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 Amendment filed on 07/23/2026; and IDS filed on 07/23/2026.
Claims 2, 4, 9-11, 15 have been amended.
Claims 2 and 5 have been canceled.
Claims 2, 4, 6-19 are pending in the instant application.
Claims 9, 11, 13 have been withdrawn from consideration.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Claim 16 is rejoined in view of Applicant’s request for rejoinder and in view of the amendment to claim 15.
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, 4, 6-8,10,12,14-19 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 in view of ERIKSEN et al (WO 99/53963).
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 patent does not recite using a therapeutic such as radioisotopes.
ERIKSEN teaches the prior art had known of therapeutics (see pg. 37-40), such as genetic material (see pg. 40, line 1), antineoplastic agents (see pg. 37, line 34), which is a chemotherapeutic, and radiochemicals, such as beta-emitters (see pg. 39, line 30), which reads on radioisotopes.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a therapeutic such as radioisotopes. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because radioisotopes, genes and chemotherapeutics are functional equivalents of therapeutics well-known in the prior art.
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, 4, 6-8, 10, 12, 14-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/755,221; 18/553,524; 18/553,535 (reference application) in view of ERIKSEN et al (WO 99/53963).
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 patent does not recite using a therapeutic such as radioisotopes.
ERIKSEN teaches the prior art had known of therapeutics (see pg. 37-40), such as genetic material (see pg. 40, line 1), antineoplastic agents (see pg. 37, line 34), which is a chemotherapeutic, and radiochemicals, such as beta-emitters (see pg. 39, line 30), which reads on radioisotopes.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a therapeutic such as radioisotopes. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because radioisotopes, genes and chemotherapeutics are functional equivalents of therapeutics well-known in the prior art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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, 4, 6, 10, 12, 14-19 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 VAN WAMEL et al (Radionuclide tumour therapy with ultrasound contrast microbubbles. Ultrasonics 42 (2 004) 903–906) and ERIKSEN et al (WO 99/53963).
Regarding independent claim 2, POSTEMA teaches ultrasound imaging contrast agent microbubbles (see abstract) can 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 and about 500kHz.
Additional disclosures include: drugs and genes delivery (see pg. 32, 2nd col), such as radionuclide cited in reference #88 to VAN WAMEL (see pg. 39, reference #88).
POSTEMA does NOT teach explicitly administering a separate therapeutic, such as radioisotopes; the details of the clustering microbubbles; or applying a first frequency of about 2-10 MHz to the cluster.
VAN WAMEL, which is reference #88 cited is POSTEMA, teaches ultrasound and contrast microbubbles can increase the uptake of radionuclide (see abstract), wherein the radionuclide is administered separately for the contrast microbubbles (see pg. 904, section 2.4). Additional disclosures include: a lower radionuclide doses could reach the same anti-tumor effect (see abstract). Thus, decreasing adverse effect.
ERIKSEN teaches the details of clustering microbubbles recited in Applicant’s claims, wherein 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 to the desired size.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a separate therapeutic, such as radioisotopes. The person of ordinary skill in the art would have been motivated to make those modifications, because it would treat tumors at a lower radiation dosage, and reasonably would have expected success because all the references dealt in the same field of endeavor, such as contrast microbubbles.
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 claim 4, as discussed above, POSTEMA teaches drugs, such as radionuclide 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 a drug, such as 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). Thus, it would have been obvious that other therapeutics can also be delivered before, with or after the contrasting microbubbles.
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 claims 15-16, as discussed above, POSTEMA teaches using a frequency of 0.5 MHz, which 500kHz.
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, 4, 6-8, 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 VAN WAMEL et al (Radionuclide tumour therapy with ultrasound contrast microbubbles. Ultrasonics 42 (2004) 903–906) and ERIKSEN et al (WO 99/53963) and OSTENSEN (WO 98/17324).
As discussed above, the references teach Applicant’s invention.
Regarding claims 7-8, the references do not teach the first application is applied for about 45 seconds or up to about 75 seconds.
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). OSTENSEN further 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.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate the first application is applied for about 45 seconds or up to about 75 seconds. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because OSTENEN has shown that the clustering microbubbles can enlarge at these settings.
Response to Amendment
Applicant argues that with at least some of the alleged species identified in the Restriction and Requirement to Elect dated November 20, 2025. As discussed in our Response filed January 14, 2026, "a requirement for restriction to a single species may be proper if the species are mutually exclusive. Claims to different species are mutually exclusive if one claim recites limitations disclosed for a first species but not a second, while a second claim recites limitations disclosed only for the second species and not the first" (MPEP § 806.04(f)). Here, Example 2 described in the Specification illustrates the alleged mutually exclusive features (diameter and circularity) are not inherently mutually exclusive and can exist in the same method. 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, these features are not mutually exclusive.
In view of Applicants amendment to claim 15, the Examiner will rejoin claim 16.
Applicant argues that amended Claim 2 now recites, inter alia, a step of "applying a first application of acoustic energy comprising a frequency of about 2-10 MHz to enlarge the cluster composition," a step of "applying a second application of acoustic energy comprising a frequency of about 200-1 000kHz to oscillate the cluster composition," and a step of "administering a separate therapeutic agent to the subject, wherein the therapeutic agent comprises radioisotopes." Claim 2 was alternatively rejected as unpatentable over Postema in view of Eriksen. The Office Action admits Postema fails to disclose clustering microbubbles or applying a first frequency of about 2-10 MHz, and relies on Eriksen for these limitations (Office Action ag pg. 14-15). However, as discussed above, Eriksen fails to disclose two steps of insonation, and the Office Action has not shown Postema discloses a method including two steps of insonation as recited. Accordingly, Applicant respectfully requests reconsideration and withdrawal of these rejections. Moreover, even assuming it would have been obvious to modify Postema with Eriksen, which Applicant does not concede, the Office Action has not shown that either Postema or Eriksen disclose at least the recited limitation of administering therapeutic radioisotopes.
The Examiner finds this argument unpersuasive, because as discussed in the rejection above, the references teach Applicant’s limitations, including the newly amended limitation of “administering therapeutic radioisotopes.
Applicant argues that none of the reference US Patents or co-pending Applications recite "administering of a therapeutic agent comprising radioisotopes," as now required by the instant claims.
The Examiner finds this argument unpersuasive, because as discussed in the rejection above, the references teach Applicant’s limitations, including the newly amended limitation of “administering therapeutic radioisotopes.
Conclusion
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 (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at (571) 272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAKE M VU/Primary Examiner, Art Unit 1618
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