DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-10 are under consideration.
Priority
This application claims priority to provisional application 63/332,594. Therefore, it is entitled to the 19th April 2022 priority date of the parent application.
Specification
The use of the term LabVIEW, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is requested to check the entire disclosure for any other terms which are trade names or a marks used in commerce, and rectify accordingly.
Claim Interpretation
sonopermeation in claims 1, 6, and 10 is being interpreted as in para [0032] to mean use of targeted image-guided drug delivery, using focused ultrasound (FUS) with “microbubble” ultrasound contrast agents (UCAs).
In the absence of guidance in the specification, Perfusion rate in claims 2 and 3 are being given the BRI to mean rate of blood flow as is customary in the field of medicine (1st line of introduction, Mudaliar A.V. et al., J Biomech Eng. 2008 Dec;130(6):061013).
Longitudinal quantitative… in claims 3 and 4 are being given the BRI to mean measurements made over time as per MeSH (MeSH Unique ID: D008137, 1974).
Claim 1 and 10 are interpreted as requiring the following steps numbered below from 1 onwards. The lettered lines a), b),.. etc., are wherein or whereby clauses which are not given patentable weight as they lack structure:
loading iNOS-expressing plasmid DNA into microbubbles to produce loaded microbubbles;
infusing the loaded microbubbles into a space surrounding the tumor in the subject;
applying image-guided focused ultrasound (FUS) to the tumor,
whereby the iNOS- expressing plasmid DNA is delivered selectively into the tumor through sonopermeation,
whereby iNOS is selectively expressed in the tumor, and
whereby nitric oxide (NO) levels in the tumor increase;
a. allowing perfusion of the tumor to increase over a period of time
b. as a result of increased nitric oxide levels; and
administering a therapeutic agent to the space surrounding the tumor in the subject,
a. whereby uptake of the therapeutic agent into the tumor occurs.
Claim 10 is similarly interpreted as claim 1:
loading iNOS-expressing plasmid DNA into microbubbles to produce loaded microbubbles;
infusing the loaded microbubbles into a space surrounding a tumor in the subject, wherein the tumor is caused by neuroblastoma;
applying image-guided focused ultrasound to the tumor,
whereby the iNOS-expressing plasmid DNA is delivered selectively into the tumor through sonopermeation,
whereby iNOS is selectively expressed in the tumor, and
whereby nitric oxide levels in the tumor increase;
a. allowing perfusion of the tumor to increase over a period of time b. as a result of increased nitric oxide levels;
monitoring perfusion rate of the tumor using longitudinal quantitative contrast-enhanced ultrasound imaging to identify an optimal time for administering the therapeutic agent,
wherein the longitudinal quantitative contrast-enhanced ultrasound imaging visualizes circulation of microbubbles in blood vessels of the tumor and the space surrounding the tumor in the subject, and
wherein the optimal time for administering the therapeutic agent is a time when the tumor perfusion rate is increased;
loading a liposome-encapsulated chemotherapy drug into microbubbles to produce therapeutic loaded microbubbles;
infusing the therapeutic loaded microbubbles into the space surrounding the tumor in the subject; and
applying image-guided focused ultrasound to the tumor,
whereby the liposome-encapsulated chemotherapy drug is delivered selectively into the tumor through sonopermeation, and
whereby the liposome-encapsulated chemotherapy drug increases apoptosis in the tumor and treats the neuroblastoma in the subject.
With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1 - 5 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Villanueva (US 20130204166 A1) in view of Teupe (Teupe, et al., Circulation. 2002;105:1104-1109).
The method recited in claim 1 is being interpreted as requiring 5 steps as detailed in the claim interpretation section above.
Regarding claim 1, Villanueva teaches a combination method of imaging and ultrasound/microbubble targeted nucleic acid delivery method, called ultrasound mediated destruction (UMTD), such method being an improvement over existing methods of gene delivery (abstract; claims 26 - 30). Villanueva’s method involves the following steps:
loading the nucleic acid into microbubbles to produce loaded Microbubbles (Example III, pg. 21, paras [0225] – [0227]);
intravenous injection of the loaded Microbubbles into the subject (Example IV, pg. 21, paras [0228] – [0229]);
Villanueva also teaches a plurality of nucleic acids are loaded onto the microbubbles (claims 1-2). Villanueva contemplates use of UMTD in gene therapy. Such nucleic acids are oligonucleotide therapeutic molecules, siRNA, shRNA, RNAi, miRNA, antisense, transcription factor decoy molecules, deoxyribonucleic acid vectors, genes, and gene fragments (claim 2), for e.g., thymidine kinase sequence (pCMV-TK) (claim 5).
Villanueva’s ultrasound device is capable of directing said microbubble population to said target cells [0007], so as to enable performing concurrent Ultrasound imaging and UMTD (Example XII, pg. 21, first few lines of para [0242]); visualizing microbubble perfusion of the tumor in real time using ultrasound at a low acoustic power to minimize microbubble destruction and then bursting microbubbles to result in perfusion of the tumors [0102].
Upon visualization of microbubbles within the tumor, microbubbles are burst using an orthogonally placed ultrasound transducer (Example XII, pg. 21, middle few lines of para [0242]);
In a proof-of-principle study, when luciferase gene was the nucleic acid of interest, c. increased expression of luciferase was seen in tumors treated so (pg. 10, paras [0107] – [109]); Fig. 2A);
Thus, imaging a microbubble population and delivery of the therapeutic nucleic acids are with image-guided focused ultrasound (FUS). In other words, the technique taught by Villanueva reads on the limitation of sonopermeation as taught in claim 1. Unless reason to believe otherwise, expression of luciferase is a result of the selective expression of the microbubble comprising luciferase gene.
The interval between destructive ultrasound bursts was adjusted to allow full microbubble reperfusion of the tumor prior to the next burst cycle. The number of destructive ultrasound bursts was adjusted to the minimum number required to destroy most bubbles in the tumor as visualized during concurrent low MI imaging . (Example XI, pg. 22, last lines of para [0242]);
Villanueva’s method includes a further therapeutic agent in ganciclovir (GCK). See recitation:
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Regarding claim 2, Villanueva teaches microbubble perfusion of the tumor in real time using ultrasound at a low acoustic power to minimize microbubble destruction and then bursting microbubbles to result in perfusion of the tumors [0102].
Regarding claims 3 and 4, Villanueva teaches time-dependent imaging of microbubble perfusion of the tumor (microbubbles are ultrasound contrast agents, it is possible to simultaneously image microbubble transit through the tumor, thereby enabling more precise real time guidance of plasmid delivery [0099].
Regarding claim 5, Villanueva teaches ultrasound (US) delivery conditions must allow for full perfusion of the target tissue prior to destruction and insonify microbubbles (MB) [0003]. In their working example Villanueva teaches, post- injection of either pCMV-TK or pEGFP-Cl loaded microbubbles and treated with ultrasound, daily ganciclovir (GCV) injections began on day 3 ([0064], Fig. 4). Thus indicating that administration of a therapeutic agent (GCV) is when a high perfusion rate is reached.
Regarding claim 8, the tumor to which the therapeutic agent is administered is a tumor caused by cancer (claims 16 – 20, see recitation below), [0248]).
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Thus, Villanueva’s method is proof of principle that delivery of therapeutic agents, nucleic acid molecules in the case of Villanueva’s method, to slow tumor growth is possible with UMTD (abstract). Villanueva teaches further optimization of treatment parameters are needed, for example, delivery of greater numbers of microbubbles to the tumor by direct arterial cannulation of the tumor blood supply or better as such direct delivery would be an invasive procedure [0143].
Villanueva does not teach the nucleic acid delivered via microbubbles is a plasmid containing iNOS or that perfusion of the tumor is a result of expressing iNOS (claim 1) or that the step of administering the therapeutic agent also follows the steps of prepping and administering the nucleic acid agent (claim 6).
However, it was known well-before the effectively filed date of instant invention that NO has a positive effect on angiogenesis. For instance, Teupe had taught vasculoprotective effects of NO have long been recognized (the well-established vasculoprotective effects of regular physiological exercise have been attributed to the shear stress–induced stimulation of NO release.24–26, pg.1108, right column, last lines). Teupe also had conducted a study wherein NOS is transfected into arterial cells via microbubble and FUS mediated method with the end-result of enhanced NO mediated pivotal vasculoprotective effects. Specifically, Teupe had perfused coronary artery vessels, in vitro, with gas-filled microbubbles further containing plasmid DNA encoding eNOS, sonopermeated the vessels, and measured expression of eNOS protein (Methods section, pg. 1105, Figure 4A). Teupe then had assessed downstream increase in NO production, by assessing the contraction/relaxation (resulting in dilation) response of the vessels (Figure 4C and D).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have been motivated by Villanueva’s assertion that for the method to work, improvements were needed and it was important to have a full perfusion state of the target and thus have acted upon the advantage of NO-mediated dilation as disclosed by Teupe and done so by introducing a plasmid encoding NOS, also taught by Teupe, into the gene therapy method of Villanueva, and arrive at a method for administering a therapeutic agent to a tumor in a subject comprising the instant claimed steps. One of skill in the art could have combined the plasmid encoding NOS as taught by Teupe with the method taught by Villanueva and in combination each element would merely perform the same function as they did separately. One of skill in the art would have reasonable expectation of success because both references contemplate use of DNA loaded microbubbles focused on to a target by sonopermeation for use in gene therapy. See MPEP 2143 I A and 2144 II.
Thus, Villanueva in view of Teupe make obvious instant claims 1 - 5 and 8.
Claim(s) 6-7 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Villanueva (US 20130204166 A1) and Teupe, (Circulation. 2002;105:1104-1109 as applied to claims 1 - 5 and 8 above, and further in view of Bellary (Bellary et al., Theranostics 2020, Vol. 10, Issue 18, 8143-8161).
The method of administering a therapeutic agent to a tumor in a subject comprising the steps of claim 1 is made obvious by the combination of Villanueva and Teupe.
Claim Interpretation for claim 6, the step of administering the therapeutic agent to the space surrounding the tumor in the subject is being interpreted as further comprising the following steps:
loading the therapeutic agent into microbubbles to produce therapeutic loaded microbubbles,
infusing the therapeutic loaded microbubbles into the space surrounding the tumor in the subject, and
applying image-guided focused ultrasound to the tumor, whereby the therapeutic agent is delivered selectively into the tumor through sonopermeation.
Villanueva teaches delivery of therapeutic agents by first loading the agent into microbubbles and followed by UMTD, as discussed for claim 1. Further recitations of Villanueva are pertinent:
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Thus, Villanueva’s method is proof of principle that delivery of therapeutic agents, nucleic acid molecules in the case of Villanueva’s method, to slow tumor growth is possible with UMTD (abstract). Villanueva teaches further optimization of treatment parameters are needed, for example, delivery of greater numbers of microbubbles to the tumor by direct arterial cannulation of the tumor blood supply or better as such direct delivery would be an invasive procedure [0143]. Villanueva further impresses upon the need to combine chemotherapy drugs as single agents are rarely effective in the treatment of cancer [0129, 0143].
Neither Villanueva nor Teupe teach that the step of administering the therapeutic agent also follows the steps of prepping and administering as for the nucleic acid agent, to wit claim 6; wherein the therapeutic agent is a liposome-encapsulated chemotherapy drug, to wit claim 7; wherein the cancer is neuroblastoma, to wit claim 9.
However, before the effective filing date of instant invention, Bellary had taught a method of delivery of doxorubicin to treat neuroblastoma (title).
Regarding claim 6, Bellary’s method comprised the steps of administering the doxorubicin to the space surrounding the tumor in the mouse comprises loading the doxorubicin into microbubbles to produce doxorubicin loaded microbubbles, infusing the doxorubicin loaded microbubbles into the space surrounding the tumor in the mouse, and applying image-guided focused ultrasound to the tumor, whereby the doxorubicin is delivered selectively into the tumor through sonopermeation (methods and materials section on pg. 8147, Fig. 1).
Regarding claim 7, Bellary’s method comprised encapsulating doxorubicin in a liposome (methods and materials section on pg. 8146; L-Dox, Fig. 1).
Regarding claim 9, Bellary’s method treats neuroblastoma (Title; NGP cells, Fig. 2, Fig. 8).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have been motivated by Villanueva’s assertion that cancer therapeutics would benefit from a combination of drugs and thus have incorporated into their method the elegant study of Bellary. Villanueva had already demonstrated that a cancer therapy such as GCV in combination with their microbubbles serves well as a therapeutic regimen. Bellary had already demonstrated that another chemotherapy such as doxorubicin administered by following the FUS protocol serves well as a cancer therapy. One of skill in the art would be motivated to substitute the GCV in Villanueva’s method with Bellary’s liposome encapsulated chemotherapy for the advantage of treating neuroblastoma. One of skill in the art could have made the substitution with a reasonable expectation of success because both references demonstrate the efficacy of therapeutic agent-loaded microbubbles focused on to a target by sonopermeation for use in treating tumors. See MPEP 2143 I B and 2144 II.
Thus, Villanueva and Teupe in view of Bellary make obvious instant claims 6 - 7 and 9.
Regarding claim 10, the teachings of Villanueva, Teupe, and Bellary discussed above as applied to claims 1 - 9 are similarly applied to claim 10. Therefore, the steps recited in claims 1 – 9 put together by the ordinary artisan would result in the method of claim 10.
Thus, Villanueva and Teupe in view of Bellary make obvious instant claim 10.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Relevant Prior Art Not relied Upon
The following art is made note of and not currently relied on, but is relevant to applicants invention: Jespersen (US 20140039320 A1). The closest prior art is applied above.
Jespersen had taught a contrast enhanced ultrasound (CEU) system or Doppler-based ultrasound system for measuring micro-vascular flow distribution in a tissue portion of a mammal, thus useful in monitoring and assessing ratio of an agent that is transported in to a particular tissue by the blood (tissue substance extraction), such as oxygen, drugs and nutrients into the tissue, and diagnosis of angiopathy (abstract, summary paras 0006 - 0009).
Jespersen had taught a need for measuring micro-vascular flow distribution of an agent (e.g., Jespersen’s working example measures oxygen as the agent) to an intended site such as…tumor ([0002], [0017]; neo-angiogenesis in malign tumors and is therefore a powerful diagnostic tool in oncology, [0037]). Jespersen’s system has an ultrasonic transducer and a processor arranged to make pertinent measurements ((101) and (110) respectively of Fig. 10). By using their system of Contrast Enhanced Ultrasound (CEU), Jespersen had taught computing cerebral metabolic rate of oxygen consumption (CMRO) by first measuring mean transit time (MTT) and a second indicator of heterogeneity, capillary transit time heterogeneity (CTTH), (σ). See pertinent recitations below:
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Jespersen had taught a step of measuring key parameters in a contrast enhanced ultrasound imaging in the process of monitoring of perfusion rate. For brevity, see claims 25 and 26 below:
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Jespersen had taught measuring an agent that is transported in to a particular tissue by the blood such as NO ([0001], [0061]; such as a gas bubble, [0095]; NO, [0099]) and demonstrated a working example of measuring oxygen (see citations for claims 2 – 3 above, as well as [0111]).
Jespersen had taught that their model predicts perfusion rate:
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Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635