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 1-2, 4-9, 11-12 and 16-17 are pending.
Claims 3, 10, 13-15 are cancelled.
Claims 16-17 are withdrawn.
Claim 1 has been amended.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
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, 4-7 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over UNGER (US 2016/0000943 A1) in view of SEGERS (US 2019/0175516 A1) and SEGERS 1 (Improved coalescence stability of monodisperse phospholipid-coated microbubbles formed by flow-focusing at elevated temperatures. Lab on a Chip. 2019.).
Regarding claim 1, UNGER teaches a process for preparing a hydrated phospholipids solvent mixture (abstract). The method comprising a solution of DPPC and DPPE-MPEG-5000 in propylene glycol, which was then heated to dissolve the phospholipids (page 8, paragraph 0070), which reads on dissolving a first phospholipid at a temperature above the phase transition temperature of the phospholipids in an organic solvent to form a dissolved phospholipid solvent mixture; and dissolving a second phospholipid at a temperature above the phase transition temperature of the phospholipids in the dissolved phospholipid solvent mixture to form a dissolved phospholipids solvent mixture. A phosphate buffer was then added to the solution and mixed (page 8, paragraph 0070), which reads on adding an aqueous phosphate buffer to the dissolved phospholipids solvent mixture to form a buffered phospholipids solvent mixture. The mixture was then stirred (page 8, paragraph 0070), which reads on stirring the buffered phospholipids solvent mixture to form a hydrated phospholipids solvent mixture.
The solution does not comprise dipalmitoyl phosphatidic acid, DPPA (page 4, paragraph 0034).
Regarding claim 4, UNGER teaches the phospholipids are DPPC and DPPE-MPEG-5000 (page 8, paragraph 0070).
Regarding claim 5, UNGER teaches propylene glycol is the solvent (page 8, paragraph 0070).
Regarding claim 6, phosphate buffered saline is used (page 9, paragraph 0077).
UNGER teaches the lipid concentration was modified to adjust the concentration and size of microbubbles (page 8, paragraph 0070). The ratio of lipids is altered to adjust the stability of the formulation (page 8, paragraph 0072) and the concentration and size of microbubbles produced (page 10, paragraph 1 and page 4, paragraph 0038).
UNGER does not teach a phospholipid concentration of 10-18 mg/mL.
SEGERS teaches a phospholipid mixture that comprises a phospholipid concentration of 10-15 mg/mL which had coalescence of less than 1% even with increasing phospholipid concentration (page 9, paragraph 0122 and paragraph 0124).
SEGERS 1 teaches that having a high total lipid concentrations are required to minimize on-chip bubble coalescence (abstract).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a concentration of 10-15 mg/mL of phospholipid. The person of ordinary skill in the art would have been motivated to make those modifications, because it provides low coalescence and UNGER teaches that the concentration can be changed to adjust the size, stability and concentration of microbubbles produced, and reasonably would have expected success because the references are in the same field of endeavor, such as phospholipid mixtures.
Regarding claims 1 and 11, The reference does not specifically teach the lipid ratios as claimed by the Applicant. The lipid ratio 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 lipid ratio in order to best achieve desired results, such as the optimal size, stability and concentration of microbubbles produced. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the lipid concentration would have been obvious at the time of Applicant's invention.
Regarding claim 7, The reference does not specifically teach the amount of time the composition is stirred as claimed by the Applicant. The amount of time the composition is stirred 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 composition is stirred in order to best achieve desired results, such as stirring until the phospholipids are fully dissolved and the composition is fully mixed (page 8, paragraph 0070). Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the amount of time the composition is stirred would have been obvious at the time of Applicant’s invention.
Regarding claim 12, Selection of any order of process steps is prima facia obvious in the absence of new or unexpected results.” See MPEP § 2144.04, IV. It would be obvious to one of ordinary skill in the art to vary the order of steps because, in such a method, where the order of steps is not critical, one of ordinary skill in the art would have recognized that varying the order of steps would result in an equivalent means of carrying out the method. In the instant case, adding the phospholipids sequentially or all at once would result in an equivalent means of carrying out the method.
Claims 1, 2, 4-8 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over UNGER (US 2016/0000943 A1), SEGERS (US 2019/0175516 A1) and SEGERS 1 (Improved coalescence stability of monodisperse phospholipid-coated microbubbles formed by flow-focusing at elevated temperatures. Lab on a Chip. 2019.) in view of ROBINSON (US 10,583,208 B2).
UNGER SEGERS and SEGERS 1 teach Applicant’s invention as discussed above.
UNGER SEGERS and SEGERS 1 do not teach filtering the mixture, specifically with a 2 micrometer filter.
Regarding claims 2 and 9, ROBINSON teaches a method of dissolving phospholipids, specifically DPPC and MPEG5000-DPPE, heating the solution to allow for complete dissolution. Then filtering to remove any undissolved foreign matter (column 22, paragraph 4) using a 0.2 micrometer filter (column 38, 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 filtering the mixture. The person of ordinary skill in the art would have been motivated to make those modifications, because it removes any undissolved foreign matter, and reasonably would have expected success because the references are in the same field of endeavor, such as method of dissolving DPPC and MPEG5000-DPPE and heating the solution to allow for complete dissolution.
Claims 1, 2, and 4-11 are rejected under 35 U.S.C. 103 as being unpatentable over UNGER (US 2016/0000943 A1), SEGERS (US 2019/0175516 A1), SEGERS 1 (Improved coalescence stability of monodisperse phospholipid-coated microbubbles formed by flow-focusing at elevated temperatures. Lab on a Chip. 2019.) and ROBINSON (US 10,583,208 B2) in view of STURM (Basic Methods for Preparation of Liposomes and Studying Their Interactions with Different Compounds, with the Emphasis on Polyphenols. International Journal of Molecular Sciences. 2021.).
UNGER, SEGERS, SEGERS 1 and ROBINSON teach Applicant’s invention as discussed above. Note, the heating of UNGER is to have the solution above the phase transition temperature for the dissolving oh the phospholipids.
UNGER, SEGERS, SEGERS 1 and ROBINSON do not teach having all steps above the phase transition temperature.
Regarding claim 9, STURM teaches that it is important the water/buffer solution, are preheated above the lipids transitional temperature (Tm), when necessary, in order to enable a smoother creation (page 3, paragraph 1). This is especially important in the case of lipids with high Tm (e.g., DPPC) (page 3, paragraph 3).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate having all steps above the phase transition temperature. The person of ordinary skill in the art would have been motivated to make those modifications, because it allows for a smoother combination of reactants, and reasonably would have expected success because the references are in the same field of endeavor, such as adding a buffer solution to dissolved lipids. Furthermore, it is known in the art that heat can accelerate the reaction rate of solutions and that keeping the solution at the phase transition temperature will ensure the phospholipids are fully dissolved and stay dissolved.
Response to Arguments
Applicant argues, Unger however does not disclose a process for preparing a hydrated phospholipids solvent mixture, wherein the concentration of the phospholipids in the hydrated phospholipids solvent mixture is in the range of from 10 up to 18 mg/ml, as found in amended claim 1.
The examiner does not find the argument persuasive because as discussed above SEGERS teaches a concentration from 10-15 mg/mL and it would be obvious to combine.
Applicant argues, coalescence of micro bubbles resulting in polydisperse micro bubbles is no longer observed when the process of the invention is applied. As further stated in paragraph [0041] of the current application as published, "To maintain a monodisperse microbubble population, coalescence should be avoided." In microfluidics, the microbubbles are produced using ''flow focusing" a gas flow to flow through a narrow constriction. The inner gas is forced by the outer coflowing liquid flow to flow through a narrow constriction. In this constriction the gas flow forms a thin gaseous thread that breaks up into uniform micro bubbles. The size of these microbubbles is governed by the gas-to-liquid flow rate ratio. The microbubbles are produced at typical production speeds of between 100,000 and 1,000,000 microbubbles per second. Once the microbubbles are produced they decelerate and collide. This is related to the microfluidic method of producing the micro bubbles. These collisions are violent and can cause coalescence (merging of two bubbles). However, it was found that this can be avoided by increasing the phospholipid concentration to the claimed range of from 10 to 18 mg/ml. The Applicant wishes to point out that this concentration range is ten-fold higher than "standard" lipid concentrations. See also paragraph [0047] of the current application as published.
The examiner does not find the argument persuasive because in order to overcome a prima facie case of obviousness, it is incumbent upon the Applicant to provide comparative test evidence that demonstrates unexpected superiority of the claimed compositions versus the closest prior art compositions, and not simply an advantage predictable from the prior art. See In re Chapman, 148 USPQ 711, 715 (CCPA, 1966). Moreover, such proffered comparisons must be commensurate in scope with the breadth of the claims. See In re Clemens, 206 USPQ 289, 296 (CCPA, 1980) and In re Coleman, 205 USPQ 1172, 1175 (CCPA 1980). In the instant case, as discussed above SEGERS teaches the concentration recited in instant claim 1. Furthermore, SEGERS teaches a phospholipid mixture that comprises a phospholipid concentration of 10-15 mg/mL which had coalescence of less than 1% even with increasing phospholipid concentration (page 9, paragraph 0122 and paragraph 0124) and SEGERS 1 teaches that having a high total lipid concentrations are required to minimize on-chip bubble coalescence (abstract). Therefor the low coalescence is an advantage predictable from the prior art.
For a complete discussion of unexpected results, Applicants are referred to MPEP 716.02 et seq.
Applicant argues, the Applicant respectfully asserts that there is no teaching or suggestion by Unger that a higher phospholipids concentration can improve the fast production of uniform micro bubbles with longer stabilization times. Unger also remains completely silent with respect to fast production of uniform micro bubbles. As such, the Applicant respectfully submits that given that the claimed concentration of phospholipids is at least 6.7-12 times more than what is taught by the prior art, one skilled in the art would have to engage in an undue amount of experimentation to have any chance of arriving at what is currently claimed in amended claim 1. Unger additionally fails to provide any motivation for going beyond the disclosed 1.50 mg/ml concentration. In other words, given that the claimed concentration range and the "standard" concentration taught by Unger are so far apart, the claimed lipid concentration is far outside a normal or reasonable range for routine optimization of parameters while still expecting a successful outcome when there is no indication of such given by the prior art. Unger simply does not provide evidence that a skilled artisan would have expected that low-concentration, stability oriented formulation taught by Under to scale into the claimed 10-18 mg/mL DPPA-free process while preserving filterability and monodisperse microbubble manufacture. In summary, one skilled in the art would not be capable of using the teachings of Unger to arrive at what is currently claimed in amended claim 1.
The examiner does not find the argument persuasive because in order to overcome a prima facie case of obviousness, it is incumbent upon the Applicant to provide comparative test evidence that demonstrates unexpected superiority of the claimed compositions versus the closest prior art compositions, and not simply an advantage predictable from the prior art. See In re Chapman, 148 USPQ 711, 715 (CCPA, 1966). Moreover, such proffered comparisons must be commensurate in scope with the breadth of the claims. See In re Clemens, 206 USPQ 289, 296 (CCPA, 1980) and In re Coleman, 205 USPQ 1172, 1175 (CCPA 1980). In the instant case, as discussed above SEGERS teaches the concentration recited in instant claim 1. Furthermore, SEGERS teaches a phospholipid mixture that comprises a phospholipid concentration of 10-15 mg/mL which had coalescence of less than 1% even with increasing phospholipid concentration (page 9, paragraph 0122 and paragraph 0124) and SEGERS 1 teaches that having a high total lipid concentrations are required to minimize on-chip bubble coalescence (abstract). Therefor the low coalescence is an advantage predictable from the prior art. Furthermore, UNGER teaches the ratio of lipids is altered to adjust the stability of the formulation (page 8, paragraph 0072) and the concentration and size of microbubbles produced (page 10, paragraph 1 and page 4, paragraph 0038). If a higher concentration is produced per synthesis, this would lead to a higher rate of production.
For a complete discussion of unexpected results, Applicants are referred to MPEP 716.02 et seq.
Conclusion
No claims are allowable.
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.
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
