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 .
Claims 1, 3-11, 18-20, 22, 24, and 29 are amended.
Claims 1, 3-11, 18-20, 22 and 24-30 are pending.
Claims 2, 12-17, 21, and 23 are cancelled.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/23/2025 has been entered.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1, 3-6, 18-20, 22, 24-27, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over CALLAN (P.N. WO 2017/089800 A1) in view of PULSIPHER (ENGINEERING THERANOSTIC MICROBUBBLES USING MICROFLUIDICS FOR ULTRASOUND IMAGING AND THERAPY: A REVIEW. Ultrasound in Med. & Biol. 2018.).
Regarding claim 1, CALLAN teaches a method of preparing gas filled microbubbles (abstract and (page 10, paragraph 2). That are covalently attached (page 9, paragraph 4) to Rose Bengal (claim 8 ), which is a sonosensitising agent. The microbubbles comprises a shell that further includes a chemotherapeutic agent (page 6, paragraph 2).The method comprising the following steps:
- providing a lipid that may be subsequently incorporated into the shell of the microbubble (page 23, paragraph 4), which reads on phospholipid capable of forming a microbubble, but which has not already been incorporated into the shell structure of a microbubble;
- a sonosensitising agent, such as Rose Bengal (claim 8), and a chemotherapeutic agent, such as paclitaxel (Page 7, paragraph 3) may be covalently linked to the lipid (pg. 23, paragraph 4 and pg. 22, paragraph 4), which reads on covalently linking at least one sonosensitising agent to said phospholipid whereby to produce a functionalized phospholipid.
- Doxorubicin, a hydrophobic chemotherapeutic agent that is listed as an alternative to Rose Bengal, was dissolved in DMSO, an organic solvent, the solution was then added to another solution containing a functionalized lipid (page 64. Paragraph 2), multiple lipids can be added to solution when preparing the microbubbles (page 35, paragraph 4), which reads on combining an organic solvent having dissolved therein a hydrophobic chemotherapeutic agent with a solution containing a plurality of said functionalized phospholipids and other non-functionalized phospholipids to provide a lipid- containing suspension; and
- the technique to form the microbubbles involves an aqueous suspension of the microbubble shell components is sonicated in the presence of the relevant microbubble component gas, e.g. oxygen (page 22, paragraph 1), which reads on agitating the lipid-containing suspension in the presence of a gas.
The sonosensitising agent is Rose Bengal (claim 8) and the hydrophobic chemotherapeutic agent is paclitaxel (Page 7, paragraph 3).
Regarding claims 3, 4, 5, 26 and 27, CALLAN teaches that both DBPC and DSPE can be used in this microbubble complex (Page 35, paragraph 4, lines 1-2), which reads on formula (I). Phosphatidylcholine can also be used (page 11, paragraph 2), which reads on formula I and II.
Regarding claim 6 and 29, CALLAN example 1 (Page 35 and 36) teaches using a functionalized lipid that is linked to PEG derivatives, which reads on biocompatible polymer.
Regarding claim 18, CALLAN the microbubble is filled with gas, such as oxygen (page 10, paragraph 2).
Regarding claim 19, CALLAN teaches that microbubbles preferably have a diameter in the range of 0.5-100 μm (Page 10, paragraph 4, line 7).
Regarding claim 20, the method produces a gas filled microbubble (abstract and (page 10, paragraph 2), wherein a sonosensitising agent, such as Rose Bengal (claim 8) may be covalently linked to the lipid (pg. 23, paragraph 4 and pg. 22, paragraph 4). A chemotherapeutic agent, such as paclitaxel (Page 7, paragraph 3) is further added.
Regarding claim 22, the method can be used to create a pharmaceutical composition that utilizes a pharmaceutically acceptable carrier or excipient (page 20, paragraph 1).
Regarding claim 24, CALLAN teaches administrating a subject with the microbubble complex and then exposing the complex to an ultrasound to rupture the microbubbles which releases the therapeutic agents (Page 27, paragraph 1), which reads on activating the sonosensitising agent.
Regarding claim 25 and 30, CALLAN teaches that this complex can be used for pancreatic cancer (Page 52, paragraph 1, line 9).
CALLAN does not teach linking the sonosensitising agent to the phospholipid prior to microbubble formation.
PULSIPHER teaches that the shell components can be chemically modified pre- or post-bubble fabrication (page 2452, paragraph 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate linking the sonosensitising agent to the phospholipid prior to microbubble formation. The person of ordinary skill in the art would have been motivated to make those modifications, because once fabricated, no further steps are needed to prepare functionalized bubbles for use in the desired application, and reasonably would have expected success because the references are in the same field of endeavor, such as the formation of microbubbles that are functionalized.
Furthermore, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Note, since the prior art teaches the same components put to together in the same steps, it would inherently have the same property of “whereby to form said gas-filled microbubble and such that the hydrophobic chemotherapeutic agent spontaneously embeds within a hydrophobic tail region of the phospholipids that form the shell structure of the gas- filled microbubble”. Furthermore, it is commonly known in chemistry that “like attracts like”, which means substances with similar polarities or intermolecular forces attract and mix well, which explains the inherent chemical property that the hydrophobic portions would embed within each other.
Claims 1, 3-8, 18-20, 22, 24-27, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over CALLAN (P.N. WO 2017/089800 A1), PULSIPHER (ENGINEERING THERANOSTIC MICROBUBBLES USING MICROFLUIDICS FOR ULTRASOUND IMAGING AND THERAPY: A REVIEW. Ultrasound in Med. & Biol. 2018.) in view of SHUTO (A Facile One-Step Synthesis of Phosphatidylhomoserines by Phospholipase D-Catalyzed Transphosphatidylation. Chem Pharm Bull. 35. 1987).
CALLAN and PULSIPHER teach Applicant invention as discussed above. As discussed above, regarding claim 8-in-part phosphatidylcholine can be used which reads on formula II.
CALLAN and PULSIPHER do not teach using an enzyme, to achieve a phosphatidylation of hydroxyl groups.
Regarding claim 7, SHUTO teaches using phospholipase D, an enzyme, to achieve a phosphatidylation of hydroxyl groups (abstract). Additional disclosures include: specific synthesis results in high yield (see abstract).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using an enzyme, to achieve a phosphatidylation of hydroxyl groups (abstract). The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because click chemistry and enzyme-catalyzed linking are functional equivalent of covalent linking.
Claims 1, 4-11, 18-20, 22, 24-27, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over CALLAN (P.N. WO 2017/089800 A1), PULSIPHER (ENGINEERING THERANOSTIC MICROBUBBLES USING MICROFLUIDICS FOR ULTRASOUND IMAGING AND THERAPY: A REVIEW. Ultrasound in Med. & Biol. 2018.) and SHUTO (A Facile One-Step Synthesis of Phosphatidylhomoserines by Phospholipase D-Catalyzed Transphosphatidylation. Chem Pharm Bull. 35. 1987) in further view of CHEN (Novel chitosan derivative for temperature and ultrasound dual-sensitive liposomal microbubble gel. Carbohydrate Polymers. 94. 2013.).
CALLAN, PULSIPHER and SHUTO teach Applicant invention as discussed above. CALLAN teaches that DSPE can be used in this microbubble complex (Page 35, paragraph 4, lines 1-2), which reads on the phospholipid part of formula (III).
CALLAN, PULSIPHER and SHUTO do not teach using succinic anhydride to modify the lipid.
Regarding claim 9-11, CHEN teaches using succinic anhydride to modify cholesterol for a microbubble gel (Materials and methods 2.1, paragraph 1). The reaction between the DSPE in CALLAN and succinic anhydride in CHEN would inherently create formula (III).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using succinic anhydride to modify the phospholipid. The person of ordinary skill in the art would have been motivated to make those modifications, because to achieve a lipid that has the specific properties needed for the therapeutic use, and reasonably would have expected success because CALLAN already teaches modifying the lipid using various methods including acids (CALLAN, page 30, paragraph 3, lines 8-15), so one skilled in the art would be able to determine the exact modification needed and substitute the modifier as needed.
Claims 1, 4-11, 18-20, 22, 24-27, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over CALLAN (P.N. WO 2017/089800 A1), PULSIPHER (ENGINEERING THERANOSTIC MICROBUBBLES USING MICROFLUIDICS FOR ULTRASOUND IMAGING AND THERAPY: A REVIEW. Ultrasound in Med. & Biol. 2018.), SHUTO (A Facile One-Step Synthesis of Phosphatidylhomoserines by Phospholipase D-Catalyzed Transphosphatidylation. Chem Pharm Bull. 35. 1987) and CHEN (Novel chitosan derivative for temperature and ultrasound dual-sensitive liposomal microbubble gel. Carbohydrate Polymers. 94. 2013.) in further view of UNGER (US 9,801,959 B2).
CALLAN, PULSIPHER, SHUTO and CHEN teach Applicant’s invention as discussed above. CALLAN teaches that DSPE, phosphatidylglycerols and phosphatidylserines can be used (page 11, paragraph 2).
CALLAN, PULSIPHER, SHUTO and CHEN does not teach using diphosphatidylglycerol.
UNGER teaches a method of making a microbubble (abstract). Various lipids can be used to form the microbubble including diphosphatidylglycerol (DPG) (column 9, paragraph 5), phosphatidylserine (column 9, paragraph 5) and DSPE can be used (column 11, paragraph 6). DPG is a specific phosphatidylglycerol.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate diphosphatidylglycerol. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because DPG, phosphatidylserine and DSPE are functional equivalents of phospholipids commonly used in the pharmaceutical industry to create microbubbles. Furthermore, CALLAN teaches that phosphatidylglycerols can be used in the method.
Response to Arguments
Applicant argues, Example discloses the separate preparation of oxygen-loaded microbubbles linked to Rose Bengal (RBO2MB) and oxygen-loaded microbubbles linked to doxorubicin (DoxO2MB). In both cases, the microbubbles are pre-formed and are linked to the respective agents via an avidin-biotin interaction, i.e. a non-covalent linkage.
Examiner does not find the argument persuasive because as discussed above it would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate linking the sonosensitising agent to the phospholipid prior to microbubble formation. The person of ordinary skill in the art would have been motivated to make those modifications, because once fabricated, no further steps are needed to prepare functionalized bubbles for use in the desired application, and reasonably would have expected success because the references are in the same field of endeavor, such as the formation of microbubbles that are functionalized.
Furthermore, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Applicant argues, claim 1 requires that the hydrophobic chemotherapeutic agent dissolved in the organic solvent in claim 1 is paclitaxel, not doxorubicin, and that it is this hydrophobic chemotherapeutic agent (i.e. paclitaxel) which is incorporated into the shell of the microbubble as a direct consequence of performing the process steps recited in claim 1. The passage at page 64, paragraph 2 of Callan makes no reference to paclitaxel.
Examiner does not find the argument persuasive because CALLAN teaches either paclitaxel and doxorubicin can be used in the composition (page 8, paragraph 2). Furthermore, obviousness does not require complete predictability and less preferred embodiments do not constitute a teaching away.
Applicant argues, the disclosure at page 64, paragraph 2 of Callan relating to the preparation of a 0.5% DMSO solution in PBS containing "Biotin-Dox" is thus of no relevance to the subject-matter of claim 1. Contrary to the Examiner's suggestion, this solution containing "Biotin-Dox" is not "added to another solution containing a functionalised lipid". Rather, it is added to a suspension of avidin-functionalised perfluorobutane microbubbles ("PFBMBs"), i.e. to a suspension containing pre-formed microbubbles. Such pre-formed microbubbles are not equivalent to the functionalised phospholipid" recited in Applicant's claim 1, i.e. a phospholipid which is covalently linked to Rose Bengal and which is capable of forming a microbubble
Examiner does not find the argument persuasive because as discussed above it would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate linking the sonosensitising agent to the phospholipid prior to microbubble formation. The person of ordinary skill in the art would have been motivated to make those modifications, because once fabricated, no further steps are needed to prepare functionalized bubbles for use in the desired application, and reasonably would have expected success because the references are in the same field of endeavor, such as the formation of microbubbles that are functionalized.
Furthermore, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Applicant argues, the non-covalent biotin-avidin linkage resulting from reaction of "BiotinDox" and avidin-functionalized perfluorobutane microbubbles in this procedure of Callan does not result in a microbubble having a shell in which the doxorubicin is embedded and held by hydrophobic interactions. This is not the same as incorporation of a hydrophobic chemotherapeutic agent within the shell of the microbubble which involves hydrophobic interactions between the hydrophobic tail region of the lipid and the chemotherapeutic agent.
Examiner does not find the argument persuasive because CALLAN teaches the sonosensitiser (or sonosensitisers) may be linked to the microbubble through covalent or non-covalent means (page 9, paragraph 4). Furthermore, since the prior art teaches the same components put to together in the same steps, it would inherently have the same property of “whereby to form said gas-filled microbubble and such that the hydrophobic chemotherapeutic agent spontaneously embeds within a hydrophobic tail region of the phospholipids that form the shell structure of the gas- filled microbubble”. Furthermore, it is commonly known in chemistry that “like attracts like”, which means substances with similar polarities or intermolecular forces attract and mix well, which explains the inherent chemical property that the hydrophobic portions would embed within each other.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. MEJIAS whose telephone number is (703)756-5666. The examiner can normally be reached M-F.
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/S.L.M./ Examiner, Art Unit 1618
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618