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Patent 2996981 Summary

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(12) Patent: (11) CA 2996981
(54) English Title: METHOD FOR HEAT TREATING BIOLOGICAL TISSUES USING PULSED ENERGY SOURCES
(54) French Title: PROCEDE DE TRAITEMENT THERMIQUE DE TISSUS BIOLOGIQUES AU MOYEN DE SOURCES D'ENERGIE PULSEES
Status: Granted
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61N 5/02 (2006.01)
  • A61N 5/067 (2006.01)
  • A61N 7/02 (2006.01)
(72) Inventors :
  • LUTTRULL, JEFFREY K. (United States of America)
  • CHANG, DAVID B. (United States of America)
  • MARGOLIS, BENJAMIN W. L. (United States of America)
(73) Owners :
  • OJAI RETINAL TECHNOLOGY, LLC (United States of America)
(71) Applicants :
  • OJAI RETINAL TECHNOLOGY, LLC (United States of America)
(74) Agent: GOWLING WLG (CANADA) LLP
(74) Associate agent:
(45) Issued: 2023-08-01
(86) PCT Filing Date: 2016-08-08
(87) Open to Public Inspection: 2017-05-04
Examination requested: 2020-09-24
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US2016/046043
(87) International Publication Number: WO2017/074532
(85) National Entry: 2018-02-27

(30) Application Priority Data:
Application No. Country/Territory Date
14/922,885 United States of America 2015-10-26
15/214,726 United States of America 2016-07-20

Abstracts

English Abstract



A method for heat treating biological tissues includes providing a pulsed
energy source having energy parameters
selected so as to raise a target temperature to a level to achieve a
therapeutic effect, while the average temperature rise of the tissue
over a prolonged period of time is maintained at or below a predetermined
level so as not to permanently damage the target tissue.
Application of the pulsed energy source to the target tissue induces a heat
shock response and stimulates heat shock protein
activation in the target tissue so as to therapeutically treat the target
tissue.


French Abstract

La présente invention concerne un procédé de traitement thermique de tissus biologiques qui comprend la fourniture d'une source d'énergie pulsée ayant des paramètres d'énergie sélectionnés de manière à augmenter une température cible à un niveau permettant d'obtenir un effet thérapeutique, tandis que l'augmentation de température moyenne du tissu sur une durée prolongée est maintenue à ou au-dessous d'un niveau prédéterminé de manière à ne pas endommager le tissu cible de façon permanente. L'application de la source d'énergie pulsée au tissu cible induit une réponse de choc thermique et stimule l'activation de protéine de choc thermique dans le tissu cible de manière à traiter thérapeutiquement le tissu cible.

Claims

Note: Claims are shown in the official language in which they were submitted.


What is claimed is:
1. A system adapted to heat treat biological tissues, characterized by:
a pulsed energy source (16) having energy parameters including wavelength or
frequency, power and a duty cycle of 10% or less that raises a target tissue
temperature
between approximately six and eleven degrees Celsius at least during
application of the pulsed
energy source to the target tissue (18) for a total pulsed train duration of
less than one second,
wherein the average temperature rise of the tissue over six minutes or less is
maintained at or
below six degrees Celsius so as to not permanently damage the target tissue.
2. The system of claim 1, wherein the pulsed energy source (16) stimulates
heat shock
protein activation in the target tissue.
3. The system of claim 1, wherein the average temperature rise of the
target tissue (18) is
maintained at approximately one degree Celsius or less over six minutes or
less.
4. The system of claim 1, wherein the pulsed energy source (16) energy
parameters are
selected so that approximately 20 to 40 joules of energy is absorbed by each
cubic centimeter
of the target tissue.
5. The system of claim 1, including a device (14) insertable into a cavity
of a body to apply
the pulsed energy source to the target tissue.
6. The system of claim 1, wherein the pulsed energy source (16) is applied
to a blood
supply close to the target tissue (18).
7. The system of claim 1, wherein the pulsed energy source (16) comprises
laser light,
microwave, radio frequency, or ultrasound.
54

8. The system of any one of claims 1, 2 or 3-6, wherein the pulsed energy
source (16)
comprises a radio frequency between approximately three to six megahertz, a
duty cycle of
between approximately 2.5% to 5%, and a pulse train duration of between
approximately 0.2 to
0.4 seconds.
9. The system of claim 8, wherein the radio frequency is generated with a
device having a
coil radii of between approximately 2 and 6 mm and between approximately 13
and 57 amp
turns.
10. The system of any one of claims 1, 2 or 3, wherein the the pulsed
energy source (16)
comprises a microwave frequency of between approximately 10 to 20 GHz, a pulse
train
duration of approximately between 0.2 and 0.6 seconds, and a duty cycle of
between
approximately 2% to 5%.
11. The system of claim 10, wherein the microwave has an average power of
between
approximately 8 and 52 watts.
12. The system of any one of claims 1, 2 or 3-6, wherein the pulsed energy
source (16)
comprises a pulsed light beam (30) having a wavelength of between
approximately 530 nm to
1300 nm, a duty cycle of less than 10%, and a pulse train duration between
approximately 0.1
and 0.6 seconds.
13. The system of claim 12, wherein the pulsed light beam (30) has a
wavelength of
between 800 nm and 1000 nm and a power of between approximately 0.5 and 74
watts.
14. The system of any one of claims 1, 2 or 3-6, wherein the pulsed energy
source (16)
comprises pulsed ultrasound (80) having a frequency of between approximately
1MHz and
5MHz, a train duration of between approximately 0.1 and 0.5 seconds and a duty
cycle of
between approximately 2% to 10%.

15. The
system of claim 14, wherein the ultrasound has a power of between
approximately
0.46 and 28.6 watts.
56

Description

Note: Descriptions are shown in the official language in which they were submitted.


METHOD FOR HEAT TREATING BIOLOGICAL TISSUES
USING PULSED ENERGY SOURCES
DESCRIPTION
BACKGROUND OF THE INVENTION
[Para 1] The present invention is generally directed to a method for heat
treating biological tissues. More particularly, the present invention is
directed
to a method for applying a pulsed energy source to biological tissue to
stimulate activation of heat shock proteins and facilitate protein repair
without
damaging the tissue.
[Para 2] The inventors have discovered that there is a therapeutic effect to
biological tissue, and particularly damaged or diseased biological tissue, by
controllably elevating the tissue temperature up to a predetermined
temperature range while maintaining the average temperature rise of the tissue

over several minutes at or below a predetermined level so as not to
permanently damage the target tissue. It is believed that raising the tissue
temperature in such a controlled manner selectively stimulates heat shock
protein activation and/or production and facilitation of protein repair, which

serves as a mechanism for therapeutically treating the tissue.
[Para 3] Heat shock proteins (HSPs) are a family of proteins that are produced

by cells in response to exposure to stressful conditions. Production of high
levels of heat shock proteins can be triggered by exposure to different kinds
of
1
Date Recue/Date Received 2022-01-31

environmental stress conditions, such as infection, inflammation, exercise,
exposure of the cell to toxins, starvation, hypoxia, or water deprivation.
[Para 4] It is known that heat shock proteins play a role in responding to a
large number of abnormal conditions in body tissues, including viral
infection,
inflammation, malignant transformations, exposure to oxidizing agents,
cytotoxins, and anoxia. Several heat shock proteins function as intra-cellular

chaperones for other proteins and members of the HSP family are expressed or
activated at low to moderate levels because of their essential role in protein

maintenance and simply monitoring the cell's proteins even under non-
stressful conditions. These activities are part of a cell's own repair system,

called the cellular stress response or the heat-shock response.
[Para 5] Heat shock proteins are typically named according to their molecular
weight. For example, Hsp60, Hsp70 and Hsp80 refer to the families of heat
shock proteins on the order of 60, 70 and 80 kilodaltons in size,
respectively.
They act in a number of different ways. For example, Hsp70 has peptide-
binding and ATPase domains that stabilize protein structures in unfolded and
assembly-competent states. Mitochondria! Hsp60s form ring-shaped
structures facilitating the assembly of proteins into native states. Hsp90
plays a
suppressor regulatory role by associating with cellular tyrosine kinases,
transcription factors, and glucocorticoid receptors. Hsp27 suppresses protein
aggregation.
[Para 6] Hsp70 heat shock proteins are a member of extracellular and
membrane bound heat-shock proteins which are involved in binding antigens
2
Date Recue/Date Received 2022-01-31

and presenting them to the immune system. Hsp70 has been found to inhibit
the activity of influenza A virus ribonucleoprotein and to block the
replication
of the virus. Heat shock proteins derived from tumors elicit specific
protective
immunity. Experimental and clinical observations have shown that heat shock
proteins are involved in the regulation of autoimmune arthritis, type 1
diabetes,
mellitus, arterial sclerosis, multiple sclerosis, and other autoimmune
reactions.
[Para 7] Accordingly, it is believed that it is advantageous to be able to
selectively and controllably raise a target tissue temperature up to a
predetermined temperature range over a short period of time, while
maintaining the average temperature rise of the tissue at a predetermined
temperature over a longer period of time. It is believed that this induces the

heat shock response in order to increase the number or activity of heat shock
proteins in body tissue in response to infection or other abnormalities.
However, this must be done in a controlled manner in order not to damage or
destroy the tissue or the area of the body being treated. The present
invention
fulfills these needs, and provides other related advantages.
SUMMARY OF THE INVENTION
[Para 8] The present invention is directed to a method for heat treating
biological tissues by applying a pulsed energy source to the target tissue to
therapeutically treat the target tissue. The pulsed energy source has energy
parameters including wavelength or frequency, duty cycle and pulse train
duration. The energy parameters are selected so as to raise a target tissue
3
Date Recue/Date Received 2022-01-31

temperature up to 11 C to achieve a therapeutic effect, wherein the average
temperature rise of the tissue over several minutes is maintained at or below
a
predetermined level so as not to permanently damage the target tissue.
[Para 9] The energy source parameters may be selected so that the target
tissue temperature is raised between approximately 6 C to 11 C at least during

application of the pulsed energy source to the target tissue. The average
temperature rise of the target tissue over several minutes is maintained at 6
C
or less, such as at approximately 1 C or less over several minutes.
[Para 10] The pulsed energy source energy parameters are selected so that
approximately 20 to 40 joules of energy is absorbed by each cubic centimeter
of the target tissue. Applying the pulsed energy source to the target tissue
induces a heat shock response and stimulates heat shock protein activation in
the target tissue without damaging the target tissue.
[Para 11] A device may be inserted into a cavity of the body in order to
apply
the pulsed energy to the tissue. The pulsed energy may be applied to an
exterior area of a body which is adjacent to the target tissue, or has a blood

supply close to a surface of the exterior area of the body.
[Para 12] The pulsed energy source may comprise a radiofrequency. The
radiofrequency may be between approximately 3 to 6 megahertz (MHz). It may
have a duty cycle of between approximately 2.5% to 5%. It may have a pulsed
train duration of between approximately 0.2 to 0.4 seconds. The
radiofrequency may be generated with a device having a coil radii of between
approximately 2 and 6 mm and approximately 13 and 57 amp turns.
4
Date Recue/Date Received 2022-01-31

[Para 13] The pulsed energy source may comprise a microwave frequency of
between 10 to 20 gigahertz (GHz). The microwave may have a pulse train
duration of approximately between 0.2 and 0.6 seconds. The microwave may
have a duty cycle of between approximately 2% and 5%. The microwave may
have an average power of between approximately 8 and 52 watts.
[Para 14] The pulsed energy source may comprise a pulsed light beam, such
as a laser light. The light beam may have a wavelength of between
approximately 530 nm to 1300 nm, and more preferably between 800 nm and
1000 nm. The pulsed light beam may have a power of between approximately
0.5 and 74 watts. The pulsed light beam has a duty cycle of less than 10%, and

preferably between 2.5% and 5%. The pulsed light beam may have a pulse train
duration of approximately 0.1 and 0.6 seconds.
[Para 1 5] The pulsed energy source may comprise a pulsed ultrasound. The
ultrasound has a frequency of between approximately 1 and 5 MHz. The
ultrasound has a train duration of approximately 0.1 and 05 seconds. The
ultrasound may have a duty cycle of between approximately 2% and 10%. The
ultrasound has a power of between approximately 0.46 and 28.6 watts.
[Para 16] Other features and advantages of the present invention will
become
apparent from the following more detailed description, taken in conjunction
with the accompanying drawings, which illustrate, by way of example, the
principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Date Recue/Date Received 2022-01-31

[Para 17] The accompanying drawings illustrate the invention. In such
drawings:
[Para 18] FIGURES lA and 1B are graphs illustrating the average power of a
laser source compared to a source radius and pulse train duration of the
laser;
[Para 19] FIGURES 2A and 2B are graphs illustrating the time for the
temperature to decay depending upon the laser source radius and wavelength;
[Para 20] FIGURES 3-6 are graphs illustrating the peak ampere turns for
various radiofrequencies, duty cycles, and coil radii;
[Para 21] FIGURE 7 is a graph depicting the time for temperature rise to
decay compared to radiofrequency coil radius;
[Para 22] FIGURES 8 and 9 are graphs depicting the average microwave
power compared to microwave frequency and pulse train durations;
[Para 23] FIGURE 10 is a graph depicting the time for the temperature to
decay for various microwave frequencies;
[Para 24] FIGURE 11 is a graph depicting the average ultrasound source
power compared to frequency and pulse train duration;
[Para 25] FIGURES 12 and 13 are graphs depicting the time for temperature
decay for various ultrasound frequencies;
[Para 26] FIGURE 14 is a graph depicting the volume of focal heated region
compared to ultrasound frequency;
[Para 27] FIGURE 15 is a graph comparing equations for temperature over
pulse durations for an ultrasound energy source;
6
Date Recue/Date Received 2022-01-31

[Para 28] FIGURES 16 and 17 are graphs illustrating the magnitude of the
logarithm of damage and HSP activation Arrhenius integrals as a function of
temperature and pulse duration;
[Para 29] FIGURE 18 is a diagrammatic view of a light generating unit that
produces timed series of pulses, having a light pipe extending therefrom, in
accordance with the present invention;
[Para 30] FIGURE 19 is a cross-sectional view of a photostimulation
delivery
device delivering electromagnetic energy to target tissue, in accordance with
the present invention;
[Para 31] FIGURE 20 is a diagrammatic view illustrating a system used to
generate a laser light beam, in accordance with the present invention;
[Para 32] FIGURE 21 is a diagrammatic view of optics used to generate a
laser
light geometric pattern, in accordance with the present invention;
[Para 33] FIGURE 22 is a diagrammatic view illustrating an alternate
embodiment of the system used to generate laser light beams for treating
tissue, in accordance with the present invention;
[Para 34] FIGURE 23 is a diagrammatic view illustrating yet another
embodiment of a system used to generate laser light beams to treat tissue in
accordance with the present invention;
[Para 35] FIGURE 24 is a cross-sectional and diagrammatic view of an end of

an endoscope inserted into the nasal cavity and treating tissue therein, in
accordance with the present invention;
7
Date Recue/Date Received 2022-01-31

[Para 36] FIGURE 25 is a diagrammatic and partially cross-sectioned view of

a bronchoscope extending through the trachea and into the bronchus of a lung
and providing treatment thereto, in accordance with the present invention;
[Para 37] FIGURE 26 is a diagrammatic view of a colonoscope providing
photostimulation to an intestinal or colon area of the body, in accordance
with
the present invention;
[Para 38] FIGURE 27 is a diagrammatic view of an endoscope inserted into a
stomach and providing treatment thereto, in accordance with the present
invention;
[Para 39] FIGURE 28 is a partially sectioned perspective view of a capsule
endoscope, used in accordance with the present invention;
[Para 40] FIGURE 29 is a diagrammatic view of a pulsed high intensity
focused ultrasound for treating tissue internal the body, in accordance with
the
present invention;
[Para 41] FIGURE 30 is a diagrammatic view for delivering therapy to the
bloodstream of a patient, through an earlobe, in accordance with the present
invention;
[Para 42] FIGURE 31 is a cross-sectional view of a stimulating therapy
device
of the present invention used in delivering photostimulation to the blood, via
an
earlobe, in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
8
Date Recue/Date Received 2022-01-31

[Para 43] As shown in the accompanying drawings, and as more fully
described herein, the present invention is directed to a system and method for

delivering a pulsed energy source, such as laser, ultrasound, ultraviolet
radiofrequency, microwave radiofrequency and the like, having energy
parameters selected to cause a thermal time-course in tissue to raise the
tissue
temperature over a short period of time to a sufficient level to achieve a
therapeutic effect while maintaining an average tissue temperature over a
prolonged period of time below a predetermined level so as to avoid permanent
tissue damage. It is believed that the creation of the thermal time-course
stimulates heat shock protein activation or production and facilitates protein

repair without causing any damage.
[Para 44] The inventors of the present invention have discovered that
electromagnetic radiation, in the form of various wavelengths of laser light,
can
be applied to retinal tissue in a manner that does not destroy or damage the
retinal tissue while achieving beneficial effects on eye diseases. It is
believed
that this may be due, at least in part, to the stimulation and activation of
heat
shock proteins and the facilitation of protein repair in the retinal tissue.
This is
disclosed in United States patent application serial numbers 14/607,959 filed
January 28, 2015, 13/798,523 filed March 13, 2013, and 13/481,124 filed May
25, 2012.
[Para 45] The inventors have found that a laser light beam can be generated

that is therapeutic, yet sublethal to retinal tissue cells and thus avoids
damaging photocoagulation in the retinal tissue which provides preventative
9
Date Recue/Date Received 2022-01-31

and protective treatment of the retinal tissue of the eye. Various parameters
of
the light beam must be taken into account and selected so that the combination

of the selected parameters achieve the therapeutic effect while not
permanently
damaging the tissue. These parameters include laser wavelength, radius of the
laser source, average laser power, total pulse duration, and duty cycle of the

pulse train.
[Para 46]
The selection of these parameters may be determined by requiring
that the Arrhenius integral for HSP activation be greater than 1 or unity.
Arrhenius integrals are used for analyzing the impacts of actions on
biological
tissue. See, for instance, The CRC Handbook of Thermal Engineering, ed. Frank
Kreith, Springer Science and Business Media (2000). At the same time, the
selected parameters must not permanently damage the tissue. Thus, the
Arrhenius integral for damage may also be used, wherein the solved Arrhenius
integral is less than 1 or unity. Alternatively, the FDA/FCC constraints on
energy deposition per unit gram of tissue and temperature rise as measured
over periods of minutes be satisfied so as to avoid permanent tissue damage.
The FDA/FCC requirements on energy deposition and temperature rise are
widely used for electromagnetic sources, and Anastosio and P. LaRivero, ed.,
Emerging Imaging Technologies. CRC Press (2012), for ultrasound sources.
Generally speaking, tissue temperature rises of between 6 C and 11 C can
create therapeutic effect, such as by activating heat shock proteins, whereas
maintaining the average tissue temperature over a prolonged period of time,
such as over several minutes, such as six minutes, below a predetermined
Date Recue/Date Received 2022-01-31

temperature, such as 6 C and even 1 C or less in certain circumstances, will
not
permanently damage the tissue.
[Para 47] The inventors have discovered that generating a subthreshold,
sublethal micropulse laser light beam which has a wavelength greater than 532
nm and a duty cycle of less than 10% at a predetermined intensity or power and

a predetermined pulse length or exposure time creates desirable retinal
photostimulation without any visible burn areas or tissue destruction. More
particularly, a laser light beam having a wavelength of between 550 nm-1300
nm, and in a particularly preferred embodiment between 810 nm and 1000 nm,
having a duty cycle of approximately 2.5%-5% and a predetermined intensity or
power (such as between 100-590 watts per square centimeter at the retina or
approximately 1 watt per laser spot for each treatment spot at the retina) and
a
predetermined pulse length or exposure time (such as between 100 and 600
milliseconds or less) creates a sublethal, "true subthreshold" retinal
photostimulation in which all areas of the retinal pigment epithelium exposed
to the laser irradiation are preserved and available to contribute
therapeutically.
In other words, the inventors have found that raising the retinal tissue at
least
up to a therapeutic level but below a cellular or tissue lethal level
recreates the
benefit of the halo effect of the prior art methods without destroying,
burning
or otherwise damaging the retinal tissue. This is referred to herein as
subthreshold diode micropulse laser treatment (SDM).
[Para 48] As SDM does not produce laser-induced retinal damage
(photocoagulation), and has no known adverse treatment effect, and has been
11
Date Recue/Date Received 2022-01-31

reported to be an effective treatment in a number of retinal disorders
(including
diabetic macular edema (DME) proliferative diabetic retinopathy (PDR), macular

edema due to branch retinal vein occlusion (BRVO), central serous
chorioretinopathy (CSR), reversal of drug tolerance, and prophylactic
treatment
of progressive degenerative retinopathies such as dry age-related macular
degeneration, Stargardts' disease, cone dystrophies, and retinitis pigmentosa.

The safety of SDM is such that it may be used transfoveally in eyes with 20/20

visual acuity to reduce the risk of visual loss due to early fovea-involving
DME.
[Para 49] A mechanism through which SDM might work is the generation or
activation of heat shock proteins (HSPs). Despite a near infinite variety of
possible cellular abnormalities, cells of all types share a common and highly
conserved mechanism of repair: heat shock proteins (HSPs). HSPs are elicited
almost immediately, in seconds to minutes, by almost any type of cell stress
or
injury. In the absence of lethal cell injury, HSPs are extremely effective at
repairing and returning the viable cell toward a more normal functional state.

Although HSPs are transient, generally peaking in hours and persisting for a
few
days, their effects may be long lasting. HSPs reduce inflammation, a common
factor in many disorders.
[Para 50] Laser treatment can induce HSP production or activation and alter

cytokine expression. The more sudden and severe the non-lethal cellular stress

(such as laser irradiation), the more rapid and robust HSP activation. Thus, a

burst of repetitive low temperature thermal spikes at a very steep rate of
change (¨ 7 C elevation with each 100ps micropulse, or 70,000 C/sec)
12
Date Recue/Date Received 2022-01-31

produced by each SDM exposure is especially effective in stimulating
activation
of HSPs, particularly compared to non-lethal exposure to subthreshold
treatment with continuous wave lasers, which can duplicate only the low
average tissue temperature rise.
[Para 51] Laser wavelengths below 550 nm produce increasingly cytotoxic
photochemical effects. At 810 nm, SDM produces photothermal, rather than
photochemical, cellular stress. Thus, SDM is able to affect the tissue without

damaging it. The clinical benefits of SDM are thus primarily produced by sub-
morbid photothermal cellular HSP activation. In dysfunctional cells, HSP
stimulation by SDM results in normalized cytokine expression, and
consequently improved structure and function. The therapeutic effects of this
"low-intensity" laser/tissue interaction are then amplified by "high-density"
laser application, recruiting all the dysfunctional cells in the targeted
tissue
area by densely / confluently treating a large tissue area, including all
areas of
pathology, thereby maximizing the treatment effect. These principles define
the
treatment strategy of SDM described herein.
[Para 52] Because normally functioning cells are not in need of repair, HSP

stimulation in normal cells would tend to have no notable clinical effect. The

"patho-selectivity" of near infrared laser effects, such as SDM, affecting
sick
cells but not affecting normal ones, on various cell types is consistent with
clinical observations of SDM. SDM has been reported to have a clinically broad

therapeutic range, unique among retinal laser modalities, consistent with
American National Standards Institute "Maximum Permissible Exposure"
13
Date Recue/Date Received 2022-01-31

predictions. While SDM may cause direct photothermal effects such as entropic
protein unfolding and disaggregation, SDM appears optimized for clinically
safe
and effective stimulation of HSP-mediated repair.
[Para 53] As noted above, while SDM stimulation of HSPs is non-specific
with
regard to the disease process, the result of HSP mediated repair is by its
nature
specific to the state of the dysfunction. HSPs tend to fix what is wrong,
whatever that might be. Thus, the observed effectiveness of SDM in retinal
conditions as widely disparate as BRVO, DME, PDR, CSR, age-related and
genetic retinopathies, and drug-tolerant NAMD. Conceptually, this facility can

be considered a sort of "Reset to Default" mode of SDM action. For the wide
range of disorders in which cellular function is critical, SDM normalizes
cellular
function by triggering a "reset" (to the "factory default settings") via HSP-
mediated cellular repair.
[Para 54] The inventors have found that SDM treatment of patients suffering

from age-related macular degeneration (AMD) can slow the progress or even
stop the progression of AMD. Most of the patients have seen significant
improvement in dynamic functional logMAR mesoptic visual acuity and
mesoptic contrast visual acuity after the SDM treatment. It is believed that
SDM
works by targeting, preserving, and "normalizing" (moving toward normal)
function of the retinal pigment epithelium (RPE).
[Para 55] SDM has also been shown to stop or reverse the manifestations of
the diabetic retinopathy disease state without treatment-associated damage or
adverse effects, despite the persistence of systemic diabetes mellitus. On
this
14
Date Recue/Date Received 2022-01-31

basis it is hypothesized that SDM might work by inducing a return to more
normal cell function and cytokine expression in diabetes-affected RPE cells,
analogous to hitting the "reset" button of an electronic device to restore the

factory default settings. Based on the above information and studies, SDM
treatment may directly affect cytokine expression via heat shock protein (HSP)

activation in the targeted tissue.
[Para 56] As heat shock proteins play a role in responding to a large
number
of abnormal conditions in body tissue other than eye tissue, it is believed
that
similar systems and methodologies can be advantageously used in treating
such abnormal conditions, infections, etc. As such, the present invention is
directed to the controlled application of ultrasound or electromagnetic
radiation
to treat abnormal conditions including inflammations, autoimmune conditions,
and cancers that are accessible by means of fiber optics of endoscopes or
surface probes as well as focused electromagnetic/sound waves. For example,
cancers on the surface of the prostate that have the largest threat of
metastasizing can be accessed by means of fiber optics in a proctoscope.
Colon tumors can be accessed by an optical fiber system, like those used in
colonoscopy.
[Para 57] As indicated above, subthreshold diode micropulse laser (SDM)
photostimulation has been effective in stimulating direct repair of slightly
misfolded proteins in eye tissue. Besides HSP activation, another way this may

occur is because the spikes in temperature caused by the micropulses in the
form of a thermal time-course allows diffusion of water inside proteins, and
Date Recue/Date Received 2022-01-31

this allows breakage of the peptide-peptide hydrogen bonds that prevent the
protein from returning to its native state. The diffusion of water into
proteins
results in an increase in the number of restraining hydrogen bonds by a factor

on the order of a thousand. Thus, it is believed that this process could be
applied to other diseases advantageously as well.
[Para 58] As explained above, the energy source to be applied to the target

tissue will have energy and operating parameters which must be determined
and selected so as to achieve the therapeutic effect while not permanently
damaging the tissue. Using a light beam energy source, such as a laser light
beam, as an example, the laser wavelength, duty cycle and total pulse train
duration parameters must be taken into account. Other parameters which can
be considered include the radius of the laser source as well as the average
laser
power. Adjusting or selecting one of these parameters can have an effect on at

least one other parameter.
[Para 59] FIGS. lA and 1B illustrate graphs showing the average power in
watts as compared to the laser source radius (between 0.1 cm and 0.4 cm) and
pulse train duration (between 0.1 and 0.6 seconds). FIG. lA shows a
wavelength of 880 nm, whereas FIG.1B has a wavelength of 1000 nm. It can be
seen in these figures that the required power decreases monotonically as the
radius of the source decreases, as the total train duration increases, and as
the
wavelength decreases. The preferred parameters for the radius of the laser
source is 1 mm-4 mm. For a wavelength of 880 nm, the minimum value of
power is 0.55 watts, with a radius of the laser source being 1 mm, and the
total
16
Date Recue/Date Received 2022-01-31

pulse train duration being 600 milliseconds. The maximum value of power for
the 880 nm wavelength is 52.6 watts when the laser source radius is 4 mm and
the total pulse drain duration is 100 milliseconds. However, when selecting a
laser having a wavelength of 1000 nm, the minimum power value is 0.77 watts
with a laser source radius of 1 mm and a total pulse train duration of 600
milliseconds, and a maximum power value of 73.6 watts when the laser source
radius is 4 mm and the total pulse duration is 100 milliseconds. The
corresponding peak powers, during an individual pulse, are obtained from the
average powers by dividing by the duty cycle.
[Para 60] The volume of the tissue region to be heated is determined by the

wavelength, the absorption length in the relevant tissue, and by the beam
width. The total pulse duration and the average laser power determine the
total
energy delivered to heat up the tissue, and the duty cycle of the pulse train
gives the associated spike, or peak, power associated with the average laser
power. Preferably, the pulsed energy source energy parameters are selected so
that approximately 20 to 40 joules of energy is absorbed by each cubic
centimeter of the target tissue.
[Para 61] The absorption length is very small in the thin melanin layer in
the
retinal pigmented epithelium. In other parts of the body, the absorption
length
is not generally that small. In wavelengths ranging from 400 nm to 2000 nm,
the penetration depth and skin is in the range of 0.5 mm to 3.5 mm. The
penetration depth into human mucous tissues in the range of 0.5 mm to 6.8
mm. Accordingly, the heated volume will be limited to the exterior or interior
17
Date Recue/Date Received 2022-01-31

surface where the radiation source is placed, with a depth equal to the
penetration depth, and a transverse dimension equal to the transverse
dimension of the radiation source. Since the light beam energy source is used
to treat diseased tissues near external surfaces or near internal accessible
surfaces, a source radii of between 1 mm to 4 mm and operating a wavelength
of 880 nm yields a penetration depth of approximately 2.5 mm and a
wavelength of 1000 nm yields a penetration depth of approximately 3.5 mm.
[Para 62]
It has been determined that the target tissue can be heated to up to
approximately 11 C for a short period of time, such as less than one second,
to
create the therapeutic effect of the invention while maintaining the target
tissue
average temperature to a lower temperature range, such as less than 6 C or
even 1 C or less over a prolonged period of time, such as several minutes. The

selection of the duty cycle and the total pulse train duration provide time
intervals in which the heat can dissipate. A duty cycle of less than 10%, and
preferably between 2.5% and 5%, with a total pulse duration of between 100
milliseconds and 600 milliseconds has been found to be effective. FIGS. 2A and

2B illustrate the time to decay from 10 C to 1 C for a laser source having a
radius of between 0.1 cm and 0.4 cm with the wavelength being 880 nm in FIG.
2A and 1000 nm in FIG. 2B. It can be seen that the time to decay is less when
using a wavelength of 880 nm, but either wavelength falls within the
acceptable
requirements and operating parameters to achieve the benefits of the present
invention while not causing permanent tissue damage.
18
Date Recue/Date Received 2022-01-31

[Para 63] It has been found that the average temperature rise of the
desired
target region increasing at least 6 C and up to 11 C, and preferably
approximately 10 C, during the total irradiation period results in HSP
activation.
The control of the target tissue temperature is determined by choosing source
and target parameters such that the Arrhenius integral for HSP activation is
larger than 1, while at the same time assuring compliance with the
conservative
FDA/FCC requirements for avoiding damage or a damage Arrhenius integral
being less than 1.
[Para 64] In order to meet the conservative FDA/FCC constraints to avoid
permanent tissue damage, for light beams, and other electromagnetic radiation
sources, the average temperature rise of the target tissue over any six-minute

period is 1 C or less. FIGS. 2A and 2B above illustrate the typical decay
times
required for the temperature in the heated target region to decrease by
thermal
diffusion from a temperature rise of approximately 10 C to 1 C as can be seen
in FIG. 2A when the wavelength is 880 nm and the source diameter is 1
millimeter, the temperature decay time is 16 seconds. The temperature decay
time is 107 seconds when the source diameter is 4 mm. As shown in FIG. 2B,
when the wavelength is 1000 nm, the temperature decay time is 18 seconds
when the source diameter is 1 mm and 136 seconds when the source diameter
is 4 mm. This is well within the time of the average temperature rise being
maintained over the course of several minutes, such as 6 minutes or less.
While
the target tissue's temperature is raised, such as to approximately 10 C, very

quickly, such as in a fraction of a second during the application of the
energy
19
Date Recue/Date Received 2022-01-31

source to the tissue, the relatively low duty cycle provides relatively long
periods of time between the pulses of energy applied to the tissue and the
relatively short pulse train duration ensure sufficient temperature diffusion
and
decay within a relatively short period of time comprising several minutes,
such
as 6 minutes or less, that there is no permanent tissue damage.
[Para 65] The parameters differ for the individual energy sources,
including
microwave, infrared lasers, radiofrequency and ultrasound, because the
absorption properties of tissues differ for these different types of energy
sources. The tissue water content can vary from one tissue type to another,
however, there is an observed uniformity of the properties of tissues at
normal
or near normal conditions which has allowed publication of tissue parameters
that are widely used by clinicians in designing treatments. Below are tables
illustrating the properties of electromagnetic waves in biological media, with

Table 1 relating to muscle, skin and tissues with high water content, and
Table
2 relating to fat, bone and tissues with low water content.
[Para 66] Table 1. Properties of Electromagnetic Waves in Biological Media:

Muscle, Skin, and Tissues with High Water Content
Reflection Coefficient
Wavelength Dielectric Conductivity Wavelength Depth of
Air-Muscle Interface Muscle-Fat Interface
Frequency in Air Constant o-H ___________________________________
XH Penetration
(MHz) (cm) EH (mho/m) (cm) (cm) r 0 r
0
1 30000 2000 0.400 436 91.3 0.982 +179
3000 160 0.625 118 21.6 0.956 +178
27.12 1106 113 0.612 68.1 14.3 0.925 +177 0.651 -
11.13
40.68 738 97.3 0.693 51.3 11.2 0.913 +176 0.652
-10.21
100 300 71.7 0.889 27 6.66 0.881 +175 0.650 -
7.96
200 150 56.5 1.28 16.6 4.79 0.844 +175 0.612 -
8.06
300 100 54 1.37 11.9 3.89 0.825 +175 0.592 -
8.14
433 69.3 53 1.43 8.76 3.57 0.803 +175 0.562 -
7.06
750 40 52 1.54 5.34 3.18 0.779 +176 0.532 -
5.69
915 32.8 51 1.60 4.46 3.04 0.772 +177 0.519 -
4.32
1500 20 49 1.77 2.81 2.42 0.761 +177 0.506 -
3.66
2450 12.2 47 2.21 1.76 1.70 0.754 +177 0.500 -
3.88
3000 10 46 2.26 1.45 1.61 0.751 +178 0.495 -
3.20
Date Recue/Date Received 2022-01-31

5000 6 44 3.92 0,89 0.788 0.749 +177 0.502 -
4.95
5800 5.17 43.3 4.73 0.775 0.720 0.746 +177 0.502
-4.29
8000 3,75 40 7.65 0.578 0.413 0.744 +176 0.513 -
6.65
10000 3 39.9 10.3 0.464 0.343 0.743 +176 0.518
-5.95
[Para 67] Table 2. Properties of Electromagnetic Waves in Biological Media:
Fat, Bone, and Tissues with Low Water Content
Reflection Coefficient
Depth of
Wavelength Dielectric Conductivity Wavelength Penetration Air-Fat
Interface Fat-Muscle Interface
Frequency in Air Constant o-L, XL
(MHz) (cm) EL (mmho/m) (cm (cm) r 0 r
0
1 30000
3000
27.12 1106 20 10.9-43.2 241 159 0.660 +174 0.651
+169
40.68 738 14.6 12.6-52.8 187 118 0.617 +1 73
0.652 +1 70
100 300 7.45 19.1-75.9 106 60.4 0.511 +168 0.650
+172
200 150 5.95 2 5.8-94.2 59.7 39.2 0.458 +168
0.612 +172
300 100 5.7 31.6-107 41 32.1 0.438 +1 69 0.592
+1 72
433 69.3 5.6 37.9-118 28.8 26.2 0.427 +1 70 0.562
+1 73
750 40 5.6 49.8-138 16.8 23 0.415 +173 0.532
+174
915 32.8 5.6 55.6-147 13.7 17.7 0.417 +1 73 0.519
+1 76
1500 20 5.6 70.8-171 8.41 13.9 0.412 +1 74 0.506
+1 76
2450 12.2 5.5 96.4-213 5.21 11.2 0.406 +176 0.500
+176
3000 10 5.5 110-234 4.25 9.74 0.406 +176 0.495
+177
5000 6 5.5 162-309 2.63 6.67 0.393 +176 0.502
+175
5900 5.17 5.05 186-338 2.29 5.24 0.388 +1 76 0.502
+1 76
8000 3.75 4.7 255-431 1.73 4.61 0.371 +176 0.513
+173 -
10000 3 4.5 324-549 1.41 3.39 0.363 +175 0.518
+174,-
[Para 68] The absorption lengths of radiofrequency in body tissue are long
compared to body dimensions. Consequently, the heated region is determined
by the dimensions of the coil that is the source of the radiofrequency energy
rather than by absorption lengths. Long distances r from a coil the magnetic
(near) field from a coil drops off as 1/r3. At smaller distances, the electric
and
magnetic fields can be expressed in terms of the vector magnetic potential,
which in turn can be expressed in closed form in terms of elliptic integrals
of
the first and second kind. The heating occurs only in a region that is
comparable in size to the dimensions of the coil source itself. Accordingly,
if it
is desired to preferentially heat a region characterized by a radius, the
source
coil will be chosen to have a similar radius. The heating drops off very
rapidly
21
Date Recue/Date Received 2022-01-31

outside of a hemispherical region of radius because of the 1/r3 drop off of
the
magnetic field. Since it is proposed to use the radiofrequency the diseased
tissue accessible only externally or from inner cavities, it is reasonable to
consider a coil radii of between approximately 2 to 6 mm.
[Para 69] The radius of the source coil(s) as well as the number of ampere
turns (NI) in the source coils give the magnitude and spatial extent of the
magnetic field, and the radiofrequency is a factor that relates the magnitude
of
the electric field to the magnitude of the magnetic field. The heating is
proportional to the product of the conductivity and the square of the electric

field. For target tissues of interest that are near external or internal
surfaces,
the conductivity is that of skin and mucous tissue. The duty cycle of the
pulse
train as well as the total train duration of a pulse train are factors which
affect
how much total energy is delivered to the tissue.
[Para 70] Preferred parameters for a radiofrequency energy source have been

determined to be a coil radii between 2 and 6 mm, radiofrequencies in the
range of 3-6 MHz, total pulse train durations of 0.2 to 0.4 seconds, and a
duty
cycle of between 2.5% and 5%. FIGS. 3-6 show how the number of ampere
turns varies as these parameters are varied in order to give a temperature
rise
that produces an Arrhenius integral of approximately one or unity for HSP
activation. With reference to FIG. 3, for an RF frequency of 6 MHz, a pulse
train
duration of between 0.2 and 0.4 seconds, a coil radius between 0.2 and 0.6 cm,

and a duty cycle of 5%, the peak ampere turns (NI) is 13 at the 0.6 cm coil
radius and 20 at the 0.2 cm coil radius. For a 3 MHz frequency, as illustrated
in
22
Date Recue/Date Received 2022-01-31

FIG. 4, the peak ampere turns is 26 when the pulse train duration is 0.4
seconds and the coil radius is 0.6 cm and the duty cycle is 5%. However, with
the same 5% duty cycle, the peak ampere turns is 40 when the coil radius is
0.2
cm and the pulse train duration is 0.2 seconds. A duty cycle of 2.5% is used
in
FIGS. 5 and 6. This yields, as illustrated in FIG. 5, 1 8 amp turns for a 6
MHz
radiofrequency having a coil radius of 0.6 cm and a pulse train duration of
0.4
seconds, and 29 amp turns when the coil radius is only 0.2 cm and the pulse
train duration is 0.2 seconds. With reference to FIG. 6, with a duty cycle of
2.5%
and a radiofrequency of 3 MHz, the peak ampere turns is 36 when the pulse
train duration is 0.4 seconds and the coil radius is 0.6 cm, and 57 amp turns
when the pulse train duration is 0.2 seconds and the coil radius is 0.2 cm.
[Para 71] The time, in seconds, for the temperature rise to decay from
approximately 1 0 C to approximately 1 C for coil radii between 0.2 cm and 0.6

cm is illustrated for a radiofrequency energy source in FIG. 7. The
temperature
decay time is approximately 37 seconds when the radiofrequency coil radius is
0.2 cm, and approximately 233 seconds when the radiofrequency coil radius is
0.5 cm. When the radiofrequency coil radius is 0.6 cm, the decay time is
approximately 336 seconds, which is still within the acceptable range of decay

time, but at an upper range thereof.
[Para 72] Microwaves are another electromagnetic energy source which can
be utilized in accordance with the present invention. The frequency of the
microwave determines the tissue penetration distance. The gain of a conical
microwave horn is large compared to the microwave wavelength, indicating
23
Date Recue/Date Received 2022-01-31

under those circumstances that the energy is radiated mostly in a narrow
forward load. Typically, a microwave source used in accordance with the
present invention has a linear dimension on the order of a centimeter or less,

thus the source is smaller than the wavelength, in which case the microwave
source can be approximated as a dipole antenna. Such small microwave
sources are easier to insert into internal body cavities and can also be used
to
radiate external surfaces. In that case, the heated region can be approximated

by a hemisphere with a radius equal to the absorption length of the microwave
in the body tissue being treated. As the microwaves are used to treat tissue
near external surfaces or surfaces accessible from internal cavities,
frequencies
in the 10-20 GHz range are used, wherein the corresponding penetration
distances are only between approximately 2 and 4 mm.
[Para 73] The temperature rise of the tissue using a microwave energy
source
is determined by the average power of the microwave and the total pulse train
duration. The duty cycle of the pulse train determines the peak power in a
single pulse in a train of pulses. As the radius of the source is taken to be
less
than approximately 1 centimeter, and frequencies between 10 and 20 GHz are
typically used, a resulting pulse train duration of 0.2 and 0.6 seconds is
preferred.
[Para 74] The required power decreases monotonically as the train duration
increases and as the microwave frequency increases. For a frequency of 10
GHz, the average power is 18 watts when the pulse train duration is 0.6
seconds, and 52 watts when the pulse train duration is 0.2 seconds. For a 20
24
Date Recue/Date Received 2022-01-31

GHz microwave frequency, an average power of 8 watts is used when the pulse
train is 0.6 seconds, and can be 26 watts when the pulse train duration is
only
0.2 seconds. The corresponding peak power are obtained from the average
power simply by dividing by the duty cycle.
[Para 75] With reference now to FIG. 8, a graph depicts the average
microwave power in watts of a microwave having a frequency of 10 GHz and a
pulse train duration from between 0.2 seconds and 0.6 seconds. FIG. 9 is a
similar graph, but showing the average microwave power for a microwave
having a frequency of 20 GHz. Thus, it will be seen that the average microwave

source power varies as the total train duration and microwave frequency vary.
The governing condition, however, is that the Arrhenius integral for HSI,
activation in the heated region is approximately 1.
[Para 76] With reference to FIG. 10, a graph illustrates the time, in
seconds,
for the temperature to decay from approximately 10 C to 1 C compared to
microwave frequencies between 58 MHz and 20000 MHz. The minimum and
maximum temperature decay for the preferred range of microwave frequencies
are 8 seconds when the microwave frequency is 20 GHz, and 16 seconds when
the microwave frequency is 10 GHz.
[Para 77] Utilizing ultrasound as an energy source enables heating of
surface
tissue, and tissues of varying depths in the body, including rather deep
tissue.
The absorption length of ultrasound in the body is rather long, as evidenced
by
its widespread use for imaging. Accordingly, ultrasound can be focused on
target regions deep within the body, with the heating of a focused ultrasound
Date Recue/Date Received 2022-01-31

beam concentrated mainly in the approximately cylindrical focal region of the
beam. The heated region has a volume determined by the focal waist of the
airy disc and the length of the focal waist region, that is the confocal
parameter. Multiple beams from sources at different angles can also be used,
the heating occurring at the overlapping focal regions.
[Para 78] For ultrasound, the relevant parameters for determining tissue
temperature are frequency of the ultrasound, total train duration, and
transducer power when the focal length and diameter of the ultrasound
transducer is given. The frequency, focal length, and diameter determine the
volume of the focal region where the ultrasound energy is concentrated. It is
the focal volume that comprises the target volume of tissue for treatment.
Transducers having a diameter of approximately 5 cm and having a focal length
of approximately 10 cm are readily available. Favorable focal dimensions are
achieved when the ultrasound frequency is between 1 and 5 MHz, and the total
train duration is 0.1 to 0.5 seconds. For example, for a focal length of 10 cm

and the transducer diameter of 5 cm, the focal volumes are 0.02 cc at 5 MHz
and 2.36 cc at 1 MHz.
[Para 79] With reference now to FIG. 11, a graph illustrates the average
source power in watts compared to the frequency (between 1 MHz and 5 MHz),
and the pulse train duration (between 0.1 and 0.5 seconds). A transducer focal

length of 10 cm and a source diameter of 5 cm have been assumed. The
required power to give the Arrhenius integral for HSP activation of
approximately 1 decreases monotonically as the frequency increases and as the
26
Date Recue/Date Received 2022-01-31

total train duration increases. Given the preferred parameters, the minimum
power for a frequency of 1 GHz and a pulse train duration of 0.5 seconds is
5.72 watts, whereas for the 1 GHz frequency and a pulse train duration of 0.1
seconds the maximum power is 28.6 watts. For a 5 GHz frequency, 0.046
watts is required for a pulse train duration of 0.5 seconds, wherein 0.23
watts
is required for a pulse train duration of 0.1 seconds. The corresponding peak
power during an individual pulse is obtained simply by dividing by the duty
cycle.
[Para 80] FIGURE 12 illustrates the time, in seconds, for the temperature
to
diffuse or decay from 10 C to 6 C when the ultrasound frequency is between 1
and 5 MHz. FIG. 13 illustrates the time, in seconds, to decay from
approximately 10 C to approximately 1 C for ultrasound frequencies from 1 to
MHz. For the preferred focal length of 10 cm and the transducer diameter of
5 cm, the maximum time for temperature decay is 366 seconds when the
ultrasound frequency is 1 MHz, and the minimum temperature decay is 15
seconds when the microwave frequency is 5 MHz. As the FDA only requires the
temperature rise be less than 6 C for test times of minutes, the 366 second
decay time at 1 MHz to get to a rise of 1 C over the several minutes is
allowable. As can be seen in FIGS. 12 and 13, the decay times to a rise of 6 C

are much smaller, by a factor of approximately 70, than that of 1 C.
[Para 81] FIGURE 14 illustrates the volume of focal heated region, in cubic

centimeters, as compared to ultrasound frequencies from between 1 and 5
MHz. Considering ultrasound frequencies in the range of 1 to 5 MHz, the
27
Date Recue/Date Received 2022-01-31

corresponding focal sizes for these frequencies range from 3.7 mm to 0.6 mm,
and the length of the focal region ranges from 5.6 cm to 1.2 cm. The
corresponding treatment volumes range from between approximately 2.4 cc
and 0.02 cc.
[Para 82] Examples of parameters giving a desired HSI, activation Arrhenius

integral greater than 1 and damage Arrhenius integral less than 1 is a total
ultrasound power between 5.8-17 watts, a pulse duration of 0.5 seconds, an
interval between pulses of 5 seconds, with total number of pulses 10 within
the
total pulse stream time of 50 seconds. The target treatment volume would be
approximately 1 mm on a side. Larger treatment volumes could be treatable by
an ultrasound system similar to a laser diffracted optical system, by applying

ultrasound in multiple simultaneously applied adjacent but separated and
spaced columns. The multiple focused ultrasound beams converge on a very
small treatment target within the body, the convergence allowing for a minimal

heating except at the overlapping beams at the target. This area would be
heated and stimulate the activation of HSPs and facilitate protein repair by
transient high temperature spikes. However, given the pulsating aspect of the
invention as well as the relatively small area being treated at any given
time, the
treatment is in compliance with FDA/FCC requirements for long term (minutes)
average temperature rise <1K. An important distinction of the invention from
existing therapeutic heating treatments for pain and muscle strain is that
there
are no high T spikes in existing techniques, and these are required for
28
Date Recue/Date Received 2022-01-31

efficiently activating HSPs and facilitating protein repair to provide healing
at
the cellular level.
[Para 83] The pulse train mode of energy delivery has a distinct advantage
over a single pulse or gradual mode of energy delivery, as far as the
activation
of remedial HSPs and the facilitation of protein repair is concerned. There
are
two considerations that enter into this advantage:
[Para 84] First, a big advantage for HSP activation and protein repair in
an
SDM energy delivery mode comes from producing a spike temperature of the
order of 10 C. This large rise in temperature has a big impact on the
Arrhenius
integrals that describe quantitatively the number of HSPs that are activated
and
the rate of water diffusion into the proteins that facilitates protein repair.
This
is because the temperature enters into an exponential that has a big
amplification effect.
[Para 85] It is important that the temperature rise not remain at the high
value (10 C or more) for long, because then it would violate the FDA and FCC
requirements that over periods of minutes the average temperature rise must
be less than 1 C (or in the case of ultrasound 6 C).
[Para 86] An SDM mode of energy delivery uniquely satisfies both of these
foregoing considerations by judicious choice of the power, pulse time, pulse
interval, and the volume of the target region to be treated. The volume of the

treatment region enters because the temperature must decay from its high
value of the order of 10 C fairly rapidly in order for the long term average
temperature rise not to exceed the long term FDA/FCC limit of 6 C for
29
Date Recue/Date Received 2022-01-31

ultrasound frequencies and 1 C or less for electromagnetic radiation energy
sources.
[Para 87] For a region of linear dimension L, the time that it takes the
peak
temperature to e-fold in tissue is roughly L2/16D, where D = 0.00143 cm2/sec
is the typical heat diffusion coefficient. For example, if L = 1 mm, the decay

time is roughly 0.4 sec. Accordingly, for a region 1 mm on a side, a train
consisting of 10 pulses each of duration 0.5 seconds, with an interval between

pulses of 5 second can achieve the desired momentary high rise in temperature
while still not exceeding an average long term temperature rise of 1 C. This
is
demonstrated further below.
[Para 88] The limitation of heated volume is the reason why RF
electromagnetic radiation is not as good of a choice for SDM-type treatment of

regions deep with the body as ultrasound. The long skin depths (penetration
distances) and Ohmic heating all along the skin depth results in a large
heated
volume whose thermal inertia does not allow both the attainment of a high
spike temperature that activates HSPs and facilitates protein repair, and the
rapid temperature decay that satisfies the long term FDA and FCC limit on
average temperature rise.
[Para 89] Ultrasound has already been used to therapeutically heat regions
of
the body to ease pain and muscle strain. However, the heating has not
followed the SDM-type protocol and does not have the temperature spikes that
are responsible for the excitation of HSPs.
Date Recue/Date Received 2022-01-31

[Para 90] Consider, then, a group of focused ultrasound beams that are
directed at a target region deep within the body. To simplify the mathematics,

suppose that the beams are replaced by a single source with a spherical
surface
shape that is focused on the center of the sphere. The absorption lengths of
ultrasound can be fairly long. Table 3 below shows typical absorption
coefficients for ultrasound at 1 MHz. The absorption coefficients are roughly
proportional to the frequency.
[Para 91] Table 3. Typical absorption coefficients for 1 MHz ultrasound in
body tissue:
Body Tissue Attenuation Coefficient at 1 MHz (cm-1)
Water 0.00046
Blood 0.0415
Fat 0.145
Liver 0.115-0.217
Kidney 0.23
Muscle 0.3-0.76
Bone 1.15
[Para 92] Assuming that the geometric variation of the incoming radiation
due to the focusing dominates any variation due to attenuation, the intensity
of
the incoming ultrasound at a distance r from the focus can be written
approximately as:
l(r) = P/(4-rrr2) [1]
where P denotes the total ultrasound power.
31
Date Recue/Date Received 2022-01-31

The temperature rise at the end of a short pulse of duration tp at r is then
dT(t) = Nap / (4-rrCvr2) [2]
where a is the absorption coefficient and Cv is the specific volume heat
capacity. This will be the case until the r is reached at which the heat
diffusion
length at tp becomes comparable to r, or the diffraction limit of the focused
beam is reached. For smaller r, the temperature rise is essentially
independent
of r. As an example, suppose the diffraction limit is reached at a radial
distance
that is smaller than that determined by heat diffusion. Then
rdif = (4Dtp)1 /2 [3]
where D is the heat diffusion coefficient, and for r<rdif, the temperature
rise at
tp is
dT(rdif, tp) = 3Poc/(8-rrCvD) when r< rdif [4]
Thus, at the end of the pulse, we can write for the temperature rise:
dTp(r) = {Pot/(47C}[(6/rdif2)Ufrdif-r) +(1/r2)U(r-rchf)] [5]
On applying the Green's function for the heat diffusion equation,
G(r,t) = (4QDt)-3/2exp[-r2/(4Dt)] [6]
to this initial temperature distribution, we find that the temperature dT(t)
at the
focal point r=0 at a time t is
dT(t) = [dT0/{(1/2) (71/2/6)}1[(1/2)(tp/t)3 /2 (Tri/2/6)(tp/t)] [7]
with
dT. = 3Poc/(8-riCvD) [8]
[Para 93] A good approximation to eq. [7] is provided by:
dT(t) dT0(tp/t)3/2 [9]
32
Date Recue/Date Received 2022-01-31

as can be seen in FIG. 15, which is a comparison of eqs. [7] and [9] for
dT(t)/
dT0 at the target treatment zone. The bottom curve is the approximate
expression of eq [9].
The Arrhenius integral for a train of N pulses can now be evaluated with the
temperature rise given by eq. [9]. In this expression,
dTN(t) = E dT(t-nti) [11]
where dT(t-nti) is the expression of eq. [9] with t replaced by t-ntrand with
'Li
designating the interval between pulses.
[Para 94]The Arrhenius integral can be evaluated approximately by dividing the

integration interval into the portion where the temperature spikes occur and
the
portion where the temperature spike is absent. The summation over the
temperature spike contribution can be simplified by applying Laplace's end
point formula to the integral over the temperature spike. In addition, the
integral over the portion when the spikes are absent can be simplified by
noting
that the non-spike temperature rise very rapidly reaches an asymptotic value,
so that a good approximation is obtained by replacing the varying time rise by

its asymptotic value. When these approximations are made, eq. [10] becomes:
Q = AN[ftp(2kBT02/(3EdT0)}exp[-(E/kB)1/(T0 + dT0+ dTN(Nti))]
+exp[-(E/kB)1/(T0 + dTN(Nti))]] [12]
where
dTN(Nti) 2.5 dT0(tp/ti)3/2 [13]
(The 2.5 in eq. [13] arises from the summation over n of (N-n)-3/2 and is the
magnitude of the harmonic number (N,3/2) for typical N of interest.)
33
Date Recue/Date Received 2022-01-31

[Para 95] It is interesting to compare this expression with that for SDM
applied
to the retina. The first term is very similar to that from the spike
contribution
in the retina case, except that the effective spike interval is reduced by a
factor
of 3 for this 3D converging beam case. The second term, involving dTN(Nti) is
much smaller than in the retina case. There the background temperature rise
was comparable in magnitude to the spike temperature rise. But here in the
converging beam case, the background temperature rise is much smaller by the
ratio (t/t03/2. This points up the importance of the spike contribution to the

activation or production of HSP's and the facilitation of protein repair, as
the
background temperature rise which is similar to the rise in a continuous
ultrasound heating case is insignificant compared to the spike contribution.
At
the end of the pulse train, even this low background temperature rise rapidly
disappears by heat diffusion.
[Para 96] FIGURES 16 and 17 show the magnitude of the logarithm of the
Arrhenius integrals for damage and for HSP activation or production as a
function of dT,õ for a pulse duration tp = 0.5 sec, pulse interval ti = 10
sec, and
total number of pulses N = 10. Logarithm of Arrhenius integrals [eq. 12] for
damage and for HSP activation as a function of the temperature rise in degrees

Kelvin from a single pulse dT., for a pulse duration tp = 0.5 sec., pulse
interval
ti = 10 sec., and a total number of ultrasound pulses N = 10. FIG. 16 shows
the logarithm of the damage integral with the Arrhenius constants A =
8.71x1033 5ec-1 and E = 3.55x10-12 ergs. FIG. 17 shows the logarithm of the
HSP activation integral with the Arrhenius constants A = 1.24x1027 sec-1 and E
34
Date Recue/Date Received 2022-01-31

= 2.66x10-12 ergs. The graphs in FIGS. 16 and 17 show that 0
¨damage does not
exceed 1 until dT. exceeds 11.3 K, whereas Onsp is greater than 1 over the
whole interval shown, the desired condition for cellular repair without
damage.
[Para 97] Equation [8] shows that when a = 0.1 cm-1, a dTc. of 11.5 K can be
achieved with a total ultrasound power of 5.8 watts. This is easily
achievable.
If a is increased by a factor of 2 or 3, the resulting power is still easily
achievable. The volume of the region where the temperature rise is constant
(i.e. the volume corresponding to r=rd = (4Dtp)1/2 ) is 0.00064 cc. This
corresponds to a cube that is 0.86 mm on a side.
[Para 98]This simple example demonstrates that focused ultrasound should be
usable to stimulate reparative HSP's deep in the body with easily attainable
equipment:
Total ultrasound power: 5.8 watts - 17 watts
Pulse time 0.5 sec
Pulse interval 5 sec
Total train duration (N=10) 50 sec
To expedite the treatment of larger internal volumes, a SAPRA system can be
used.
[Para 99]The pulsed energy source may be directed to an exterior of a body
which is adjacent to the target tissue or has a blood supply close to the
surface
of the exterior of the body. Alternatively, a device may be inserted into a
cavity
of a body to apply the pulsed energy source to the target tissue. Whether the
energy source is applied outside of the body or inside of the body and what
Date Recue/Date Received 2022-01-31

type of device is utilized depends upon the energy source selected and used to

treat the target tissue.
[Para 100] Photostimulation, in accordance with the present invention, can be
effectively transmitted to an internal surface area or tissue of the body
utilizing
an endoscope, such as a bronchoscope, proctoscope, colonoscope or the like.
Each of these consist essentially of a flexible tube that itself contains one
or
more internal tubes. Typically, one of the internal tubes comprises a light
pipe
or multi-mode optical fiber which conducts light down the scope to illuminate
the region of interest and enable the doctor to see what is at the illuminated

end. Another internal tube could consist of wires that carry an electrical
current
to enable the doctor to cauterize the illuminated tissue. Yet another internal

tube might consist of a biopsy tool that would enable the doctor to snip off
and
hold on to any of the illuminated tissue.
[Para 101] In the present invention, one of these internal tubes is used as an

electromagnetic radiation pipe, such as a multi-mode optical fiber, to
transmit
the SDM or other electromagnetic radiation pulses that are fed into the scope
at
the end that the doctor holds. With reference now to FIG. 18, a light
generating
unit 10, such as a laser having a desired wavelength and/or frequency is used
to generate electromagnetic radiation, such as laser light, in a controlled,
pulsed manner to be delivered through a light tube or pipe 12 to a distal end
of
the scope 14, illustrated in FIG. 19, which is inserted into the body and the
laser light or other radiation 16 delivered to the target tissue 18 to be
treated.
36
Date Recue/Date Received 2022-01-31

[Para 102] With reference now to FIG. 20, a schematic diagram is shown of a
system for generating electromagnetic energy radiation, such as laser light,
including SDM. The system, generally referred to by the reference number 20,
includes a laser console 22, such as for example the 810 nm near infrared
micropulsed diode laser in the preferred embodiment. The laser generates a
laser light beam which is passed through optics, such as an optical lens or
mask, or a plurality of optical lenses and/or masks 24 as needed. The laser
projector optics 24 pass the shaped light beam to a delivery device 26, such
as
an endoscope, for projecting the laser beam light onto the target tissue of
the
patient. It will be understood that the box labeled 26 can represent both the
laser beam projector or delivery device as well as a viewing system/camera,
such as an endoscope, or comprise two different components in use. The
viewing system/camera 26 provides feedback to a display monitor 28, which
may also include the necessary computerized hardware, data input and
controls, etc. for manipulating the laser 22, the optics 24, and/or the
projection/viewing components 26.
[Para 103] With reference now to FIG. 21, in one embodiment, the laser light
beam 30 may be passed through a collimator lens 32 and then through a mask
34. In a particularly preferred embodiment, the mask 34 comprises a
diffraction grating. The mask/diffraction grating 34 produces a geometric
object, or more typically a geometric pattern of simultaneously produced
multiple laser spots or other geometric objects. This is represented by the
multiple laser light beams labeled with reference number 36. Alternatively,
the
37
Date Recue/Date Received 2022-01-31

multiple laser spots may be generated by a plurality of fiber optic
waveguides.
Either method of generating laser spots allows for the creation of a very
large
number of laser spots simultaneously over a very wide treatment field. In
fact,
a very high number of laser spots, perhaps numbering in the hundreds even
thousands or more could be simultaneously generated to cover a given area of
the target tissue, or possibly even the entirety of the target tissue. A wide
array
of simultaneously applied small separated laser spot applications may be
desirable as such avoids certain disadvantages and treatment risks known to be

associated with large laser spot applications.
[Para 104] Using optical features with a feature size on par with the
wavelength of the laser employed, for example using a diffraction grating, it
is
possible to take advantage of quantum mechanical effects which permits
simultaneous application of a very large number of laser spots for a very
large
target area. The individual spots produced by such diffraction gratings are
all
of a similar optical geometry to the input beam, with minimal power variation
for each spot. The result is a plurality of laser spots with adequate
irradiance to
produce harmless yet effective treatment application, simultaneously over a
large target area. The present invention also contemplates the use of other
geometric objects and patterns generated by other diffractive optical
elements.
[Para 105] The laser light passing through the mask 34 diffracts, producing a
periodic pattern a distance away from the mask 34, shown by the laser beams
labeled 36 in FIG. 21. The single laser beam 30 has thus been formed into
hundreds or even thousands of individual laser beams 36 so as to create the
38
Date Recue/Date Received 2022-01-31

desired pattern of spots or other geometric objects. These laser beams 36 may
be passed through additional lenses, collimators, etc. 38 and 40 in order to
convey the laser beams and form the desired pattern. Such additional lenses,
collimators, etc. 38 and 40 can further transform and redirect the laser beams

36 as needed.
[Para 1 06] Arbitrary patterns can be constructed by controlling the shape,
spacing and pattern of the optical mask 34. The pattern and exposure spots
can be created and modified arbitrarily as desired according to application
requirements by experts in the field of optical engineering. Photolithographic

techniques, especially those developed in the field of semiconductor
manufacturing, can be used to create the simultaneous geometric pattern of
spots or other objects.
[Para 1 07] FIG. 22 illustrates diagrammatically a system which couples
multiple light sources into the pattern-generating optical subassembly
described above. Specifically, this system 20' is similar to the system 20
described in FIG. 20 above. The primary differences between the alternate
system 20' and the earlier described system 20 is the inclusion of a plurality
of
laser consoles, the outputs of which are each fed into a fiber coupler 42. The

fiber coupler produces a single output that is passed into the laser projector

optics 24 as described in the earlier system. The coupling of the plurality of

laser consoles 22 into a single optical fiber is achieved with a fiber coupler
42
as is known in the art. Other known mechanisms for combining multiple light
39
Date Recue/Date Received 2022-01-31

sources are available and may be used to replace the fiber coupler described
herein.
[Para 108] In this system 20' the multiple light sources 22 follow a similar
path as described in the earlier system 20, i.e., collimated, diffracted,
recollimated, and directed to the projector device and/or tissue. In this
alternate system 20' the diffractive element must function differently than
described earlier depending upon the wavelength of light passing through,
which results in a slightly varying pattern. The variation is linear with the
wavelength of the light source being diffracted. In general, the difference in
the
diffraction angles is small enough that the different, overlapping patterns
may
be directed along the same optical path through the projector device 26 to the

tissue for treatment.
[Para 109] Since the resulting pattern will vary slightly for each wavelength,
a
sequential offsetting to achieve complete coverage will be different for each
wavelength. This sequential offsetting can be accomplished in two modes. In
the first mode, all wavelengths of light are applied simultaneously without
identical coverage. An offsetting steering pattern to achieve complete
coverage
for one of the multiple wavelengths is used. Thus, while the light of the
selected wavelength achieves complete coverage of the tissue, the application
of the other wavelengths achieves either incomplete or overlapping coverage of

the tissue. The second mode sequentially applies each light source of a
varying
wavelength with the proper steering pattern to achieve complete coverage of
the tissue for that particular wavelength. This mode excludes the possibility
of
Date Recue/Date Received 2022-01-31

simultaneous treatment using multiple wavelengths, but allows the optical
method to achieve identical coverage for each wavelength. This avoids either
incomplete or overlapping coverage for any of the optical wavelengths.
[Para 11 0] These modes may also be mixed and matched. For example, two
wavelengths may be applied simultaneously with one wavelength achieving
complete coverage and the other achieving incomplete or overlapping coverage,
followed by a third wavelength applied sequentially and achieving complete
coverage.
[Para 1 1 1] FIG. 23 illustrates diagrammatically yet another alternate
embodiment of the inventive system 20". This system 20" is configured
generally the same as the system 20 depicted in FIG. 20. The main difference
resides in the inclusion of multiple pattern-generating subassembly channels
tuned to a specific wavelength of the light source. Multiple laser consoles 22

are arranged in parallel with each one leading directly into its own laser
projector optics 24. The laser projector optics of each channel 44a, 44b, 44c
comprise a collimator 32, mask or diffraction grating 34 and recollimators 38,

40 as described in connection with FIG. 21 above - the entire set of optics
tuned for the specific wavelength generated by the corresponding laser console

22. The output from each set of optics 24 is then directed to a beam splitter
46 for combination with the other wavelengths. It is known by those skilled in

the art that a beam splitter used in reverse can be used to combine multiple
beams of light into a single output. The combined channel output from the
final beam splitter 46c is then directed through the projector device 26.
41
Date Recue/Date Received 2022-01-31

[Para 112] In this system 20" the optical elements for each channel are tuned
to produce the exact specified pattern for that channel's wavelength.
Consequently, when all channels are combined and properly aligned a single
steering pattern may be used to achieve complete coverage of the tissue for
all
wavelengths.
[Para 113] The system 20" may use as many channels 44a, 44b, 44c, etc. and
beam splitters 46a, 46b, 46c, etc. as there are wavelengths of light being
used
in the treatment.
[Para 114] Implementation of the system 20" may take advantage of different
symmetries to reduce the number of alignment constraints. For example, the
proposed grid patterns are periodic in two dimensions and steered in two
dimensions to achieve complete coverage. As a result, if the patterns for each

channel are identical as specified, the actual pattern of each channel would
not
need to be aligned for the same steering pattern to achieve complete coverage
for all wavelengths. Each channel would only need to be aligned optically to
achieve an efficient combination.
[Para 115] In system 20", each channel begins with a light source 22, which
could be from an optical fiber as in other embodiments of the pattern-
generating subassembly. This light source 22 is directed to the optical
assembly 24 for collimation, diffraction, recollimation and directed into the
beam splitter which combines the channel with the main output.
[Para 116] It will be understood that the laser light generating systems
illustrated in FIGS. 20-23 are exemplary. Other devices and systems can be
42
Date Recue/Date Received 2022-01-31

utilized to generate a source of SDM laser light which can be operably passed
through to a projector device, typically in the form of an endoscope having a
light pipe or the like. Other forms of electromagnetic radiation may also be
generated and used, including ultraviolet waves, microwaves, other
radiofrequency waves, and laser light at predetermined wavelengths. Moreover,
ultrasound waves may also be generated and used to create a thermal time-
course temperature spike in the target tissue sufficient to activate or
produce
heat shock proteins in the cells of the target tissue without damaging the
target
tissue itself. In order to do so, typically, a pulsed source of ultrasound or
electromagnetic radiation energy is provided and applied to the target tissue
in
a manner which raises the target tissue temperature, such as between 6 C and
11 C, transiently while only 6 C or 1 C or less for the long term, such as
over
several minutes.
[Para 117] For deep tissue that is not near an internal orifice, a light pipe
is
not an effective means of delivering the pulsed energy. In that case, pulsed
low
frequency electromagnetic energy or preferably pulsed ultrasound can be used
to cause a series of temperature spikes in the target tissue.
[Para 118] Thus, in accordance with the present invention, a source of pulsed
ultrasound or electromagnetic radiation is applied to the target tissue in
order
to stimulate HSP production or activation and to facilitate protein repair in
the
living animal tissue. In general, electromagnetic radiation may be ultraviolet

waves, microwaves, other radiofrequency waves, laser light at predetermined
wavelengths, etc. On the other hand, if electromagnetic energy is to be used
43
Date Recue/Date Received 2022-01-31

for deep tissue targets away from natural orifices, absorption lengths
restrict
the wavelengths to those of microwaves or radiofrequency waves, depending on
the depth of the target tissue. However, ultrasound is to be preferred to long

wavelength electromagnetic radiation for deep tissue targets away from natural

orifices.
[Para 119] The ultrasound or electromagnetic radiation is pulsed so as to
create a thermal time-course in the tissue that stimulates HSP production or
activation and facilitates protein repair without causing damage to the cells
and
tissue being treated. The area and/or volume of the treated tissue is also
controlled and minimized so that the temperature spikes are on the order of
several degrees, e.g. approximately 10 C, while maintaining the long-term rise

in temperature to be less than the FDA mandated limit, such as 1 C. It has
been
found that if too large of an area or volume of tissue is treated, the
increased
temperature of the tissue cannot be diffused sufficiently quickly enough to
meet the FDA requirements. However, limiting the area and/or volume of the
treated tissue as well as creating a pulsed source of energy accomplishes the
goals of the present invention of stimulating HSP activation or production by
heating or otherwise stressing the cells and tissue, while allowing the
treated
cells and tissues to dissipate any excess heat generated to within acceptable
limits.
[Para 120] It is believed that stimulating HSP production in accordance with
the present invention can be effectively utilized in treating a wide array of
tissue abnormalities, ailments, and even infections. For example, the viruses
44
Date Recue/Date Received 2022-01-31

that cause colds primarily affect a small port of the respiratory epithelium
in the
nasal passages and nasopharynx. Similar to the retina, the respiratory
epithelium is a thin and clear tissue. With reference to FIG. 24, a cross-
sectional view of a human head 48 is shown with an endoscope 14 inserted into
the nasal cavity 50 and energy 16, such as laser light or the like, being
directed
to tissue 18 to be treated within the nasal cavity 50. The tissue 18 to be
treated could be within the nasal cavity 50, including the nasal passages, and

nasopharynx.
[Para 121] To assure absorption of the laser energy, or other energy source,
the wavelength can be adjusted to an infrared (IR) absorption peak of water,
or
an adjuvant dye can be used to serve as a photosensitizer. In such a case,
treatment would then consist of drinking, or topically applying, the adjuvant,

waiting a few minutes for the adjuvant to permeate the surface tissue, and
then
administering the laser light or other energy source 16 to the target tissue
18
for a few seconds, such as via optical fibers in an endoscope 14, as
illustrated
in FIG. 24. To provide comfort of the patient, the endoscope 14 could be
inserted after application of a topical anesthetic. If necessary, the
procedure
could be repeated periodically, such as in a day or so.
[Para 122] The treatment would stimulate the activation or production of heat
shock proteins and facilitate protein repair without damaging the cells and
tissues being treated. As discussed above, certain heat shock proteins have
been found to play an important role in the immune response as well as the
well-being of the targeted cells and tissue. The source of energy could be
Date Recue/Date Received 2022-01-31

monochromatic laser light, such as 810 nm wavelength laser light,
administered in a manner similar to that described in the above-referenced
patent applications, but administered through an endoscope or the like, as
illustrated in FIG. 24. The adjuvant dye would be selected so as to increase
the
laser light absorption. While this comprises a particularly preferred method
and
embodiment of performing the invention, it will be appreciated that other
types
of energy and delivery means could be used to achieve the same objectives in
accordance with the present invention.
[Para 123] With reference now to FIG. 25, a similar situation exists for the
flu
virus, where the primary target is the epithelium of the upper respiratory
tree,
in segments that have diameters greater than about 3.3 mm, namely, the upper
six generations of the upper respiratory tree. A thin layer of mucous
separates
the targeted epithelial cells from the airway lumen, and it is in this layer
that
the antigen-antibody interactions occur that result in inactivation of the
virus.
[Para 124] With continuing reference to FIG. 25, the flexible light tube 12 of
a
bronchoscope 14 is inserted through the individual's mouth 52 through the
throat and trachea 54 and into a bronchus 56 of the respiratory tree. There
the
laser light or other energy source 16 is administered and delivered to the
tissue
in this area of the uppermost segments to treat the tissue and area in the
same
manner described above with respect to FIG. 24. It is contemplated that a
wavelength of laser or other energy would be selected so as to match an IR
absorption peak of the water resident in the mucous to heat the tissue and
46
Date Recue/Date Received 2022-01-31

stimulate HSI, activation or production and facilitate protein repair, with
its
attendant benefits.
[Para 125] With reference now to FIG. 26, a colonoscope 14 could have
flexible optical tube 12 thereof inserted into the anus and rectum 58 and into

either the large intestine 60 or small intestine 62 so as to deliver the
selected
laser light or other energy source 16 to the area and tissue to be treated, as

illustrated. This could be used to assist in treating colon cancer as well as
other gastrointestinal issues.
[Para 126] Typically, the procedure could be performed similar to a
colonoscopy in that the bowel would be cleared of all stool, and the patient
would lie on his/her side and the physician would insert the long, thin light
tube portion 12 of the colonoscope 14 into the rectum and move it into the
area of the colon, large intestine 60 or small intestine 64 to the area to be
treated. The physician could view through a monitor the pathway of the
inserted flexible member 12 and even view the tissue at the tip of the
colonoscope 14 within the intestine, so as to view the area to be treated.
Using
one of the other fiber optic or light tubes, the tip 64 of the scope would be
directed to the tissue to be treated and the source of laser light or other
radiation 16 would be delivered through one of the light tubes of the
colonoscope 14 to treat the area of tissue to be treated, as described above,
in
order to stimulate HSI, activation or production in that tissue 18.
[Para 127] With reference now to FIG. 27, another example in which the
present invention can be advantageously used is what is frequently referred to
47
Date Recue/Date Received 2022-01-31

as "leaky gut" syndrome, a condition of the gastrointestinal (GI) tract marked
by
inflammation and other metabolic dysfunction. Since the GI tract is
susceptible
to metabolic dysfunction similar to the retina, it is anticipated that it will

respond well to the treatment of the present invention. This could be done by
means of subthreshold, diode micropulse laser (SDM) treatment, as discussed
above, or by other energy sources and means as discussed herein and known in
the art.
[Para 1 28] With continuing reference to FIG. 27, the flexible light tube 12
of
an endoscope or the like is inserted through the patient's mouth 52 through
the throat and trachea area 54 and into the stomach 66, where the tip or end
64 thereof is directed towards the tissue 18 to be treated, and the laser
light or
other energy source 16 is directed to the tissue 18. It will be appreciated by

those skilled in the art that a colonoscope could also be used and inserted
through the rectum 58 and into the stomach 66 or any tissue between the
stomach and the rectum.
[Para 1 29] If necessary, a chromophore pigment could be delivered to the GI
tissue orally to enable absorption of the radiation. If, for instance,
unfocused
810 nm radiation from a laser diode or LED were to be used, the pigment would
have an absorption peak at or near 810 nm. Alternatively, the wavelength of
the energy source could be adjusted to a slightly longer wavelength at an
absorption peak of water, so that no externally applied chromophore would be
required.
48
Date Recue/Date Received 2022-01-31

[Para 130] It is also contemplated by the present invention that a capsule
endoscope 68, such as that illustrated in FIG. 28, could be used to administer

the radiation and energy source in accordance with the present invention. Such

capsules are relatively small in size, such as approximately one inch in
length,
so as to be swallowed by the patient. As the capsule or pill 68 is swallowed
and
enters into the stomach and passes through the GI tract, when at the
appropriate location, the capsule or pill 68 could receive power and signals,
such as via antenna 70, so as to activate the source of energy 72, such as a
laser diode and related circuitry, with an appropriate lens 74 focusing the
generated laser light or radiation through a radiation-transparent cover 76
and
onto the tissue to be treated. It will be understood that the location of the
capsule endoscope 68 could be determined by a variety of means such as
external imaging, signal tracking, or even by means of a miniature camera with

lights through which the doctor would view images of the GI tract through
which the pill or capsule 68 was passing through at the time. The capsule or
pill 68 could be supplied with its own power source, such as by virtue of a
battery, or could be powered externally via an antenna, such that the laser
diode 72 or other energy generating source create the desired wavelength and
pulsed energy source to treat the tissue and area to be treated.
[Para 131] As in the treatment of the retina in previous applications, the
radiation would be pulsed to take advantage of the micropulse temperature
spikes and associated safety, and the power could be adjusted so that the
treatment would be completely harmless to the tissue. This could involve
49
Date Recue/Date Received 2022-01-31

adjusting the peak power, pulse times, and repetition rate to give spike
temperature rises on the order of 10 C, while maintaining the long term rise
in
temperature to be less than the FDA mandated limit of 1 C. If the pill form 68

of delivery is used, the device could be powered by a small rechargeable
battery
or over wireless inductive excitation or the like. The heated/stressed tissue
would stimulate activation or production of HSP and facilitate protein repair,

and the attendant benefits thereof.
[Para 132] From the foregoing examples, the technique of the present
invention is limited to the treatment of conditions at near body surfaces or
at
internal surfaces easily accessible by means of fiber optics or other optical
delivery means. The reason that the application of SDM to activate HSP
activity
is limited to near surface or optically accessibly regions of the body is that
the
absorption length of IR or visible radiation in the body is very short.
However,
there are conditions deeper within tissue or the body which could benefit from

the present invention. Thus, the present invention contemplates the use of
ultrasound and/or radio frequency (RF) and even shorter wavelength
electromagnetic (EM) radiation such as microwave which have relatively long
absorption lengths in body tissue. The use of pulsed ultrasound is preferable
to RF electromagnetic radiation to activate remedial HSP activity in abnormal
tissue that is inaccessible to surface SDM or the like. Pulsed ultrasound
sources
can also be used for abnormalities at or near surfaces as well.
[Para 133] With reference now to FIG. 29, with ultrasound, a specific region
deep in the body can be specifically targeted by using one or more beams that
Date Recue/Date Received 2022-01-31

are each focused on the target site. The pulsating heating will then be
largely
only in the targeted region where the beams are focused and overlap.
[Para 134] As illustrated in FIG. 29, an ultrasound transducer 78 or the like
generates a plurality of ultrasound beams 80 which are coupled to the skin via

an acoustic-impedance-matching gel, and penetrate through the skin 82 and
through undamaged tissue in front of the focus of the beams 80 to a target
organ 84, such as the illustrated liver, and specifically to a target tissue
86 to
be treated where the ultrasound beams 80 are focused. As mentioned above,
the pulsating heating will then only be at the targeted, focused region 86
where
the focused beams 80 overlap. The tissue in front of and behind the focused
region 86 will not be heated or affected appreciably.
[Para 135] The present invention contemplates not only the treatment of
surface or near surface tissue, such as using the laser light or the like,
deep
tissue using, for example, focused ultrasound beams or the like, but also
treatment of blood diseases, such as sepsis. As indicated above, focused
ultrasound treatment could be used both at surface as well as deep body
tissue,
and could also be applied in this case in treating blood. However, it is also
contemplated that the SDM and similar treatment options which are typically
limited to surface or near surface treatment of epithelial cells and the like
be
used in treating blood diseases at areas where the blood is accessible through
a
relatively thin layer of tissue, such as the earlobe.
[Para 136] With reference now to FIGS. 30 and 31, treatment of blood
disorders simply requires the transmission of SDM or other electromagnetic
51
Date Recue/Date Received 2022-01-31

radiation or ultrasound pulses to the earlobe 88, where the SDM or other
radiation source of energy could pass through the earlobe tissue and into the
blood which passes through the earlobe. It would be appreciated that this
approach could also take place at other areas of the body where the blood flow

is relatively high and/or near the tissue surface, such as fingertips, inside
of the
mouth or throat, etc.
[Para 137] With reference again to FIGS. 30 and 31, an earlobe 88 is shown
adjacent to a clamp device 90 configured to transmit SDM radiation or the
like.
This could be, for example, by means of one or more laser diodes 92 which
would transmit the desired frequency at the desired pulse and pulse train to
the
earlobe 88. Power could be provided, for example, by means of a lamp drive
94. Alternatively, the lamp drive 94 could be the actual source of laser
light,
which would be transmitted through the appropriate optics and electronics to
the earlobe 88. The clamp device 90 would merely be used to clamp onto the
patient's earlobe and cause that the radiation be constrained to the patient's

earlobe 88. This may be by means of mirrors, reflectors, diffusers, etc. This
could be controlled by a control computer 96, which would be operated by a
keyboard 98 or the like. The system may also include a display and speakers
100, if needed, for example if the procedure were to be performed by an
operator at a distance from the patient.
[Para 138] The proposed treatment with a train of electromagnetic or
ultrasound pulses has two major advantages over earlier treatments that
incorporate a single short or sustained (long) pulse. First, the short
(preferably
52
Date Recue/Date Received 2022-01-31

subsecond) individual pulses in the train activate cellular reset mechanisms
like
HSP activation with larger reaction rate constants than those operating at
longer
(minute or hour) time scales. Secondly, the repeated pulses in the treatment
provide large thermal spikes (on the order of 10,000) that allow the cell's
repair
system to more rapidly surmount the activation energy barrier that separates a

dysfunctional cellular state from the desired functional state. The net result
is a
"lowered therapeutic threshold" in the sense that a lower applied average
power
and total applied energy can be used to achieve the desired treatment goal.
[Para 139]
Although several embodiments have been described in detail
for purposes of illustration, various modifications may be made without
departing from the scope and spirit of the invention. Accordingly, the
invention
is not to be limited, except as by the appended claims.
53
Date Recue/Date Received 2022-01-31

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date 2023-08-01
(86) PCT Filing Date 2016-08-08
(87) PCT Publication Date 2017-05-04
(85) National Entry 2018-02-27
Examination Requested 2020-09-24
(45) Issued 2023-08-01

Abandonment History

There is no abandonment history.

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Next Payment if standard fee 2024-08-08 $277.00
Next Payment if small entity fee 2024-08-08 $100.00

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Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $400.00 2018-02-27
Maintenance Fee - Application - New Act 2 2018-08-08 $100.00 2018-05-23
Maintenance Fee - Application - New Act 3 2019-08-08 $100.00 2019-05-15
Maintenance Fee - Application - New Act 4 2020-08-10 $100.00 2020-06-25
Request for Examination 2021-08-09 $800.00 2020-09-24
Maintenance Fee - Application - New Act 5 2021-08-09 $204.00 2021-07-30
Maintenance Fee - Application - New Act 6 2022-08-08 $203.59 2022-07-29
Final Fee $306.00 2023-05-24
Maintenance Fee - Patent - New Act 7 2023-08-08 $210.51 2023-08-04
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
OJAI RETINAL TECHNOLOGY, LLC
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Request for Examination 2020-09-24 3 78
Amendment 2020-11-26 9 345
Claims 2020-11-26 2 91
Examiner Requisition 2021-10-06 5 195
Amendment 2022-01-31 61 2,509
Description 2022-01-31 53 2,163
Examiner Requisition 2022-08-05 3 170
Amendment 2022-11-25 13 437
Claims 2022-11-25 3 104
Abstract 2018-02-27 1 64
Claims 2018-02-27 4 91
Drawings 2018-02-27 25 389
Description 2018-02-27 53 1,861
Representative Drawing 2018-02-27 1 12
International Search Report 2018-02-27 3 158
National Entry Request 2018-02-27 3 80
Cover Page 2018-04-13 1 44
Final Fee 2023-05-24 4 90
Representative Drawing 2023-07-04 1 12
Cover Page 2023-07-04 1 47
Electronic Grant Certificate 2023-08-01 1 2,528