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 is amended.
Claims 18-28 are added.
Claims 1, 8-14, and 18-28 are pending.
Claims 1 and 14 are withdrawn.
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 8-13, and 19-28 are rejected under 35 U.S.C. 103 as being unpatentable over LEE ( WO 2011/017524) in view of OJHA (Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles. Pharmaceutics. 2019.).
Regarding claim 8, LEE teaches a method of forming dried microbubbles, wherein the microbubbles comprise a shell and a gas core (claim 1), with a diameter of 28.0 µm (page 15, paragraph 3), polydispersity index of 1.2% (page 15, paragraph 3), the microbubbles are made to be administered to a subject (claim 17) and are therefore physiologically inert (Applicant’s specification, page 8, paragraph 3), the microbubbles are collected on a petri dish containing water into a monolayer (page 21, paragraph 4), which reads on adsorbed on a hydrophilic surface in the form of at least one monolayer. The microbubbles can also be formed on a glass slide, which is also a hydrophilic surface (page 17, paragraph 1). The microbubbles were then dried (page 21, paragraph 4). Since the microbubbles are using the same components in the same steps, it would be inherent that the microbubbles would embed in a film formed by the shell material. Furthermore, since it is a monolayer, a thin film would be formed.
Regarding claim 9, 11, 12 and 23-27, LEE teaches the microbubbles are collected on a petri dish containing water into a monolayer (page 21, paragraph 4), which reads on adsorbed on a hydrophilic surface in the form of at least one monolayer. The microbubbles are formed by introducing gas through a liquid phase (page 2, paragraph 3). LEE teaches polyvinyl alcohol can be added to the composition (page 9, paragraph 1), which Applicant’s specification defines as a surfactant and a cryoprotectant (Applicant’s specification, page 10, paragraph 5). Polyvinyl alcohol has hydroxyl groups. The gas can be compressed air (page 7, paragraph 2).
Regarding claim 10, LEE teaches the generated bubbles flowed into a collection tube and was then collected onto the petri dish (page 17, paragraph 1), which reads on contacting said hydrophilic surface with the tip of a tube through which said microbubbles exit.
Regarding claim 13, LEE teaches the microbubbles are collected on a petri dish containing water into a monolayer (page 21, paragraph 4), which reads on adsorbed on a hydrophilic surface in the form of at least one monolayer. The microbubbles were then dried (page 21, paragraph 4), which reads on the method produced dried monodisperse microbubbles adsorbed on a hydrophilic surface in the form of at least one monolayer.
Regarding claim 19, LEE teaches a method of forming dried microbubbles, wherein the microbubbles comprise a shell and a gas core (claim 1), with a diameter of 28.0 µm (page 15, paragraph 3).
Regarding claim 20, LEE teaches the bubbles have a polydispersity index of 1.2% (page 15, paragraph 3).
Regarding claim 22, LEE teaches using a flow-focusing microfluidic device (page 16, paragraph 3).
Regarding claim 28, LEE teaches the inner gas can be a hydrophobic gas (page 7, paragraph 2).
Additional disclosures: LEE teaches the microbubbles are used for ultrasound imaging (claim 20). The shell thickness can be precisely controlled during the process (page 18, paragraph 1) and the shell thickness can be adjusted to increase the stability of the microbubble for a desired radius (page 18, paragraph 3). Scanning electron microscopy was used to image the microbubbles to determine the presence of shells (page 15, paragraph 3).
LEE does not teach freeze-drying the microbubbles.
Regarding claim 1, OJHA teaches that lyophilization (freeze-drying) is widely used to increase shelf-life and promote product development for microbubbles that are used for ultrasound imaging (abstract). OHJA further teaches that the lyophilization can be performed with affecting the microbubbles size (abstract).
Regarding claim 21, OHJA teaches freeze-drying should be carried out at temperatures
below the collapse temperature of the product and freeze drying was performed below -31 °C as this was the collapse temperature of the product being freeze dried (page 7, paragraph 4).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate freeze drying the microbubbles. The person of ordinary skill in the art would have been motivated to make those modifications, because freeze-drying is widely used to increase shelf-life, and reasonably would have expected success because it is an alternative way of drying microbubbles vs evaporating as taught in LEE and the references are in the same field of endeavor such as microbubbles used for ultrasound imaging.
The reference does not specifically teach the shell thickness as claimed by the Applicant. The shell thickness is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal shell thickness in order to best achieve desired results, such as finding the optimal shell thickness to have stability for a desired radius of microbubble. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the shell thickness would have been obvious at the time of Applicant’s invention.
The reference does not specifically teach the amount of time the collection of microbubbles onto the hydrophilic surface takes as claimed by the Applicant. The amount of time the collection of microbubbles onto the hydrophilic surface takes is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal amount of time the collection of microbubbles onto the hydrophilic surface takes in order to best achieve desired results, such as allowing enough for time for an optimal amount of microbubbles to collect onto the surface, while not doing it for too long that the surface collects too many microbubbles that could lead to it noy drying properly to form the monolayer. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the amount of time the collection of microbubbles onto the hydrophilic surface takes would have been obvious at the time of Applicant’s invention.
The reference does not specifically teach the amount of time the freeze drying takes as claimed by the Applicant. The amount of time for freeze drying is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal amount of time for freeze drying in order to best achieve desired results, such as freeze-drying the product for long enough to achieve the final freeze-dried product. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the amount of time of freeze drying would have been obvious at the time of Applicant’s invention.
Claims 8-13, and 18-28 are rejected under 35 U.S.C. 103 as being unpatentable over LEE ( WO 2011/017524) and OJHA (Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles. Pharmaceutics. 2019.) in view of OPS Diagnostics (Bacteria Freeze Drying Protocol. 2017 via Wayback Machine.).
LEE and OJHA teach Applicant’s invention as discussed above.
LEE and OJHA do not teach having the hydrophilic surface being BLAH.
Regarding claim 18, OPS Diagnostics teaches that borosilicate glass can be used for freeze drying and is in particular better due to it being more durable (page 2, paragraph 9).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate borosilicate glass. The person of ordinary skill in the art would have been motivated to make those modifications, because it can be used for freeze-drying and is preferred because it is durable, and reasonably would have expected success because the references are in the same field of endeavor, such as freeze drying protocols and LEE teaches using glass.
Response to Arguments
Applicant argues, with respect to the distribution of the microbubbles, the rejection cites at page 5 of the Office Action Lee's statement, "[t]he compound bubbles were collected in a Petri dish containing water, forming a monolayer." (Lee P21, lines 27-29). However, this statement should not be read in isolation as the rejection does, but should be read in conjunction with other disclosures of Lee. For example, Lee discloses, "[t]he bubbles may be collected substantially in a monolayer at the surface of an aqueous liquid (e.g., water)"(see page 8, lines 1-3) and "[t]he organic solvent was removed simply via evaporation, such as by heating the entire system. Because the bubbles floated to the water surface, the evaporation of the solvent occurred very rapidly" (seep 17, lines 11-15). Reading these disclosures, a person skilled in the art would understand that the bubbles are not adsorbed on a hydrophilic surface, but rather the bubbles are floating on the surface of the water. Thus, Lee does not disclose microbubbles adsorbed on the surface of a hydrophilic solid.
The Examiner does not find the argument persuasive because water is hydrophilic and would therefor read on a hydrophilic surface. Furthermore, as the Applicant states above, the solvent was dissolved, which would leave the microbubbles only adsorbed onto the glass surface, which would read on a single layer of microbubbles on a hydrophilic surface.
Applicant argues, Ojha does not teach or suggest freeze-drying microbubbles adsorbed on a hydrophilic surface in the form of at least one monolayer. Applicant submits that even if Lee is modified according to Ojha, the combination does not lead to the process for preparing freeze-dried microbubbles recited in claim 8, which comprises forming microbubbles adsorbed on the surface of a hydrophilic solid, and freeze-drying microbubbles adsorbed on a hydrophilic surface in the form of at least one monolayer. The microbubbles of Ojha can be calculated as having the polydispersity index of 23.5% (see 4. Calculation of the Polydispersity Index (PDI). Thus, even if the freeze-drying method of Ojha is combined with Lee, which the Applicant does not concede, the microbubbles having PDI below 10%, as recited in claim 8, cannot be obtained.
The Examiner does not find the argument persuasive because OJHA is not cited to teach microbubbles adsorbed on a hydrophilic surface in the form of at least one monolayer, but rather to show the benefits of lyophilization. Furthermore, as discussed above, OHJA teaches the size of the microbubbles does not change upon lyophilization. Polydispersity is defined as the variation in the size or mass of particles or molecules within a specific sample. Since LEE teaches the low polydispersity index as claimed and OHJA teaches that the size of the microbubbles does not change after lyophilization, the polydispersity index would not change either. The Applicant discussed the synthesis of the microbubbles in OHJA led to a high polydispersity index, however, OHJA is only used for the lyophilization, since the synthesis taught in LEE gives the low polydispersity index claimed and follows the specific steps as described in the instant claims. Furthermore, since LEE teaches the same components and the same steps of synthesis, and OHJA teaches freeze-drying, it is unclear why the microbubbles would have a higher degradation after freeze-drying than the Applicant’s invention.
In the declaration, Applicant argues, PBCA-MB synthesized by OHJA are based on anionic-emulsion polymerization using an Ultra-Turrax T-50 basic which is a dispersing device
known for producing high emulsion polydispersity as indicated in the publication Physicochemical Characterization of the Shell Composition of PBCA-Based Polymeric Microbubbles, Lia Appold et al. Macromol. Biosci. 2017, 17. (herein provided). It should be noted that OHJA does not describe the measurement of the polydispersity of microbubbles. However, the microbubbles were obtained by the same method as described in Appold et al. It can therefore be assumed that OHJA’s microbubbles have a high PDI index (at least 20-30%). This can be confirmed by performing measurements on an enlargement of figure I representing the microbubbles.
The Examiner does not find the argument persuasive because OHJA teaches the size of the microbubbles does not change upon lyophilization. Polydispersity is defined as the variation in the size or mass of particles or molecules within a specific sample. Since LEE teaches the low polydispersity index as claimed and OHJA teaches that the size of the microbubbles does not change after lyophilization, the polydispersity index would not change either. The Applicant discussed the synthesis of the microbubbles in OHJA led to a high polydispersity index, however, OHJA is only used for the lyophilization, since the synthesis taught in LEE gives the low polydispersity index claimed and follows the specific steps as described in the instant claims. Furthermore, since LEE teaches the same components and the same steps of synthesis, and OHJA teaches freeze-drying, it is unclear why the microbubbles would have a higher degradation after freeze-drying than the Applicant’s invention.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/S.L.M./Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618
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