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 .
Acknowledgement of Receipt
Applicant’s Response, filed 9/15/2025, in reply to the Office Action mailed 3/14/2025, is acknowledged and has been entered. Claims 1 and 27 have been amended. Claims 1-10, 18, 23, 26, 27 and 31 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. New grounds for rejection are set forth herein, necessitated by claim amendment.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 7-10 and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Back et al. (Radiation Oncology, 2017, 12, 46).
Back discloses reducing radiation dose to normal brain through a risk adapted dose reduction protocol for patients with favourable subtype anaplastic glioma. In patients with isocitrate dehydrogenase (IDH) mutated anaplastic glioma determine the dosimetric benefits of delivering radiation therapy using a PET guided integrated boost IMRT technique (ib-IMRT) compared with standard IMRT (s-IMRT) in reducing dose to normal brain (page 1).
Ten patients with anaplastic glioma, identified as a favourable molecular subgroup through presence of IDH mutation, and managed with radiation therapy using an ib-IMRT were enrolled into a dosimetric study comparing two RT techniques: s-IMRT to 59.4Gy or ib-IMRT with 59.4/54Gy regions. Gross Tumour volume (GTV) and Clinical Target Volumes (CTV) were determined by MRI, 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET imaging. A standard risk Planning Target Volume (PTVsr) receiving 59.4Gy (PTV59.4) in the s-IMRT technique was determined by MRI T2Flair and FET PET. For the ib-IMRT technique this PTVsr volume was treated to 54Gy, and the high-risk PTV (PTVhr) receiving 59.4Gy was determined as a higher risk region by FDG PET and MRI gadolinium enhancement. Standard dosimetric criteria and normal tissue constraints based on recent clinical trials were used in target delineation and planning. Normal Brain was defined as Brain minus CTV. Endpoints for dosimetric evaluation related to mean Brain dose (mBrainDose), brain volume receiving 40Gy (Brainv40) and 20Gy (Brainv20). The variation between the dosimetric endpoints for both techniques was examined using Wilcoxon analysis. Results: The 10 patients had tumours located in temporal (1), parietal (3), occipital (2) and bifrontal (4) regions. In ib-IMRT technique the median volume of PTVhr was 25.5 cm3 compared with PTVsr of 300.0 cm3. For dose to PTVhr the two treatments were equivalent (p = 0.33), and although the ibIMRT had a prescribed 10% dose reduction from 59.4Gy to 54Gy the median reduction was only 5.9%. The ib-IMRT dosimetry was significantly improved in normal brain endpoints specifically mBrainDose (p = 0.007), Brainv40 (p = 0.005) and Brainv20 (p = 0.001), with a median reduction of 9.3%, 19.0 and 10.8% respectively. After a median follow-up of 38 months two patients have progressed, with no isolated relapse in the dose reduction region.
In conclusion, an approach using ib-IMRT for anaplastic glioma produces significant dosimetric advantages in relation to normal brain dose compared with s-IMRT plan. This is achieved without a significant reduction to the target volume dose despite the reduction in prescribed dose. This technique has advantages to minimise potential late neurocognitive effects from high dose radiation in patients with favorable subtype anaplastic glioma with predicted median survival beyond ten years.
Technological improvements in diagnostic imaging, nuclear medicine and radiation therapy treatment can potentially deliver a more targeted dose of radiation to the tumour and spare normal brain. Similarly in favourable anaplastic glioma (AG) there may be a less aggressive region of the tumour that may be managed with lower radiation dose as utilized in primary low grade glioma. This study aims to evaluate the dosimetric benefits of a novel radiation approach for favourable AG utilizing improved targeting of radiation therapy (intensity modulated radiation therapy) to areas within the tumour at different dose levels (integrated boost) defined by MRI and nuclear medicine techniques (dose painting) (page 2).
Accordingly, a method for treating a human subject, comprising administering to brain tissue of a human subject an effective amount of one or more therapeutic agents (i.e. radiation), imaging the subject to assess the one or more administered therapeutic agents; and adjusting dose and/or distribution of the one or more therapeutic agents based on imaging data obtained following the administering of the one or more therapeutic agents is achieved.
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.
Claim(s) 1-8, 18, 26, 27 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Treat et al. (Int. J. Cancer, 2007, 121, p. 901–907).
Treat teaches a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 6 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 6 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r 5 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRI guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies (page 901).
In order to deliver DOX to the brain in a targeted manner, we first investigated the use of MRI-guided focused ultrasound to induce local BBB disruption in the rat brain when transmitted through the intact skull. Successful BBB disruption was confirmed by localized regions of increased signal intensity on T1-weighted MR images of the brain, because of the penetration of the MR contrast agent through the BBB (Fig. 2a).
Accordingly, administration of a therapeutically effective amount of a therapeutic agent to brain tissue through the BBB is taught as well as imaging and assessment of the therapeutic agent.
With regard to claims 7 and 8 and adjusting dose and/or distribution, is noted that the claims do not actively recite a second administration step, only that administration is modified based on the imaging assessment. Further, Treat discloses variation in therapeutic level of DOX with Optison, such that an Optison dose of 0.1 mL/kg, the delivery of therapeutic levels of DOX by focused ultrasound had only minimal vascular effects but no macroscopic tissue damage in the brain. These effects are certainly less than would be caused by the invasive procedures required for currently available methods of intratumoral delivery of chemotherapy agents. We delivered even greater concentrations of DOX to the brain with 0.2 and 0.5 mL/kg Optison, but the tissue damage was more significant and greater than previously seen in rabbits (page 906). Although further investigation is required to evaluate its efficacy in animal tumor models and to optimize its parameters for clinical application, our technique using MRI-guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with primary or metastatic CNS malignancies (page 906).
Treat teaches administration to rat, rather than a human.
Walczak discloses a method of administering a therapeutic agent directly to the brain parenchym through a compromised region of the blood-brain barrier in a subject having a brain disorder, comprising: (a) disrupting the blood-brain barrier (BBB) at an isolated region by locally administering an effective amount of a hyperosmolar agent at said region using a catheter, and (b) administering a therapeutically effective amount of a therapeutic agent, wherein said disrupting step is performed using non-invasive MR (magnetic resonance) imaging with a contrast agent to visualize local parenchymal transcatheter perfusion at said isolated BBB region thereby indicating that the BBB region is compromised (paragraph 0009).
In another aspect, the present invention provides a computer-implemented system for measuring, monitoring, processing, and calculating a model for optimized BBB opening in a subject undergoing BBB hyperosmolar-based perfusion during real-time MRI imaging (paragraph 0016).
Treatment,” particularly “active treatment,” refers to performing an intervention to treat prostate cancer in a subject, e.g., reduce at least one of the growth rate, reduction of tumor burden, reduce or maintain the tumor size, or the malignancy (e.g., likelihood of metastasis) of the tumor; or to increase apoptosis in the tumor by one or more of administration of a therapeutic agent, e.g., chemotherapy or hormone therapy; administration of radiation therapy (e.g., pellet implantation, brachytherapy), or surgical resection of the tumor, or any combination thereof appropriate for treatment of the subject based on grade and stage of the tumor and other routine considerations. Active treatment is distinguished from “watchful waiting” (i.e., not active treatment) in which the subject and tumor are monitored, but no interventions are performed to affect the tumor. Watchful waiting can include administration of agents that alter effects caused by the tumor (e.g., incontinence, erectile dysfunction) that are not administered to alter the growth or pathology of the tumor itself (paragraph 0058).
Advantages are precise anatomic visualization and the ability to continuously monitor the tissue effect (paragraph 0075).
MRI-guided targeted IA mannitol-induced BBBD in rabbit brainstems could be performed, allowing for highly selective delivery of chemotherapeutic agents to the pons. Assessment of therapeutic drug delivery after BBBD could be depicted with fluorescent agents (paragraph 0193).
DSC MRI of IA Feraheme boluses allowed real-time assessment of local parenchymal perfusion, manifested as MRI signal reduction (hypointensity) (data not shown). Real-time DSC MRI depicted distinct areas of parenchymal perfusion, whereas conventional x-ray DSA showed perfused vasculature. Rapid Feraheme washout with clearance of the hypointensities immediately after the bolus allowed for repetitive boluses at different speeds and microcatheter locations with subsequent DSC imaging; thus these parameters could be adjusted to achieve the desired perfusion territory (paragraph 0206).
A transfemoral approach for microcatheter IA mannitol delivery to the vertebrobasilar system in rabbits is feasible and produces BBBD. Assessment of BBBD for chemotherapy should consider the size of therapeutic agent, as differential extravasation across the BBB was seen with gadolinium versus EB (paragraph 0224).
Accordingly, administration of an effective amount of therapeutic agent is administered to a subject and imaging and assessment is taught. A subject may be a human or animal (paragraph 0055).
It would have been obvious to one of ordinary skill in the art at the time of the invention to extend the teaching of using MRI guided focused ultrasound to achieve therapeutic levels of DOX in the brain to human patients when the teaching of Treat is taken in view of Walczak. One would have been motivated to do so because Treat teaches that MRI-guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with primary or metastatic CNS malignancies. One would have had a reasonable expectation of success in doing so because Treat teaches that parameters may be optimized for clinical application, and because Walczak teaches that BBBD for chemotherapy including, administration of an effective amount of therapeutic agent is administered to a subject and imaging and assessment is taught, in which a subject may be a human or animal. Further, Walczak teaches highly selective delivery of chemotherapeutic agents to the pons, which is interpreted to encompass control distribution of the one or more therapeutic agents based on imaging data.
Conclusion
No claims are allowed at this time.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618