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 .
Priority
The instant application, which is a national stage entry of PCT/US20/60435 filed on 11/13/2020, claims priority from the provisional application 62935754 filed on 11/15/2019.
Acknowledgement of Receipt
Applicant's response filed on 04/04/2025 to the Office Action mailed on 11/06/2024 is acknowledged.
Claim Status
Claims 1-14 are pending.
Claims 1 and 10 are currently amended.
Claims 13 and 14 are newly added.
Claims 1-14 have been examined.
Claims 1-14 are rejected.
Withdrawn Claim Objection
Response to Applicant’s Arguments
The objection to claims 1 and 10 are withdrawn in view of the amendments to the claims.
Maintained and New 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
This rejection is reiterated from the previous office action and modified in view of the amendments to the claims.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over John Callan et al (US20180344872A1, publication date: 12/06/2018) (Hereinafter Callan) and Ine De Cock et al (Ultrasound and microbubble mediated drug delivery: Acoustic pressure as determinant for uptake via membrane pores or endocytosis, Journal of Controlled Release, Volume 197, 2015, Pages 20-28, ISSN 0168-3659, retrieved from <https://www.sciencedirect.com/science/article/pii/S0168365914007342>) (Hereinafter De Cock), evidenced by Chowdhury S. Abdullah et al (Abdullah, C.S., Alam, S., Aishwarya, R. et al. Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration. Sci Rep 9, 2002 (2019), retrieved from <https://doi.org/10.1038/s41598-018-37862-3>) (Hereinafter Abdullah), also evidenced by Radiology Key (Physics of Ultrasound, downloaded in October 2024, retrieved from <https://radiologykey.com/physics-of-ultrasound-3/>) (Hereinafter Radiology Key), also evidenced by The Physics Hypertextbook (downloaded in October 2024, retrieved from <https://physics.info/intensity/>) (Hereinafter The Physics Hypertextbook).
Regarding claims 1 and 3, Callan teaches “methods of sonodynamic therapy comprising the co-administration of a microbubble-chemotherapeutic agent complex together with a microbubble-sonosensitiser complex . . . Such methods find particular use in the treatment of cancer” (abstract). Callan teaches “A method of sonodynamic treatment of cells or tissues of a patient, which method comprises: (a) administering to the affected cells or tissues an effective amount of a pharmaceutical composition as claimed in claim 9 or claim 10; and (b) subjecting said cells or tissues to ultrasound, irradiation and/or light.” (claim 21) wherein the pharmaceutical composition is “A pharmaceutical composition comprising a microbubble-chemotherapeutic agent complex” (claim 9) “which comprises a microbubble attached to or associated with at least one chemotherapeutic agent, preferably via a non-covalent linkage, e.g. via a biotin-avidin interaction” (claim 3). Specifically, in example 17, Callan teaches “combined Anthracycline/Sonodynamic Therapy of Human Breast Cancer MDA-MB-231 Tumours Using Oxygen Loaded Microbubble Rose Bengal and Doxorubicin Conjugates” (para 215). Instant specification teaches the term “patient” to be “a human or animal” (instant specification page 10 line 21). Callan teaches mice (animal) with tumors to be treated wherein the tumor has an average volume of 100 mm3 (para 221). Since mice have hearts, they would also have at least one cardiac function parameter. Thus, Callan meets every element of instantly claimed step (i) “a patient comprising a cancerous tumor and at least one cardiac function parameter, said cancerous tumor having a volume.” The pharmaceutical composition disclosed by Callan in example 17 is “DoxO2MB” (para 221). For the microbubbles (MB), Callan teaches “coating of the microbubbles can increase stability of the payload, particularly when the coating material serves as an immobilisation matrix for the sonosensitiser or chemotherapeutic agent” (para 36) where “Lipids forming either a monolayer, bilayer or multilamellar structure may also be used. Examples of these include unilamellar or multilammellar liposomes and micelles” (para 37). Callan also teaches “the shell of the microbubble will comprise a surfactant or a polymer (para 32). Thus, Callan meets the instantly claimed (ii) “a pharmaceutically acceptable composition comprising a doxorubicin-lipopolycomplex and a polymer microbubble.” Regarding the ultrasound irradiation, Callan teaches “The frequency and intensity of the ultrasound which may be used can be selected based on the need to achieve selective destruction of the microbubble at the target site and may, for example, be matched to the resonant frequency of the microbubble . . . Ultrasound may be applied in continuous or pulsed mode and may be either focused or delivered as a columnar beam” (para 92) and “In cases where the ultrasound frequencies and/or intensities that are needed to achieve cavitation (or microbubble destruction) and those required to cause sonosensitiser activation are different, these different sets of ultrasound parameters (frequency/intensity) may be applied simultaneously or in a two (or multiple)-step procedure.” (para 94). Callan also teaches “composition is contacted with cells or tissues of a patient and, either simultaneously or sequentially, said cells or tissues are subjected to irradiation with ultrasound and/or light” (claim 12) and also teaches microbubbles to be injected (para 31, para 221) which meets the instantly claimed (iv) “b) injecting said pharmaceutically acceptable composition into said patient; c) exposing said cancerous tumor to at least one of said plurality of combined ultrasonic waves concurrently with said injecting.” Callan also shown tumor volume reduction (figure 19) which meets the instantly claimed “reducing said cancerous tumor volume without a clinical impairment of said at least one cardiac function parameter.” While Callan is silent regarding a cardiac function parameter, as discussed above, patients have hearts, thus would also have a cardiac function parameter. Evidentiary reference Abdullah provides the evidence that it is widely known in the field that doxorubicin induces cardiomyopathy (abstract) including systolic dysfunction (Figure 1E, H), decrease in ejection fraction (Figure 6H), fractional shortening (Figure 6E). Since Callan teaches a non-invasive/minimally invasive doxorubicin treatment without adverse side effects (para 10), Callan invention inherently meets “without a clinical impairment of said at least one cardiac function parameter” limitation.
Regarding claims 2 and 7, Callan teaches “microbubble attached to or associated with at least one chemotherapeutic agent, preferably via a non-covalent linkage, e.g. via a biotin-avidin interaction” (claim 3).
Regarding claim 4, evidentiary reference Abdullah provides the evidence that doxorubicin induced decrease (impairment) in percentage fractional shortening goes from about 40% to about 25% (about 50% impairment) which is more that 30% of a baseline value.
Regarding claims 5 and 8, Callan teaches “Polymer materials which are suitable for use in forming the shell of the microbubble include proteins, in particular albumin, particularly human serum albumin. Other biocompatible polymers which may be used include poly(vinyl alcohol) (PVA), poly(D,L-lactide-co-glycolide) (PLGA), cyanoacrylate, poloxamers (Pluronics) or combinations thereof” (para 34) and also teaches “Gases which are suitable for incorporation within the microbubbles for use according to the invention include air, nitrogen, oxygen, carbon dioxide, hydrogen” (para 40).
Regarding claim 6, Callan teaches “a microbubble having a diameter in the range 0.5 to 100 μm” (claim 6) and also teaches “Particularly suitable for use in the invention are microbubbles having a diameter of less than about 10 μm, more preferably 1 to 8 μm, particularly preferably up to 5 μm, e.g. about 2 μm” (para 31). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. MPEP 2144.05 I.
Regarding claims 9-10, Callan does not directly give kPa values. However, Callan teaches “Ultrasound frequencies will typically be in the range 20 kHz to 10 MHz, preferably 0.1 to 2 MHz. Ultrasound may be delivered as either a single frequency of a combination of different frequencies. Intensity (i.e. power density) of the ultrasound may range from about 0.1 W/cm2 to about 1 kW/cm2, preferably from about 1 to about 50 W/cm2. Treatment times will typically be in the range of 1 ms to 20 minutes and this will be dependent on the intensity chosen, i.e. for a low ultrasound intensity the treatment time will be prolonged and for a higher ultrasound intensity the treatment time will be lower” (para 92). From the abovementioned ranges, both kPa and cycles can be calculated. Evidentiary reference Radiology Key is used to determine the density and speed of sound in soft tissue (approximately 1000 kg/m3 and 1540 m/s respectively). Evidentiary reference Physics Hypertextbook provides the following equation to calculate acoustic pressure:
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Solving for P for minimum intensity value taught by Callan (square root of 2 x 1000 W/m2 x 1000 kg/m3 x 1540 m/s) equals 55.5 kPa. For maximum intensity value (when I is 10,000,000 W/m2) P is 5547 kPa. For preferred intensity range (10000-500000 W.m2), the range is calculated as 175.7 kPa-1240 kPa. The instantly claimed acoustic pressure ranges overlap with the values taught by Callan.
Regarding claim 11, Callan teaches “Ultrasound frequencies will typically be in the range 20 kHz to 10 MHz, preferably 0.1 to 2 MHz” as discussed above. The instantly claimed frequency ranges are within the ranges taught by Callan.
Regarding claim 12, Callan does not directly give cycle number values. However, these too can be calculated. Treatment time range taught by Callan is 1 ms-20 min which is 0.001 s to 1200 s. Frequency multiplied by time will give number of cycles. Minimum frequency times minimum time taught by Callan is 20,000 Hz x 0.001 s which equals 20 cycles. Maximum frequency times maximum time taught by Callan is 10,000,000 Hz x 1200 s which equals 12,000,000 cycles. The instantly claimed cycle number range are within the range taught by Callan. Lastly, it is also noted that example 17 of Callan results in 328 kPa and 3000 cycles.
Regarding claim 1, while Callan teaches “different sets of ultrasound parameters (frequency/intensity) may be applied simultaneously or in a two (or multiple)-step procedure”, Callan is silent regarding “a first ultrasonic pulse having a higher acoustic pressure than a second ultrasonic pulse.”
Regarding claim 5, while Callan teaches poly(D,L-lactide-co-glycolide) (PLGA), Callan does not specifically teach polylactide (PLA) only.
Regarding claims 1 and 5, De Cock teaches that acoustic pressure is a determinant for uptake via membrane pores or endocytosis in ultrasound mediated drug delivery (title, abstract). De Cock teaches that “acoustic pressure is a major determinant of microbubble behavior. As a consequence, we were able to direct cellular uptake towards endocytosis or direct cytoplasmic entry via pores, solely by changing acoustic pressure. Low acoustic pressure enhanced uptake by mainly stimulating endocytosis. Real-time recordings revealed that at these pressures gentle membrane deformation occurred. In literature, membrane deformation is linked to upregulated endocytosis. In contrast, high acoustic pressures lead to uptake via membrane pores. The primary radiation force propelled microbubbles towards cells at high velocity. Upon collision, pores were created in the cell membrane. When designing drug delivery experiments, these findings may be considered in order to select optimal ultrasound settings. In this way, drugs are delivered at the right site, which may boost therapeutic efficiency.” (page 27 right column).
It would have been obvious to one of ordinary skill in the art at the time of instant application to have combined the teachings of Callan and De Cock and achieve the instant invention. As discussed above, Callan teaches different sets of ultrasound parameters (frequency/intensity) may be applied simultaneously or in a two (or multiple)-step procedure. Callan also teaches “The frequency and intensity of the ultrasound which may be used can be selected based on the need to achieve selective destruction of the microbubble at the target site: (para 92). Thus, a person of ordinary skill in the art would use a high acoustic pressure to achieve selective destruction of microbubble at the site of interest and then use a low acoustic pressure to increase the effectiveness of the treatment in view of the motivations provided by De Cock. De Cock provides the motivation of using both high and low acoustic pressures since each direct cellular uptake via a different method (low acoustic pressure for endocytosis and high acoustic pressure for membrane pore opening). Thus, a person of ordinary skill in the art would be motivated to incorporate the teachings of De Cock into the teachings of Callan with a reasonable expectation of successfully delivering drugs at the right site and boost therapeutic efficiency.
Claim 5 in addition to claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over John Callan et al (US20180344872A1, publication date: 12/06/2018) (Hereinafter Callan), Ine De Cock et al (Ultrasound and microbubble mediated drug delivery: Acoustic pressure as determinant for uptake via membrane pores or endocytosis, Journal of Controlled Release, Volume 197, 2015, Pages 20-28, ISSN 0168-3659, retrieved from <https://www.sciencedirect.com/science/article/pii/S0168365914007342>) (Hereinafter De Cock) and J. M. Escoffre et al (Doxorubicin Delivery into Tumor Cells with Ultrasound and Microbubbles, Mol. Pharmaceutics 2011, 8, 799–806, retrieved from <dx.doi.org/10.1021/mp100397p>) (Hereinafter Escoffre).
Regarding claim 1, Callan and De Cock teach as discussed above.
Regarding claim 5, while Callan teaches poly(D,L-lactide-co-glycolide) (PLGA), Callan does not specifically teach polylactide (PLA) only.
Regarding claim 5, Escoffre teaches “Polylactide-Shelled PEG and Vevo Micromarker microbubbles were the best microbubbles for efficient doxorubicin delivery in the U-87 MG and MDA-MB-231 cells, respectively” (abstract, table 1).
It would have been obvious to one of ordinary skill in the art at the time of instant application to have combined the teachings of Callan, De Cock and Escroffe and achieve the instant invention. De Cock motivation is discussed above. As discussed above, Escroffe teaches using PLA for shelling microbubbles when using doxorubicin. Using PLA as opposed to other polymers listed in Callan is interpreted as simple substitution of one known element for another to obtain predictable results.
Response to Applicant’s Arguments
Applicant argues that the instantly cited prior art does not teach or suggest the use of sequential exposure of high then low acoustic pressures to provide/improve an immediate and sustained release profile of doxorubicin from a microbubble. Applicant’s arguments have been fully considered but found not to be persuasive. As Applicant admits, Callan et al. teach “using different acoustic pressures”. Callan et al. teach “different sets of ultrasound parameters (frequency/intensity) may be applied … in a two (or multiple)-step procedure” (page 94), i.e. sequentially. Therefore, Callan et al. suggests application of sequential acoustic pressure of different intensities (i.e. low and high) to a patient following administering of the composition to the patient. While, the Callan et al. does not explicitly describe that doing so would provide/improve an immediate and sustained release profile of doxorubicin from a microbubble, this is an inherent property of the method as suggested by the prior art. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007)(The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. “The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.”). When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986). In the instant case, the application of acoustic pressure sequentially in varying intensities is being used to in the same manner as instantly claimed, i.e. applied to a patient following administration of the composition. Therefore, it would be expected that the prior art method would also result in an immediate and sustained release profile.
Applicant also argues that the instantly cited prior art does not teach or suggest the use of sequential exposure of high then low acoustic pressures in combination with the instantly claimed pharmaceutically acceptable composition to reduce side effects, in particular impairment if at least one cardiac function parameter. Applicant’s arguments have been fully considered but found not to be persuasive. Similar to the previous argument, it would also be expected that the prior art method would result in prevention of a clinical impairment of at least one cardiac function parameter.
With regard to new claims 13 and 14, these limitations are inherent properties of the method of as suggested by the prior art, for the reasons given in the arguments above.
For the foregoing reasons the rejection is maintained and new claims 13 and 14 are also rejected over the same rejection.
New 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.
This is a new ground of rejection necessitated by the amendment to the claims.
Claim 14 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The instant specification as originally filed nowhere describes expressly or through implication of a “greater clinical efficacy”.
This is a new ground of rejection necessitated by the amendment to the claims.
Claims 1-14 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.
Claim 1 recites “delivering an immediate and sustained release profile of said doxorubicin lipopolycomplex to said cancerous tissue”. The phrase “immediate and sustained release profile” with regard to the instantly claimed composition is indefinite. Immediate release profiles and sustained release profiles are two distinct profiles and are seen as opposite of each other. Sandeep et al. (IMMEDIATE DRUG RELEASE DOSAGE FORM: A REVIEW, Published 2013) teach “Immediate release tablets are those which disintegrate rapidly and get dissolved to release the medicaments. Immediate release may be provided for by way of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable extent, the rate of drug release and/or absorption. This term excludes formulations which are adapted to provide for “modified”, “controlled”, “sustained”, “prolonged”, “extended” or “delayed” release of drug.” (page 155). Therefore, it is not clear how a formulation which release all of the active ingredient immediately, would also be able to release (non-existent) active agent over a period of time.
Claims 2-14 are rejected for being dependent, directly or indirectly, upon an indefinite claim.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614