18381930DETAILED 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/7/2025 has been entered.
Status of Claims
Claims 17 and 28 have been amended. Claims 17, 18 and 21-28 are pending and are examined herein on the merits for patentability.
Priority
The instant Application is a Divisional and claims the benefit of Application No. 16/636,611, filed February 4, 2020, which claims benefit of PCT Application No. PCT/US2018/045783, filed August 8, 2018, which claims benefit of U.S. Provisional Patent Application No. 62/545,970 filed August 15, 2017, and 62/666,417 filed May 3, 2018. It is noted that the ‘970 Provisional Application does not provide written support for the claimed limitations of the claims amended as filed on 10/7/2025, including the full range of limitations directed to delivering an ultrasound pulse... at a burst length of 10-100 ms, as claimed in instant claim 17. Accordingly, for the purpose of applying prior art, the effective date of instant claims 17, 18 and 21-27 is considered to be the filing date of the ‘417 Provisional Application, or May 3, 2018.
It is noted that the effective filing date of claim 28, which recites a burst length of 50 ms, is considered to be August 15, 2017, the filing date of the ‘970 Application.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. 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) 17, 18 and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Airan et al. (Nano Lett., 2017, 17, p. 652−659).
Airan discloses nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems.
We focused on delivery of agents that may readily cross the blood-brain barrier and propose to use focused ultrasound-mediated drug uncaging from nanoparticle carriers with the ultrasound focusing providing a limit on the spatial extent of the drug-based neuromodulation (pages 652-3).
We have generated ultrasound-gated nanoparticle carriers of the small molecule anesthetic propofol. These particles are modified forms of prior described ultrasound-gated “phase-change” particles that were originally designed for chemo-therapeutic delivery. These particles are made of a biodegradable, biocompatible polyethylene glycol-b-polycapro-lactone block copolymer matrix encapsulating a liquid perfluorocarbon core and the drug of interest. Under sonication, the perfluorocarbon core undergoes a liquid togas phase transition, thereby releasing the drug cargo (Figure1). Perfluoropentane was chosen for the perfluorocarbon given its relatively high boiling point while encapsulated that would prevent spontaneous phase change (page 653).
In Figure 2B, the propofol-loaded nanoemulsions with a liquid PFP core are sonicated at a higher frequency such as 1 MHz in these experiments. That sonication induces a liquid to gas phase transition of the PFP which thins the encoated drug-loaded polymer shell, inducing drug release.
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Particles that encapsulated propofol with a liquid perfluorocarbon core and a biodegradable, biocompatible polymer coating were produced (Figure 1) and sized via nanoparticle tracking analysis (Figure 2C). There was a single nanoscale peak of 320 ± 150 nm.
To evaluate the in vivo biodistribution and intravascular residence time of the nanoparticles, the particles were initially doped with a custom synthesized hydrophobic dye. Following intravenous administration of these doped nanoparticles, timed blood samples demonstrated that the whole-blood fluorescence has a decay profile that is faithfully characterized with a double exponential decay model (page 654).
We have then demonstrated the safety of this technique by observing no appreciable injury nor BBB opening within the sonicated brain (page 654).
To demonstrate and assess the functional potency of particle release in vivo, an acute pentylenetetrazol (PTZ)-induced status epilepticus protocol 20 was developed for adult male Fischer 344 rats (Figure 4A,B). We specifically chose this protocol and preparation as prior groups have used this system to assess the degree to which FUS may directly modulate neural activity. Following seizure induction and particle administration, there was no significant difference in baseline EEG power between animals receiving propofol-loaded particles and particles generated with no drug (“Blank”; Supporting Information). Importantly, following FUS administration first at 1.0 MPa estimated peak in situ pressure and then at 1.5 MPa.
Ex vivo 17.6 T MRI, in vivo 11.7 T MRI, and histology confirmed that no deleterious effect of FUS and particle administration was visible (Figure 5). In particular, given the high susceptibility dependence of the MRI protocol used here (note the blooming artifact from microscopic air bubbles along the brain periphery in Figure 5A), the lack of any noted susceptibility artifact or brain parenchymal signal change within the sonicated region confirms the lack of petechial hemorrhage or other cavitation induced damage to the brain parenchyma. Notably, the 17.6 T MRI evaluation covered the entire brain in both axial and coronal planes, without interslice gaps, ensuring that a complete evaluation of the parenchyma was completed for each brain. All MRI images were reviewed by a board certified neuroradiologist. In vivo MRI also confirmed no damage to the brain parenchyma of particle administration and sonication, and no evidence of blood-brain barrier opening with this technique (page 655).
These particles release their drug cargo with dose responses with both peak in situ pressure and with sonication burst length (Figure 2). The threshold peak in situ pressure of 0.5 MPa and the maximal pressure of 1.5 MPa that were used here are both achievable by current clinical transcranial MRg FUS systems. Additionally, the dynamic range of the burst length dose response between 10 ms and 50−100 ms is also achievable with these clinical transcranial MRg FUS systems (page 656).
The particular ultrasound transducer used in this study is known to have a fwhm of ∼1.5 mm transaxially and ∼5 mm longitudinally at 1 MHz (personal communication with the vendor, FUS Instruments, Toronto, CA), providing an effective initial spatial extent for the action of the particles in this preparation (page 658).
With regard to clinical translation, each component of these particles has been previously approved for clinical use indifferent contexts. Additionally, the sonication pressures and burst lengths used in this study are well achievable by FDA-approved transcranial MRg FUS systems that are currently in clinical use. Taken together, this provides a pathway toward clinical translation that is otherwise unavailable to other targeted molecular neuromodulation strategies. Further, the chemistry that enables these particles to encapsulate a given drug relies mainly upon the lipophilicity of the drug in question, so that it may bind the hydrophobic domains of the encapsulating block copolymer and the hydrophobic polymer−perfluorocarbon interface. Given that most molecules that passively cross the blood-brain barrier are highly lipophilic, this suggests that the nanotechnology strategy presented here could be adapted for focal and targeted delivery of most any small molecule that naturally crosses the blood-brain barrier, including imaging agents as well as compounds that act directly upon the adrenergic, serotonergic, or dopaminergic systems, in addition to the excitation/inhibition axis that propofol modulates. This opens the door to a wide variety of potential nanotechnological tools for targeted clinical modulation of brain activity.
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) 17, 18, 21-23 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Airan et al. (Nano Lett., 2017, 17, p. 652−659) in view of Rajewski et al. (US 2009/0098209).
Airan discloses focused ultrasound release of propofol loaded nanoemulsions as set forth above.
With regard to claim 27, propofol is not specifically recited as an epilepsy treatment.
Rajewski teaches that in addition to its anesthetic effects, propofol has a range of other biological and medical applications. For example, it has been reported to be an anti-emetic, an anti-epileptic and an anti-pruritic. These applications of propofol are typically observed at sub-hypnotic doses. It has also been hypothesized that propofol, due to its antioxidant properties, may be useful in the treatment of inflammatory conditions, especially inflammatory conditions with a respiratory component, and in the treatment of neuronal damage related to neurodegeneration associated with the generation of reactive oxygen species.
It would be obvious to one of ordinary skill in the art at the time of the invention that propofol formulations as taught by Airan is an epilepsy treatment agent. One would have been motivated to do so, with a reasonable expectation of success, because Rajewski teaches that in addition to anesthetic effects, propofol is known to be an anti-epileptic.
Claim(s) 17, 18, 21-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Airan et al. (Nano Lett., 2017, 17, p. 652−659) in view of Krusz et al. (J. Head and Face Pain, 2000, 40(3), p. 224-30 (abstract)).
Airan teaches focused ultrasound release of propofol loaded nanoemulsions as set forth above.
With regard to claim 25, propofol is not specifically recited as a pain treatment.
Krusz teaches the unique effectiveness of propofol, an intravenous anesthetic agent, in treating refractory migraines and other headaches in the setting of an outpatient headache center. This is the first known report of the utility of this agent specifically for the treatment of intractable headache. Seventy-seven patients were treated for intractable headache in the clinic with intravenous propofol, for both migraine and nonmigrainous headache refractory to the usual methods of abortive treatment. The average reduction in headache intensity was 95.4% after an average of 20 to 30 minutes of intravenous propofol treatment, using a patient-rated visual analog scale of 0 to 10. Sixty-three of 77 patients reported complete abolition of their headache.
It would be obvious to one of ordinary skill in the art at the time of the invention that propofol formulations as taught by Airan is a pain treatment agent. One would have been motivated to do so, with a reasonable expectation of success, because Krusz teaches that in addition to anesthetic effects, propofol is known to treat migraine headache.
Claim(s) 17, 18, 21-24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Airan et al. (Nano Lett., 2017, 17, p. 652−659) in view of Timbie et al. (Journal of Controlled Release, 2015, 219, p. 61–75).
Airan teaches focused ultrasound release of propofol loaded nanoemulsions as set forth above.
With regard to claim 24 and 26, a treatment agent is not specifically recited as a psychiatric or cancer treatment.
Timbie teaches that the blood–brain barrier (BBB) remains one of the most significant limitations to treatments of central nervous system (CNS) disorders including brain tumors, neurodegenerative diseases and psychiatric disorders. It is now well-established that focused ultrasound (FUS) in conjunction with contrast agent microbubbles may be used to non-invasively and temporarily disrupt the BBB, allowing localized delivery of systemically administered therapeutic agents as large as 100 nm in size to the CNS. Importantly, recent technological advances now permit FUS application through the intact human skull, obviating the need for invasive and risky surgical procedures. When used in combination with magnetic resonance imaging, FUS may be applied precisely to pre-selected CNS targets. Indeed, FUS devices capable of sub-millimeter precision are currently in several clinical trials. FUS mediated BBB disruption has the potential to fundamentally change how CNS diseases are treated, unlocking potential for combinatorial treatments with nanotechnology, markedly increasing the efficacy of existing therapeutics that otherwise do not cross the BBB effectively, and permitting safe repeated treatments. This article comprehensively reviews recent studies on the targeted delivery of therapeutics into the CNS with FUS and offers perspectives on the future of this technology (page 61).
As FUS technology improves, it may be capable of replacing invasive surgical techniques and offers an exciting alternative to traditional approaches. Numerous studies have demonstrated the ability of FUS to deliver a wide range of payloads across the BBB including imaging agents, small molecule drugs, ~ 150 kDa antibodies, recombinant proteins, ~ 20 nm viruses, ~ 60 nm NPs, 100 nm liposomes and even 10 μm stem cells. As a result, FUS has opened doors to novel treatments for CNS disorders like neurodegenerative disease, GBM, and psychiatric disorders. Particularly, despite its advantages and immense potential, nanotechnology has largely been excluded from applications in the brain owing to difficulties in delivery, which can be overcome with FUS. While the BBB has long been considered the greatest bottleneck in the development of treatments for CNS disease, FUS may fundamentally revolutionize how such diseases are approached (page 70).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a treatment agent for psychiatric disease or cancer as the drug in the formulations taught by Airan when the teaching of Airan is taken in view of Timbie. One would have been motivated to do so because Airan teaches that useful may be compounds that act directly upon the adrenergic, serotonergic, or dopaminergic systems, and Timbie teaches that focused ultrasound delivery of drugs across the BBB allows novel treatments for CNS disorders like neurodegenerative disease, GBM, and psychiatric disorders.
Claim(s) 17, 18, 21-23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Airan et al. (Nano Lett., 2017, 17, p. 652−659) in view of Treat et al. (Int. J. Cancer, 2007, 121, p. 901–907).
Airan teaches focused ultrasound release of propofol loaded nanoemulsions as set forth above.
With regard to claim 26, Airan does not specifically recite wherein the treatment agent is for cancer.
Treat teaches that the clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate 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.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide doxorubicin as a drug in the formulations taught by Airan when the teaching of Airan is taken in view of Treat. One would have been motivated to do so, with a reasonable expectation of success, because Airan is concerned with delivery of lipophilic drugs across the BBB, and Treat teaches that ultrasound can be used to assist delivery of encapsulated doxorubicin through the BBB in chemotherapy of brain tumor.
Claim(s) 17, 18, 26 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Oncotarget, 2017, 8(24), p. 38927-38936) in view of Yang et al. (J. Acoust. Soc. Am., 2009, 126, p. 3344–3349).
Zhang teaches that the blood-brain barrier (BBB) is the foremost obstacle which highly prevents effective therapeutic agents from transferring into brain parenchyma and functioning properly. For achieving an effective therapeutic concentration at diseased tissues, the doses of drugs that cannot cross BBB must be high enough. However, high drug doses can easily induce severe side-effects and undesired drug accumulation at non-diseased sites. Therefore, studies aimed at providing helpful ways for drug delivery across BBB with high efficiency are necessary. It has been demonstrated that focused ultrasound (FUS) could locally, transiently and reversibly increase the permeability of BBB in the presence of microbubbles(MBs), which shows tremendous potentials for targeted delivery of chemotherapeutic agents.
The aim of the study was to synthesize one kind of polymeric phase shift perfluorocarbon nanodroplets were provided and investigated whether it can serve as an alternative mediating agent for FUS induced BBB opening. Due to the applicable natural boiling point (29°C), perfluoropentane (PFP) was chosen in this study. To achieve this aim, PEGylated PLGA based PFP-encapsulated (PEG-PLGA-PFP) nanodroplets were prepared by a double emulsion method. Poly (ethylene glycol) - poly (lactide-co- glycolic acid) (PEG-PLGA), an amphiphilic copolymer which contained merits of PEG for long half-time and high stability in circulation and PLGA for good biocompatibility and biodegradability was selected as the shell materials (page 38928).
The spherical shell-core morphology of PEG-PLGA-PFP nanodroplet and the inner center dark mass of the sphere indicated the existence of liquid PFP core are shown in Figure 1. The mean size distribution was 316.0 ± 7.9 nm (page 38928).
PLGA nanoparticles have been proved to be one kind of effective drug delivery system. For the nanodroplets that we composed in this study, hydrophobic therapeutic agents can be easily encapsulated in the PLGA shell, and further surface modification with specific ligands would make these nanodroplets have active-targeting function. Ho et al. demonstrated that drug penetration can be enhanced via vascular disruption induced by using phase shift nanoscale droplets. Thus, drug loaded targeted phase shift nanodroplets combined with FUS for simultaneous BBB opening and extravascular therapy in the brain would be the next main direction for future study (page 38932).
A portable FUS system was provided by the Department of Biomedical Engineering of Chongqing Medical University. Continuous FUS exposures were generated by a 1 MHz single-element focused transducer (diameter = 40 mm, focus length = 18 mm). The diameter and length of the focal zone with half-maximum of the pressure amplitude were 2.2 mm and 6.9 mm, respectively. The transducer was fixed in a handheld probe with a panhead and the center of the focal zone was about 8.2 mm away from the tip.
Figure 6B illustrated experimental setup for testing in vivo FUS-induced BBB opening. The same FUS system was used for in vivo protocols. For relatively precise targeting, its handheld probe was fixed on the left-right axis of the stereotaxic apparatus, and the targeted region was set at the position of 3.0 mm lateral and 0.5 mm anterior to the bregma, and 3.0 mm below the skull surface. The space between probe and skull surface was fill with a self-made degassed water tank whose bottom was an ultrasound permeable membrane, and ultrasound coupling gel was applied between the skull and the membrane.
Confirmation of BBB opening and assessment of brain tissue injury is taught. Twenty-four rats were randomly divided into three groups. Continuous FUS sonication (0.5, 1.0 or 1.5 MPa) was performed 20s after intravenous administration of PEG-PLGA-PFP nanodroplets (10 mg/kg) into the tail vein, and the duration was fixed at 3 min. To verify the successful opening of BBB, rats were intravenously injected with EB (100 mg/kg) after FUS sonication immediately (page 38933-4).
PEGylated PLGA-based PFP encapsulated phase shift nanodroplets were successfully fabricated. Significant EB extravasation and satisfied biosecurity could be achieved by the systematic administration of this nanodroplets combined with FUS at acoustic pressure of 1.0MPa. Prolonged duration of sonication could broaden the time window of BBB opening. In summary, these promising results indicate that the PEG-PLGA-PFP nanodroplets could serve as an effective alternative mediating agent and have great potential for ultra-precise control of BBB opening and target drug delivery (page 38934).
Zhang does not specifically exemplify wherein the nanoparticles further comprise a hydrophobic therapeutic agent for delivery of a drug that can cross the BBB, and does not specifically teach wherein the burst length of the ultrasound pulse is 50 ms.
Yang teaches that it has been shown that focused ultrasound (FUS) is capable of noninvasive and reversible disruption of the blood-brain barrier (BBB) at target regions when applied in the presence of ultrasound contrast agent (UCA). The purpose of this study was to investigate the effects of UCA dose on the reversibility of BBB disruption induced by the same acoustical power of FUS. Sonications were applied at an ultrasound frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The brains of 66 male Sprague-Dawley rats were subjected to sonications with three doses of UCA. BBB integrity was evaluated via femoral vein injection of Evans Blue (EB) while the rats were anesthetized. The relationship between UCA dose and the region of EB extravasation was evaluated at an acoustic power of 1.43 W. The BBB disruption, as indexed by the amount of EB extravasation, was the largest immediately after the sonications. The quantity of Evans blue extravasation decreased as a function of time at various UCA doses. This study demonstrates that the appropriate dose of UCA not only enhance the BBB opening but also effectively aid in controlling the duration of BBB disruption (page 3344).
Ultrasound parameters are set forth on page 3345. The rat’s head was mounted on the stereotaxic apparatus with the nose bar positioned 3.3 mm below the interaural line. Sonications were pulsed with a burst length of 50 ms at a 5% duty cycle and a repetition frequency of 1 Hz. Each sonication protocol lasted 60 s. The FUS was delivered to one location in the right hemisphere brain at the position of 3.5 mm posterior and 2.5 mm lateral to the bregma, and 5.7 mm below the skull surface. The UCA SonoVue, Bracco International, Amsterdam, The Netherlands was injected into the femoral vein of the rats about 15 s before each sonication. It contains phospholipid-coated microbubbles with mean diameter 2.5 µm and concentration = 1–5 108 bubbles/ml. In in vivo experiments, the rats were sonicated with UCA at three doses (150, 300, and 450 µl/kg) at an acoustic power of 1.43 W.
This study evaluated the relationship between UCA dose and the reversibility of BBB disruption based on the amount of EB extravasation. The results demonstrate that UCA not only enhances BBB opening but also can be used to control the duration BBB disruption. Future studies should attempt to optimize the ultrasound and UCA parameters so as to obtain appropriate opening and closure of the BBB for use in practical applications. (page 3349).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a hydrophobic therapeutic agent in the PEGylated PLGA-based PFP encapsulated phase shift nanodroplets taught by Zhang. One would have been motivated to do so because Zhang specifically teaches that PLGA nanoparticles have been proved an effective drug delivery system for hydrophobic drugs, and it was shown that prolonged duration of sonication could broaden the time window of BBB opening. One would have had a reasonable expectation of success in delivering a hydrophobic compound that can pass through the BBB upon administering PEG-PLGA-PFP nanodroplets containing a hydrophobic drug and delivering an ultrasound pulse to the brain because Zhang’s results indicate that the PEG-PLGA-PFP nanodroplets could serve as an effective alternative mediating agent and have great potential for ultra-precise control of BBB opening and target drug delivery. With regard to claim 18, B-Mode and CEUS images of nanodroplets before and after FUS sonication (Figure 2). With regard to claim 26, focused ultrasound for targeted delivery of chemotherapeutic agents is taught to be desirable.
It would have been further obvious to one of ordinary skill in the art at the time of the invention to modify the burst length of focused ultrasound as means of optimizing the sonication parameters in the methods taught by Zhang when the teaching of Zhang is taken in view of Yang. Each of Zhang and Yang are directed to control of BBB opening upon application of ultrasound. One would have been motivated to provide focused ultrasound with a burst length of 50 ms as functionally equivalent, with a reasonable expectation of success, because such a burst length in shown in the art to be suitable for transiently increasing permeability of the BBB using microbubbles. With regard to the limitation of without physically disrupting the BBB, it is noted that both Zhang and Yang are directed to reversibly increasing the permeability of the BBB, as such encompass the claimed limitation that the BBB is not physically disrupted.
Conclusion
No claims are allowed.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618