisms to increase the local permeability of the vasculature and/or sonoporation and/or endocytosis and hence increase delivery and retention of drugs”. Thus, Applicant have not further limited the subject matter in claim 15, because the narrowest interpretation for “resonance frequency” would be 0.2 to 1 MHZ (200-1000 kHz), which is the same frequency recited in claim 1, and the broadest interpretation for “resonance frequency” is 0.05 to 2 MHZ (50-2000 kHz), which is broader than claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
Claim(s) 2-5, 7-8, 10, 12, 15, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over ERIKSEN et al (WO 99/53963) in view of OSTENSEN (WO 98/17324).
Regarding independent claim 2, ERIKSEN teaches a method of treating many different types of diseases (see pg. 40, line 4-5) comprised of:
administration of a gas-containing contrast agent preparations (see abstract) comprised of dispersed gas and an oil-in-water emulsion (see abstract), which reads on administering a cluster composition of gaseous component and oil component;
applying an irradiation of ultrasound beam at 1.5MHz (see pg. 41, line 16-17),
which is about 2 MHz, and reads on applying a first application of acoustic energy comprising a frequency of about 2-10 MHz.
ERICKSON further teaches growth of the dispersed gas may be induced or enhanced by application of appropriate amounts of energy, such as sound energy at lower or higher frequencies. Wherein this permits particularly effective control of factors such as the onset and rate of growth of the dispersed gas. Additional disclosures include: oscillatory movement is imparted to the gas microbubbles through application of ultrasonic energy (see pg. 26, line 4-7 and line 15-16).
ERKISEN does NOT teach applying a frequency of about 200-1000kHz.
OSTENSEN, which is incorporated by ERIKSEN (see ERIKSEN at pg. 1, line 30-31), teaches that ultrasound in the range of 1 kHz and 10 MHz, with continuous or pulse pattern, promote or enhance growth of the dispersed gas (see OSTENSEN at pg. 23, line 5-15). Additional disclosures include: oscillating microbubbles (see pg. 22, line 32).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate another different frequency, such as 1 kHz. The person of ordinary skill in the art would have been motivated to make those modifications, because decreasing the frequency from 1.5 MHz to 1 MHz would decrease the rate of growth of the gas-containing contrast agent when one skilled in the art wishes to slow down the rate of growth, and reasonably would have expected success because both references dealt in the same field of endeavor, such as gas-containing contrast agent preparations.
Regarding claims 3-5, ERIKSEN teaches delivery of therapeutic drugs (see pg. 36, line 27+), such as adenosine (see pg. 36, line 20) and antineoplastic agents (see pg. 37, line 34+), which reads on chemotherapeutic.
Regarding claims 7-8, OSTENSEN teaches microbubble growth can be conducted by ultrasound, such as using frequency of 2.25 MHz for 1 minute (see pg. 75, line 24-35), which reads on about 45 seconds and 75 seconds and additionally reads on a frequency of about 2-10 MHz.
Regarding claim 10, ERIKESEN teaches adenosine may be made substantially simultaneously with administration of the contrast agent composition, followed 10 seconds later by slow injection of a further 150 μg/kg of adenosine (see pg. 36, line 15-20).
Regarding claim 12, ERIKSEN teaches diameter of 1-7 um (see pg. 19, line 35), such as median size of 3.2 (see pg. 43, line 6).
Regarding claim 15, Applicant’s specification discloses “It has been found that the application of low frequency ultrasound, close to the resonance frequencies of the large, activated bubbles (i.e. frequency components in the range 0.05 to 2 MHZ, preferably in the range 0.1 to 1.5 MHZ, most preferably in the range of 0.2 to 1 MHZ), can be used to produce mechanical and/or thermal bio-effect mechanisms to increase the local permeability of the vasculature and/or sonoporation and/or endocytosis and hence increase delivery and retention of drugs”. As discussed above, OSTENSEN teaches using a frequency of 1 kHz.
Regarding claim 17, ERIKSEN teaches oil/diffusible component capable diffusion into the gas component to promote growth (see abstract).
Regarding claims 18-19, ERIKSEN teaches having opposite charges (see abstract), such as attractive electrostatic affinity (see pg. 5, line 5-10).
Claim(s) 2-8, 10, 12, 14-15, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over ERIKSEN et al (WO 99/53963) in view of OSTENSEN (WO 98/17324) and) and MILLER et al (Bioeffects Considerations for Diagnostic Ultrasound Contrast Agents. J Ultrasound Med 2008; 27:611–632).
As discussed above, the references teach Applicant’s invention.
Regarding claims 6 and 14, the references do NOT teach using a mechanical index of 0.2-0.4.
MILLER teaches the bioeffects consideration for diagnostic ultrasound contrast agents (see title), such as microbubbles (see abstract), wherein mechanical index (MI) values greater than 0.4 causes cardiomyocyte death, inflammatory cell infiltration, and premature ventricular contractions (see abstract); thus, it’s obvious for one skilled in the art to use mechanical index less than 0.4. Additional disclosures include: pulsed ultrasound (see pg. 620 at Table 2); pulsed ultrasound with MI of about 0.19 and 0.31 (see pg. 615, 1st and pg. 620, Table 1 and 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using an MI of less than 0.4, such as 0.19 or 0.31. The person of ordinary skill in the art would have been motivated to make those modifications, because it would avoid adverse effects, such as cardiomyocyte death, inflammatory cell infiltration, and premature ventricular contractions, and reasonably would have expected success because all the references dealt within the same field of reference, such as ultrasound contrast agent microbubbles.
Claim(s) 2-6, 10, 12, 14-15, 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over POSTEMA et al (Contrast-enhanced and targeted ultrasound. World J Gastroenterol 2011 January 7; 17(1): 28-41) in view of ERIKSEN et al (WO 99/53963).
Regarding independent claim 2, POSTEMA teaches ultrasound imaging contrast agent microbubbles (see abstract) can also be used for drugs and genes delivery (see pg. 32-34), in treatments, such as antineoplastic treatment (see pg. 34, 2nd col) comprised of:
injecting (see pg. 34, 1st col), which reads on administering, the ultrasound microbubbles (see abstract), such as clustering microbubbles (see pg. 32, Figure 32), which has a layer of oil (see pg. 33, 1st col) and gas phase (see pg. 33, 1st col);
applying sonication (see pg. 32, 2nd col), such as a frequency 0.5MHz with MI (mechanical index) of 0.1 or 0.35 (see pg. 31, Figure 3), which reads on applying a second frequency of about 200-1000 kHz.
Additional disclosures include: drugs and genes delivery (see pg. 32, 2nd col).
POSTEMA does NOT teach details about clustering microbubbles; or applying a first frequency of about 2-10 MHz.
ERIKSEN teaches the prior art had known of ultrasonic gas-containing contrast agent preparations comprised of disperse gas phase and oil phase emulsions (see abstract), wherein the gas phase and oil phase have affinity for each other as a result of having opposite charges (see abstract), which would result in clustering microbubbles composition, which is similar to the ultrasound cluster microbubbles described in POSTEMA.
ERIKSEN further teaches that growth of the dispersed gas may be induced or enhanced by application of appropriate amounts of energy, such as sound energy at lower or higher frequencies. Wherein this permits particularly effective control of factors such as the onset and rate of growth of the dispersed gas, and permits such growth to be localised to particular areas of the body of a subject, for example so as to effect temporary retention of gas in the microvasculature of a target organ/area (see pg. 4, line 24-37), such as tumours (see pg. 41, line 5-15). Ultrasound frequencies, such as 1.5 MHz (see pg. 41, line 17), which reads on applying a first application of acoustic energy comprising of about 2 to 10 MHz to enlarge the cluster composition.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate ERIKSEN’s ultrasound clustering microbubbles and applying a first frequency of 1.5 MHz, which is about 2 MHz. The person of ordinary skill in the art would have been motivated to make those modifications, because it would enlarge the gas microbubbles to be localized in the desired targeted area, such as cancerous areas, for cancer drug delivery, and reasonably would have expected success because both references dealt in the same field of endeavor, such as ultrasound contrast agent microbubbles.
Regarding claims 3-5, as discussed above, POSTEMA teaches drugs and genes can be delivered with the ultrasound imaging microbubbles.
Regarding claims 6 and 14, POSTEMA teaches using a mechanical index of 0.35.
Regarding claim 10, ERIKESEN teaches adenosine may be made substantially simultaneously with administration of the contrast agent composition, followed 10 seconds later by slow injection of a further 150 μg/kg of adenosine (see pg. 36, line 15-20).
Regarding claim 12, ERIKSEN teaches diameter of 1-7 um (see pg. 19, line 35), such as median size of 3.2 (see pg. 43, line 6).
Regarding claim 15, Applicant’s specification discloses “the resonance frequencies of the large, activated bubbles (i.e. frequency components in the range 0.05 to 2 MHZ, preferably in the range 0.1 to 1.5 MHZ, most preferably in the range of 0.2 to 1 MHZ), can be used to produce mechanical and/or thermal bio-effect mechanisms to increase the local permeability of the vasculature and/or sonoporation and/or endocytosis and hence increase delivery and retention of drugs”. As discussed above, ERIKSEN teaches using a frequency of 0.5 MHz.
Regarding claim 17, ERIKSEN teaches oil/diffusible component capable diffusion into the gas component to promote growth (see abstract).
Regarding claims 18-19, ERIKSEN teaches having opposite charges (see abstract), such as attractive electrostatic affinity (see pg. 5, line 5-10).
Telephonic Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAKE MINH VU whose telephone number is (571)272-8148. The examiner can normally be reached Mon-Fri 9:00am-5:30pm.
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/JAKE M VU/Primary Examiner, Art Unit 1618