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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 27-46 in the reply filed on June 29, 2026 is acknowledged.
Claim Objections
Claims 33, 34 and 35 are objected to because of the following informalities:
In claims 33, 34 and 35, in line 1, --- the --- should be inserted before “transcutaneous”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 29 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.
With regards to claim 29, in line 2, the claim recites that the transcutaneous ultrasound parameters “comprise 1.05 MHz..”. It is unclear as to what parameter the 1.05 Mhz value corresponds to. For examination purposes, Examiner assumes the parameter corresponds to a frequency. Claims 30 and 45 are similarly rejected (see “MHz” limitations).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 27, 30, 33-35 and 40 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Unger et al. (US Pub No. 2001/0031740).
With regards to claim 27, Unger et al. disclose a method to provide therapeutic levels of human Factor VIII protein expression in blood of a subject, the method comprising:
administering a liver-specific human Factor VIII plasmid and microbubbles while simultaneously applying transcutaneous ultrasound directed at the subject's liver (paragraphs [0098]-[0100], [0103]-[0104], referring to applying ultrasound energy to the target tissue to facilitate gene expression using a transcutaneous application; paragraphs [0105]-[0106], referring to DNA encoding certain proteins being used in the treatment of many different types of diseases, including Factor VIII to treat Hemophilia B; paragraph [0115], referring to administration of compositions, such as intravascularly, wherein a carrier may be used and one method of administration is by using a catheter inserted into the blood stream of a patient, wherein ultrasound may be applied externally; paragraphs [0051]-[0052], referring to the compositions further comprising a carrier, wherein the carrier may include microbubbles);
thereby providing therapeutic levels of human Factor VIII protein expression in the blood of the subject, wherein the method does not produce clinically-relevant liver damage (paragraphs [0015]-[0020], referring to treating a patient comprising administering to a patient a therapeutically effective amount of a compound or a composition comprising therapeutically effective amount of a compound and applying ultrasound; paragraph [0106], referring to the treatment of the liver and DNA encoding certain proteins being used in the treatment of diseases, including Factor VIII to treat Hemophilia B).
With regards to claim 30, Unger et al. disclose that transcutaneous ultrasound parameters comprises 1.0-1.1 MHz (paragraph [0129], referring to ultrasound energy being applied with a center frequency at approximately 1.0 MHz).
With regards to claim 33, Unger et al. disclose that transcutaneous ultrasound is applied for 7-9 minutes (paragraph [0121], referring to a period of ultrasound treatment being over 25 minutes, which encompasses 7-9 minutes).
With regards to claim 34, Unger et al. disclose that transcutaneous ultrasound is applied for 8 minutes (paragraph [0121], referring to a period of ultrasound treatment being over 25 minutes, which encompasses 7-9 minutes).
With regards to claim 35, Unger et al. disclose that transcutaneous ultrasound is applied via a geometrically focused ultrasound (paragraphs [0131], [0165], referring to a shell of the transducer being constructed for geometric focusing).
With regards to claim 40, Unger et al. disclose that the method occurs without open surgery (paragraph [0096], referring to the route of administration including non-open surgical procedures, such as providing the composition intravenously, intravascularly, etc.).
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.
Claim(s) 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. as applied to claim 27 above, and further in view of Sun et al. (“Development of therapeutic microbubbles for enhancing ultrasound-mediated gene delivery”, 2014).
With regards to claim 28, as discussed above, Unger et al. meet the limitations of claim 27. However, Unger et al. do not specifically disclose that the microbubbles are RN18 microbubbles.
Sun et al. disclose the use of RN18 microbubbles to enhance microbubble (MB) functions in a wide range of therapeutic US/MB gene and drug delivery approach, wherein RN18 provides elevated stability (Abstract; pg. 117, right column, last paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the microbubbles of Unger et al. comprise RN18 microbubbles, as taught by Sun et al., in order to enhance the microbubble function by providing enhanced stability (Abstract).
Claim(s) 29 and 31-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. as applied to claim 27 above, alone.
With regards to claims 29 and 31-32, as discussed above, Unger et al. meet the limitations of claim 27. However, Unger et al. do not specifically disclose that the transcutaneous ultrasound parameters comprise 1.05 MHz, a 2.5 MPa derated peak negative pressure (PNP), a 50 Hz pulse repetition frequency (PRF) and a 200 us pulse duration (PD). Further, with regards to claims 31-32, Unger et al. do not specifically disclose that the transcutaneous parameters comprise a 2.0-3.0 MPa derated PNP or comprises a 45-55 Hz PR and a 200 micro-second pulse duration.
Unger discloses that the amount of energy and time of exposure and other parameters of the ultrasound may be modified (Abstract; paragraphs [0128]-[0129]) and therefore, it would have been within the skill of one of ordinary skill in the art, through routine experimentation/optimization, to adopt the above ultrasound parameters (i.e. 1.05 MHz, a 2.5 MPa derated peak negative pressure (PNP), a 50 Hz pulse repetition frequency (PRF), a 200 us pulse duration (PD) or a 2.0-3.0 MPa derated PNP or a 45-55 Hz PR and a 200 micro-second pulse duration) in order to determine the optimal ultrasound parameters that provide a desired clinical application outcome.
Claim(s) 36-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. as applied to claim 27 above, and further in view of Yoshino et al. (“Naked plasmid DNA transfer to the porcine liver using rapid injection with large volume”, 2006).
With regards to claim 36, as discussed above, Unger et al. meet the limitations of claim 27. Unger et al. further disclose that the human Factor VIII plasmid is administered via a balloon catheter in a blood vessel of a patient (paragraphs [0115], [0163], [0165]).
However, Unger et al. do not specifically disclose that the balloon catheter is positioned in a hepatic vein of the subject via jugular vein access.
Yoshino et al. disclose a naked plasmid DNA transfer method of rapid injection with large volume for gene therapy of the liver (Abstract; pg. 1700, right column, 2nd-5th paragraphs). An occlusion balloon catheter was inserted from the right external jugular vein with the angiocatheter sheath and into the left hepatic vein, navigated under fluoroscopic control (Abstract; pg. 1701, “Anesthesia and surgical preparation”). The hepatic vein was occluded with the balloon catheter and the surgeon held the left outer lobe of the liver with the hands to fix the liver and the occlusion balloon and to prevent leakage of the solution (pg. 1701, “Anesthesia and surgical preparation”). Their technique of inserting a catheter into only a selected portion of the liver reduced liver toxicity and increased gene transfer efficiency (Abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the balloon catheter of Unger et al. be positioned in a hepatic vein of the subject via jugular vein access, as taught by Yoshino et al., in order to insert a catheter into only a selected portion of the liver to reduce liver toxicity and increase gene transfer efficiency (Abstract).
With regards to claim 37, Unger et al. disclose that the balloon catheter is inflated to occlude blood flow during the administering (paragraphs [0115], [0163]). Yoshino et al. further discloses this limitation (pg. 1701, “Anesthesia and surgical preparation”).
Claim(s) 38-39 and 41-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. as applied to claim 27 above, and further in view of Song et al. (“Ultrasound Combined with Microbubbles Mediated Factor VIII Plasmid Gene Therapy in Hemophilia a Mice”, December 2015).
With regards to claims 38-39, as discussed above, Unger et al. meet the limitations of claim 27. However, Unger et al. do not specifically disclose that the subject has hemophilia A and that the liver-specific human Factor VIII plasmid comprises hFVIII-X10.
Song et al. disclose delivering a therapeutic FVIII plasmid into the liver of hemophilia A mice, wherein a novel plasmid encoding a B domain-deleted FVIII variant containing mutations of 10 amino acids in the A1 domain (BDDFVIII-X10) was constructed and showed improved gene transfer efficiency (Abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the subject of Unger et al. have hemophilia A and have the liver-specific human Factor VIII plasmid of Unger et al. comprise hFVIII-X10, as taught by Song et al., in order to provide improved gene transfer efficiency and treat hemophilia A (Abstract).
With regards to claim 41, as discussed above, Unger et al. meet the limitations of claim 27. However, Unger et al. do not specifically disclose that the method further comprises detecting the human Factor VIII protein in a blood sample derived from the subject.
Song et al. disclose delivering a therapeutic FVIII plasmid into the liver of hemophilia A mice, wherein blood and liver samples were collected at serial time points after treatment to determine FVIII activity in plasma and liver damage (Abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the method further comprise detecting the human Factor VIII protein in a blood sample derived from the subject, as taught by Song et al., in order to determine FVIII activity in plasma and liver damage (Abstract).
With regards to claim 42, Song et al. disclose that the detecting is 3, 7, or 28 days after the administering (Abstract, referring to the detecting on day 4 and day 28).
Claim(s) 43-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. as applied to claim 27 above, and further in view of Yang et al., “Effects of diagnostic ultrasound-targeted microbubble destruction on permeability of normal liver in rats”, 2012).
With regards to claims 43-44, as discussed above, Unger et al. meet the limitations of claim 27. However, Unger et al. do not specifically disclose that ALT levels return to normal within one week of the administering and AST levels return to normal within 3 days of the administering.
Yang determined whether ultrasound-targeted microbubble destruction group (UTMD) can increase the capillary permeability and cell membrane permeability in liver tissue and to evaluate the safety of this technique (Abstract; pg. 1066, left column, 2nd paragraph). Blood samples before treatment and after the treatment were acquired and ALT levels were measured, wherein it was found that the levels of serum ALT and AST gradually returned to their respective pre-treatment values at 24 hr after treatment, (pg. 1067, left column, last paragraph; pg. 1068, Section 3.3), Thus UTMD can thus increase the capillary and cell membrane permeabilities in normal liver tissue without a significant increase in hepatic and renal toxicity (Abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to modify the ultrasound parameters of Unger et al. such that ALT levels return to normal within one week of the administering and that AST levels return to normal within 3 days of the administering, as taught by Yang et al., in order to ensure treatment without a significant increase in hepatic and renal toxicity (Abstract).
Claim(s) 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. as applied to claim 27 above, and further in view of Sun et al. and Yang et al..
With regards to claim 45, as discussed above, Unger et al. meet the limitations of claim 27. Further, Unger et al. disclose that the transcutaneous ultrasound directed at the subject’s liver is applied via a geometrically focused transducer for 8 minutes (paragraph [0121], referring to a period of ultrasound treatment being over 25 minutes, which encompasses 7-9 minutes; paragraphs [0131], [0165], referring to a shell of the transducer being constructed for geometric focusing) and that the method occurs without open surgery and does not produce clinically-relevant liver damage (paragraph [0096], referring to the route of administration including non-open surgical procedures, such as providing the composition intravenously, intravascularly, etc.).
However, Unger et al. do not specifically disclose that the microbubbles comprise RN18 microbubbles; and the ultrasound parameters comprise 1.05 MHz, a 2.5 MPa derated peak negative pressure (PNP), a 50 Hz pulse repetition frequency (PRF), and wherein alanine transaminase (ALT) levels return to normal within one week of the administering and aspartate transarminase (AST) levels return to normal within 3 days of the administering.
Sun et al. disclose the use of RN18 microbubbles to enhance microbubble (MB) functions in a wide range of therapeutic US/MB gene and drug delivery approach, wherein RN18 provides elevated stability (Abstract; pg. 117, right column, last paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the microbubbles of Unger et al. comprise RN18 microbubbles, as taught by Sun et al., in order to enhance the microbubble function by providing enhanced stability (Abstract).
However, the above combined references do not specifically disclose that the ultrasound parameters comprise 1.05 MHz, a 2.5 MPa derated peak negative pressure (PNP), a 50 Hz pulse repetition frequency (PRF), and wherein alanine transaminase (ALT) levels return to normal within one week of the administering and aspartate transarminase (AST) levels return to normal within 3 days of the administering.
Yang determined whether ultrasound-targeted microbubble destruction group (UTMD) can increase the capillary permeability and cell membrane permeability in liver tissue and to evaluate the safety of this technique (Abstract; pg. 1066, left column, 2nd paragraph). Blood samples before treatment and after the treatment were acquired and ALT levels were measured, wherein it was found that the levels of serum ALT and AST gradually returned to their respective pre-treatment values at 24 hr after treatment, (pg. 1067, left column, last paragraph; pg. 1068, Section 3.3), Thus UTMD can thus increase the capillary and cell membrane permeabilities in normal liver tissue without a significant increase in hepatic and renal toxicity (Abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to modify the ultrasound parameters of Unger et al. such that ALT levels return to normal within one week of the administering and that AST levels return to normal within 3 days of the administering, as taught by Yang et al., in order to ensure treatment without a significant increase in hepatic and renal toxicity (Abstract).
However, the above combined references do not specifically disclose that the ultrasound parameters comprise 1.05 MHz, a 2.5 MPa derated peak negative pressure (PNP), a 50 Hz pulse repetition frequency (PRF).
Unger discloses that the amount of energy and time of exposure and other parameters of the ultrasound may be modified (Abstract; paragraphs [0128]-[0129]) and therefore, it would have been within the skill of one of ordinary skill in the art, through routine experimentation/optimization, to adopt the above ultrasound parameters (i.e. 1.05 MHz, a 2.5 MPa derated peak negative pressure (PNP), a 50 Hz pulse repetition frequency (PRF)) in order to determine the optimal ultrasound parameters that provide a desired clinical application outcome.
Claim(s) 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Unger et al. in view of Sun et al. and Yang et al., as applied to claim 45 above, and further in view of Song et al..
With regards to claim 46, as discussed above, the above combined references meet the limitations of claim 45.
However, the above combined references do not specifically disclose that the method further comprises detecting the human Factor VIII protein in a blood sample derived from the subject 28 days after the administering.
Song et al. disclose delivering a therapeutic FVIII plasmid into the liver of hemophilia A mice, wherein blood and liver samples were collected at serial time points, including 28 days, after treatment to determine FVIII activity in plasma and liver damage (Abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the method further comprise detecting the human Factor VIII protein in a blood sample derived from the subject 28 days after the administering, as taught by Song et al., in order to determine FVIII activity in plasma and liver damage (Abstract).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE L FERNANDEZ whose telephone number is (571)272-1957. The examiner can normally be reached Monday-Friday 9:00 AM - 5:30 PM (ET).
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/KATHERINE L FERNANDEZ/Primary Examiner, Art Unit 3798
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