DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 1 objected to because of the following informalities:
In the last line of claim 1, "ultrasound transducer system" should be changed to "ultrasonic transducer system" for consistency with the rest of the claims because it is clear from the context of the claims and specification that the Applicant intended to refer to the previously set forth ultrasonic transducer system.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-4, 10-11, and 13-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding claims 2 and 13, the claims recite wherein the ultrasonic transducer system is configured to administer a bolus into bloodstream of the subject to locally increase the temperature of the blood using HIFU. The original Specification, as presented, fails to describe the invention in such terms that one skilled in the art can make and use the claimed invention without undue experimentation and therefore fails the enablement requirement set forth under 35 U.S.C. 112(a). See MPEP 2164, citing In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
The following factors are to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”:
(A) the breadth of the claims;
(B) the nature of the invention;
(C) the state of the prior art;
(D) the level of one of ordinary skill;
(E) the level of predictability in the art;
(F) the amount of direction provided by the inventor;
(G) the existence of working examples; and
(H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure (see MPEP 2164.01(a)).
Here, for example:
(A) Breadth of the claims – the claim recites a method of introducing a bolus into a bloodstream using HIFU.
(B) Nature of the invention – the invention is directed to performing thermodilution, which typically involves injecting a bolus such as saline into the bloodstream with a needle and syringe, but the invention instead uses HIFU to inject the bolus.
(C) State of the prior art – Presently, HIFU can be used to increase permeability for drugs into tissue, bypass the blood brain barrier, and trigger the release of drugs from microbubbles, but it is not currently used to inject saline into a blood stream because in the above known scenarios, the drugs have already been injected into the patient, HIFU is simply used to help the drugs permeate into the desired areas. In other words, in the prior art, HIFU is not itself performing the introduction of the drugs into the bloodstream.
(D) Level of ordinary skill – To date, one of ordinary skill in the art would recognize that one could not use HIFU to administer a bolus into the bloodstream of a patient.
(F) Amount of direction provided by the inventor – The original Specification, as presented, provides no direction as to how to use HIFU to administer a bolus into a bloodstream of a patient.
(G) Existence of working examples – The Applicant does not provide any working examples in the original Specification.
In light of the above, it is asserted that the original Specification, as presented, fails to describe the invention in such terms that one skilled in the art can make and use the claimed invention without undue experimentation. Accordingly, claims 2 and 13 are rejected under 35 U.S.C. 112(a). Their dependent claims are also rejected 112a because they inherent the same 112a deficiencies outlined above.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 6, and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 3, claim 1 requires “locally increasing temperature of blood” and claim 3 requires using a cold saline to do so. It is unclear how cold saline can be used to increase temperature. A person having ordinary skill in the art would understand that cold saline would decrease local temperature as that is the primary purpose of cold saline. Clarification is required. Accordingly, this claim is rejected under 112b.
Regarding claim 6, the claim recites the limitation “the bolus”. There is insufficient antecedent basis for this limitation in the claim. No bolus has previously been set forth. Did the Applicant intend for claim 6 to depend on claim 2? Clarification is required. To overcome this rejection, the Examiner recommends amending claim 6 to depend on claim 2.
Regarding claim 9, the claim recites “wherein a thermodilution profile amplitude of the thermodilution curve is increased by placing an HIFU focal point and a thermometry measurement point closer to each other”. Is this claim requiring that the system perform this step or be configured to perform this step? Or is the system simply supposed to be set up in a manner such that this is true? Clarification is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 5, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Krivitski et al. (US20240032812, hereafter Krivitski) and Routh et al. (US20080312562, hereafter Routh).
Regarding claims 1 and 12, Krivitski discloses an apparatus for performing thermodilution (Krivitski, Para 15; “An apparatus is disclosed […] configured to generate a dilution curve; and a controller operably connected to the first sensor, the controller configured to calculate the flow rate in the flow in the conduit, wherein the calculated flow rate at least partly corresponds to the generated dilution curve.”) and a computer program product comprising a non-transitory computer readable medium having computer readable code embodied therein, the computer readable code being configured such that, on execution by a suitable computer or processor, the computer or processor is caused to perform a method for performing non-invasive thermodilution (Krivitski, Para 45; “wherein the controller includes a processor having hardware and software configured to implement the present algorithms, as set forth below and in FIG. 10 , and can include local or remote memory.”), comprising:
an ultrasonic transducer system comprising one or more ultrasonic transducers or transducer arrays (Krivitski, Para 36; "For example, if a thermal sensor is employed, the thermal sensor can be any sensor that can measure temperature, for example, but not limited to [...] ultrasound velocity sensor (blood ultrasound velocity changes with temperature)"), the ultrasonic transducer system configured to:
locally increase the temperature of blood of a subject (Krivitski, Para 41; "An injectable indicator may be any of the known indicators including saline, electrolytes, water and temperature gradient indicator bolus. Preferably, the indicator is non toxic with respect to the patient and non reactive with the material of the system. The indicator may be any substance that will change a blood chemical or physical characteristic. The indicator may be a physically injected material such as saline.") (Krivitski, Para 72; "Depending on the type of indicator, such as being cooler or warmer than the flow in the conduit 8, the apex may be a maximum or a minimum of the dilution curve. From the start of the dilution curve (generally coinciding with the start of the introduction period to the apex of the dilution curve corresponds to the duration of the introduction period.") (Krivitski, Abstract; "The determination of the indicator temperature is extrapolated or estimated from (i) an observed temperature curve of an indicator sensor on the catheter that records a substitution of warmed fluid in the sheath by the introduced indicator "); and
measure a corresponding change in temperature of the blood downstream using ultrasonic thermometry (Krivitski, Para 36; "For example, if a thermal sensor is employed, the thermal sensor can be any sensor that can measure temperature, for example, but not limited to [...] ultrasound velocity sensor (blood ultrasound velocity changes with temperature)") (Krivitski, Para 36; "The sensors are employed to detect passage of the indicator and thus measures, identified or monitors a blood parameter or property, and particularly variations of the blood parameter or property. Thus, the sensors are capable of sensing a change is a blood property, parameter or characteristic. "); and
a processor communicatively coupled to the ultrasonic transducer system, wherein the processor is configured to create a thermodilution curve based on receiving signals pertaining to the measure of the change in temperature from the ultrasound transducer system (Krivitski, Para 16; "with an introduction of an indicator into the flow; and a controller operably connected to the sensor, the controller configured to calculate a flow rate in the conduit, wherein the calculated flow rate at least partly corresponds to an identified portion of the dilution curve, the identified portion created after a termination of the introduction of the indicator into the flow.") (Krivitski, Para 47; "A temperature signal, such as an indicator and more particularly an indicator having a lower temperature or a higher temperature than the flow of the flow rate to be calculated Q, is introduced into the flow at an upstream location and a downstream dilution signal is sensed. Eq1 where Q—is the flow rate to be calculated, Tb is the initial temperature of the flow, Tinj is the temperature of the indicator, k is a constant, wherein k is typically taken to be 1.08, Vinj is the volume of indicator, and S is the area under the dilution curve recorded by a dilution sensor in the flow to be measured." ) (Krivitski, Para 22; "FIG. 6 is a graphical representation of determining the time constant of the sensor, the catheter, or both the sensor and the catheter when moving from a steady warm temperature to a steady cold temperature.").
Krivitski does not clearly and explicitly disclose locally increasing the temperature of blood of a subject using high-intensity focused ultrasound (HIFU).
In an analogous ultrasound blood flow measurement system field of endeavor Routh discloses locally increasing temperature of blood of a subject using high-intensity focused ultrasound (HIFU) (Routh, Para 19; "The application of the HIFU energy over an extended region of the artery allows the blood to be heated to a sufficient temperature ").
The use of the techniques of using HIFU to raise local temperature taught by Routh in the invention of Krivitski would have comprised only application of a known technique to a known device ready for improvement to yield the predictable result of raising blood temperature using HIFU; and similar modifications have previously been held to involve only routine skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Krivitski to include locally increasing the temperature of blood of a subject using high-intensity focused ultrasound (HIFU) as taught by Routh in order to use a precise and reliable method of increasing local temperature.
Regarding claim 5, Krivitski as modified by Routh above discloses all of the limitations of claim 1 as discussed above.
Krivitski further discloses wherein the ultrasonic transducer system (Krivitski, Para 36; "For example, if a thermal sensor is employed, the thermal sensor can be any sensor that can measure temperature, for example, but not limited to [...] ultrasound velocity sensor (blood ultrasound velocity changes with temperature)") measures a blood flow rate of the subject (Krivitski, Para 16; "with an introduction of an indicator into the flow; and a controller operably connected to the sensor, the controller configured to calculate a flow rate in the conduit, wherein the calculated flow rate at least partly corresponds to an identified portion of the dilution curve, the identified portion created after a termination of the introduction of the indicator into the flow.") (Krivitski, Para 47; "A temperature signal, such as an indicator and more particularly an indicator having a lower temperature or a higher temperature than the flow of the flow rate to be calculated Q, is introduced into the flow at an upstream location and a downstream dilution signal is sensed. Eq1 where Q—is the flow rate to be calculated, Tb is the initial temperature of the flow, Tinj is the temperature of the indicator, k is a constant, wherein k is typically taken to be 1.08, Vinj is the volume of indicator, and S is the area under the dilution curve recorded by a dilution sensor in the flow to be measured." ).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Krivitski and Routh as applied to claim 1 above, and further in view of Krivitski et al., (US20060129053, hereafter Krivitski ‘053).
Regarding claim 6, Krivitski as modified by Routh above discloses all of the limitations of claim 1 as discussed above.
Krivitski does not clearly and explicitly disclose wherein the processor is configured to derive a cardiac output of the subject from the thermodilution curve based on a thermal dissipation of the bolus due to bloodstream in the heart of the subject.
In an analogous thermodilution system field of endeavor Krivitski ‘053 discloses deriving a cardiac output of a subject from a thermodilution curve based on a thermal dissipation of the bolus due to bloodstream in a heart of the subject (Krivitski ‘053, Para 183-184; “In thermodilution measurements of cardiac output, a first distal thermal sensor is located in the pulmonary artery and produces dilution curves, and a second thermal sensor is located in the central vein, in the aperture (or within the aperture) through which indicator solution enters the blood stream. In this way, the second thermal sensor measures the temperature of the solution (injectate) entering the blood. […] a second proximal thermal sensor 36 a (FIG. 1, 2) for measuring the temperature of the indicator injection (injectate) is located in a part of the catheter 10 that is out of the blood stream. In this case, the temperature of injected indicator is measured just prior to the indicator entering the part of the catheter that is located in the blood stream. The heating/cooling of the indicator while passing through the length of the catheter that is in thermal contact with the blood flow of the A-V shunt (before exiting through ports into the blood flow) is negligible or can be accounted. Also, the surrounding air has a relatively low thermal conductance (in contrast to the flowing blood) and the thermal sensor 36 a will more accurately represent temperature Ti. It is also noted that the volume of the indicator injection V must be sufficiently large to be significantly greater than a priming volume of any liquid contained in the portion of the injection lumen that is located within the blood vessel and thus has a temperature that is approximate to the temperature of the blood.”) (Krivitski ‘053, Para 182-194; generally describing the process).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Krivitski wherein the processor is configured to derive a cardiac output of the subject from the thermodilution curve based on a thermal dissipation of the bolus due to bloodstream in the heart of the subject in order to allow for medical practitioners to determine if there is sufficient flow as needed as taught by Krivitski ‘053 (Krivitski ‘053, Para 7-8).
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Krivitski and Routh as applied to claim 1 above, and further in view of Sano et al., (US20030191389, hereafter Sano).
Regarding claim 7, Krivitski as modified by Routh above discloses all of the limitations of claim 1 as discussed above.
Krivitski does not clearly and explicitly disclose wherein the processor is configured to analyze the thermodilution curve using a frequency profile based on signal processing.
In an analogous thermodilution system field of endeavor Sano discloses analyzing a thermodilution curve using a frequency profile based on signal processing (Sano, Para 37; "an automatic cardiac output calculation processing/analyzing function, or basic analysis, i.e., a curve analysis (FFT analysis, blood stream speed gradient analysis, chronological brightness change analysis), etc.").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Krivitski wherein the processor is configured to analyze the thermodilution curve using a frequency profile based on signal processing as taught by Sano (Sano, Para 7-8) in order to diagnose a heart as needed by allowing a user to evaluate cardiac function and monitor changes.
Regarding claim 8, Krivitski as modified by Routh and Sano above discloses all of the limitations of claim 7 as discussed above.
Krivitski does not clearly and explicitly disclose wherein the processor is configured to analyze the thermodilution curve using one of a Fast Fourier Transform (FFT) signal processing and an impulse response function.
Sano further discloses analyzing a thermodilution curve using one of a Fast Fourier Transform (FFT) signal processing (Sano, Para 37; "an automatic cardiac output calculation processing/analyzing function, or basic analysis, i.e., a curve analysis (FFT analysis, blood stream speed gradient analysis, chronological brightness change analysis), etc.").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Krivitski wherein the processor is configured to analyze the thermodilution curve using one of a Fast Fourier Transform (FFT) signal processing and an impulse response function as taught by Sano (Sano, Para 7-8) in order to diagnose a heart as needed by allowing a user to evaluate cardiac function and monitor changes.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Krivitski and Routh as applied to claim 1 above, and further in view of Bruyne et al., (Bernard De Bruyne, Nico H.J. Pijls, Leif Smith, Maria Wievegg, et al., Coronary Thermodilution to Assess Flow Reserve: Experimental Validation, Circulation Volume 104, Number 17, Inc., Oct 23, 2001, https://doi.org/10.1161/hc4201.099223, hereafter Bruyne).
Regarding claim 9, Krivitski as modified by Routh above discloses all of the limitations of claim 1 as discussed above.
Krivitski does not clearly and explicitly disclose wherein a thermodilution profile amplitude of the thermodilution curve is increased by placing an HIFU focal point and a thermometry measurement point closer to each other.
In an analogous thermodilution system field of endeavor Bruyne discloses wherein a thermodilution profile amplitude of a thermodilution curve is increased by placing an temperature increase point and a measurement point closer to each other (Bruyne, Pg 2005, Figure 2 showing this phenomenon (see y-axis, amplitude is higher at 6cm gap than at 12 cm gap)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Krivitski wherein a thermodilution profile amplitude of the thermodilution curve is increased by placing an HIFU focal point and a thermometry measurement point closer to each other in order to provide better insight into blood flow as taught by Bruyne (Bruyne, Pg 2006).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20170203131 – discloses using HIFU to increase permeability of tissues to drugs
US20190366123 - discloses using HIFU to increase permeability of tissues to drugs through the blood brain barrier
US20080281200 - uses a bolus to focus HIFU, not to inject the bolus into the blood vessel
US20230285274 – discloses using HIFU to burst microbubbles to deliver drugs
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/JOHN D LI/Primary Examiner, Art Unit 3798
