Office Action 12: Final Rejection (2023-10-31)
Rejection types: 103 - Obviousness

CLAIMS:
Amendments to the claims:

Please amend the claims as follows.
1\. (Currently Amended) A method for droplet formation for sample preparation for sequencing, the method comprising:providing a first aqueous fluid from a first reservoir into a first inlet channel on a microfluidic substrate, the first aqueous fluid comprising biological material;
providing, via a second inlet channel, a second aqueous fluid comprising primers;
coalescing the first aqueous fluid with the second aqueous fluid to form an aqueous sample fluid;
providing an immiscible carrier fluid via at least one oil supply line;
applying a pressure to flow the immiscible carrier fluid into a nozzle disposed within the immiscible carrier fluid and into a main channel within the nozzle; and
adjusting pressure in one or more of the inlet channels, thereby to produce a plurality of droplets comprising the aqueous sample fluid in the main channel wherein the nozzle is immersed, by design, within the immiscible carrier fluid, thereby preventing the aqueous sample fluid from wetting surfaces of the nozzle or the main channel.

2-3. (Cancelled)

4\. (Previously Presented) The method of claim 1, wherein the nozzle has complete isolation from any continuous aqueous phase.

5-11. (Cancelled)610

12\. (Previously Presented) The method of claim 1, wherein the aqueous fluids further comprise reagents for conducting an amplification reaction.
Application No. 15/480,739 13. (Previously Presented) The method of claim 12, wherein the amplification reaction is a PCR reaction and the method comprises performing the PCR reaction in the one of the droplets to yield PCR products and breaking the droplets to release the PCR products from the droplets.

14-20. (Cancelled)1519

21\. (Previously Presented) The method of claim 1, wherein the at least one oil supply line provides a constant flow of the carrier fluid into the nozzle while the plurality of droplets are formed.

22-30. (Cancelled)2329

31\. (Previously Presented) The method of claim 1, wherein the immiscible carrier fluid comprises an oil.

32\. (Previously Presented) The method of claim 31, wherein the oil comprises a fluorocarbon oil.

33\. (Previously Presented) The method of claim 31, wherein the oil comprises a surfactant.

34\. (Previously Presented) The method of claim 33, wherein the surfactant is a fluorosurfactant.

35-38. (Cancelled)3637

39\. (Previously Presented) The method of claim 13, wherein the microfluidic substrate is a chip that includes heating and cooling lines.
Application No. 15/480,739 40. (Previously Presented) The method of claim 39, wherein the PCR reaction is performed by sending the one of the droplets through a serpentine path between the heating and cooling lines in the chip.

OFFICE ACTION:
DETAILED ACTION
The present Office Action is responsive to the Amendment received on September 1, 2023 and the supplemental amendment received on October 23, 2023 (herein, referred together as “Amendment” or “Response”).
Notice of Pre-AIA  or AIA  Status
The present application is being examined under the pre-AIA  first to invent provisions.
Preliminary Remark
Claims 2, 3, 5-11, 14-20, 22-30, and 35-38 are canceled.
Claim Rejections - 35 USC § 112
The rejection of claims 3 and 21 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, made in the Office Action mailed on June 1, 2023 is withdrawn in view of the Amendment.
Claim Rejections - 35 USC § 103
The rejection of claim 3 under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 584 586 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004) and Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49), made in the Office Action mailed on June 1, 2023 is withdrawn in view of the Amendment, canceling the rejected claim.
The following is a quotation of pre-AIA  35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection of claims 1, 4, 12, 13, 21, 31, 39, and 40 under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 584 586 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004) and Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49), made in the Office Action mailed on June 1, 2023 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received in the Amendment have been considered but they have not been found persuasive for the reasons set forth in the, “Response to Arguments” section.
The Rejection:
With regard to claim 1, Cho et al. teach a method of performing nucleic acid amplification reaction (“a method and apparatus for amplifying nucleic acids”, Abstract), the method comprising:
providing a first aqueous fluid from a first reservoir into a first inlet channel on a microfluidic substrate, the first aqueous fluid comprising a biological material (see Fig. 6, Target DNA reservoir 442);
providing via a second inlet channel, a second aqueous fluid comprising primer (see Fig. 6, see primer reservoir 444);
coalescing the first aqueous fluid with the second aqueous fluid to form an aqueous sample fluid (see Fig. 6, channel where the aqueous droplets merge therein prior to entry into main channel);
providing an immiscible carrier fluid via at least one oil supply line (see Fig. 6, see oil 152),
applying a pressure to flow the immiscible fluid into a main channel (“oil 131 … inserted into the reaction channel 130 via the respective inlet channels … 151 at a constant flow rate”, section [0053] evidences the presence of a source of pressure driven flow).
With regard to claims 12 and 13 the aqueous fluids further comprise reagents for conducting an amplification (see Fig. 6, element 446, “for example, polymerase, dNTPs, and buffer”, section [0076]).
With regard to claim 21, the oil flow is constant flow (see section [0053]).
With regard to claim 31, the immiscible fluid is oil (“oil introduction”, section [0076]).
With regard to claims 39 and 40, the microfluidic substrate is a chip that includes a heating and cooling lines (see Figure 7, T1, T2, and T3, wherein the PCR reaction is performed as the droplets travel past the different temperature zones of heating and cooling (also, “substrate 110 has two areas having different temperatures, for example, 65oC area and 95oC area … heating unit 120 may also be comprised of three or more heaters having different temperatures”, section [0050]).
Cho et al. do not disclose that the device comprises a nozzle disposed within the immiscible carrier fluid which leads into the main channel where emulsion droplets enter for nucleic acid amplification reaction, wherein the nozzle comprises a ferrule immersed in oil thereby inhibiting the aqueous droplets to wet the surfaces of the nozzle or the main channel (claims 1 and 3), wherein the nozzle has complete isolation from any continuous aqueous phase (claim 4).
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Kumacheva et al. teach a device for producing droplets within a channel, wherein in an embodiment, aqueous droplets are generated and enters a main channel that is prefilled with immiscible fluid, so as to prevent the aqueous droplets from contacting the main channel and its entry (see below Figure 21b, reproduced below):
“present invention discloses a versatile strategy of synthesis of polymeric particles using a ‘lab on chip’ with pre-designed size shape, morphology and composition” (page 9, lines 18-30)
“Figures 21a and 21b is a schematic illustration of the formulation of droplets by two different mechanism using the microfluidic reactor 120 … Immiscible liquids L1 and L2 (e.g., oil and aqueous phases) are forced into the narrow orifice …” (page 20, lines 23-26)
Bhagat et al. teach a prior art known means of coupling a channel to another channel via a ferrule (see Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cho et al. with the teachings of Kumacheva et al. and Benett et al., thereby arriving at the invention as claimed.
As discussed above, Cho et al. already teach a microfluidic device comprising separate reservoirs that provide template nucleic acids and reagents for amplification reaction, which are connected to a main channel flowing with oil.  The resulting configuration produces individual droplets of amplification reaction reagents that are surrounded by flowing oil which are flowed past different sections of the microfluidic chip zones having different temperatures.
While Cho et al. did not explicitly teach that the single channel which coalesces the template nucleic acid and amplification reagents leads into the main channel is completely surrounded by oil, such a configuration has been taught by Kumacheva et al. as shown above that result in the same result of providing an emulsified droplet of precisely controlled size (see page 9, lines 29-35).
As to connecting the main channel to the portion where the aqueous droplets are dispersed (see below left region where droplets are formed and the right region (b) the main channel where emulsion droplets flow through in the figure from
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Kumacheva et al.), use of any such prior known coupling means, such as ferrule would have been an obvious implementation, who use does not provide any perceivable functional advantage over that of Kumacheva et al..
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id.  at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the invention as claimed is prima facie obvious over the cited references.
Response to Arguments:
Applicants traverse the rejection.
Applicants contend that claim 1 as amended recites that the nozzle is immersed by design, within the immiscible carrier fluid thereby preventing the aqueous fluid from wetting the surface of the nozzle or the main channel (page 6, Response).
Applicants contend that Cho (of record), while disclosing generation of aqueous droplets (PCR droplets) within immiscible carrier fluid (oil), the artisan does not teach or suggest the concept of a nozzle or the concept of phase wetting of surface (page 6, Response)
With regard to Kumacheva’s teachings, Applicants are completely silent on whether the artisans teach the concept of using a nozzle.  Rather, Applicants stress that the carrier fluid employed by Kumacheva is aqueous solution, and the droplets formed therein are oil droplets.  By Applicants’ silence, the Office assumes that Applicants are admitting that Kumacheva does teach a droplet generation device which comprises a nozzle, and Applicants’ contention is that because the carrier fluid employed by Kumacheva is aqueous, nozzle is “wetted” by the aqueous phase.
This argument has been carefully considered but have not been found persuasive because the rejection is based on a combination of references.
As admitted by Applicants, Cho teaches the generation of aqueous droplets surrounded by an immiscible carrier fluid (i.e., oil) for the purposes of performing a PCR reaction, well-known in the art as emulsion PCR.  The fundamental basis of this technology rests on the immiscible nature of the two fluids, which are oil and water (or aqueous).  The two are immiscible and therefore, one forms a droplet inside the body of another.
Whether the oil forms a droplet inside the body of an aqueous fluid, or the aqueous fluid forms a droplet inside the body of oil, is to be expected, such properties would have been recognized by one of ordinary skill in the art.
While Applicants attempt to make much of Kumacheva generating droplets of oil in the body of an aqueous carrier fluid, one of ordinary skill in the art would have recognized that the droplet formations would occur in the reverse orientation (i.e., aqueous in the body of oil carrier) because the two, as discussed above, are recognized as being immiscible.
Because the rejection is based on Cho in view of Kumacheva (not the reverse), one of ordinary skill in the art who is considering the teachings of Cho, which involves the generation of aqueous droplets containing PCR reagents in the immiscible, oil carrier fluid, when viewing the teachings of Kumacheva who teach the use of a nozzle configuration in which oil droplets are generated, would have recognized that the same nozzle configuration would have generated the aqueous droplets in oil carrier.
Applicants are reminded that when considering obviousness, the references being combined need not be wholly combined in their entirety.
“Additionally, Patent Owner’s argument that the Petition fails to explain why a POSITA “would combine particular components from the prior art in a specific way” seeks to impose a bodily incorporation requirement that is not required for obviousness. Prelim. Resp. 24. “The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference,” but rather whether “a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention.” Allied Erecting & Dismantling Co. v. Genesis Attachments, LLC, 825 F.3d
1373, 1381 (Fed. Cir. 2016) (internal citations omitted).
Also, in KSR International Co v. Teleflex Inc, the Supreme Court stated that, “A person of ordinary skill in the art is also a person of ordinary creativity, not an automation” (82 USPQ2d at 1397) and that “in many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle” and take into account, “the inference and creative steps that a person of ordinary skill in the art would employ” (82 USPQ2d at 1396).
Lastly, the Office notes that the droplet generation means taught by Kumacheva satisfies the “nozzle” construct:
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As seen, L1 channels are carrying a carrier fluid, while L2 is an immiscible fluid (to L1) which become droplets in the L1 fluid body.  The opening entrance through which L2 fluid travel through to become droplets is considered a nozzle, and this nozzle structure is surrounded at all times by L1 carrier fluid and provides an opening into the main channel (the channel located right side of the nozzle where droplets are generated), and where formed droplets are completely surrounded the carrier fluid.
Kiss et al. (Analytical Chemistry, 2008, vol. 80, pages 8975-8981) evidence that the Office’s interpretation of the term, “nozzle” is consistent with the art, wherein the artisans, refer to a structure found in Fig 1B (see below), wherein the opening through which aqueous fluid pass through into a main channel (forming droplets) is referred to as a nozzle.
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“(B) Optical image of droplet generation at the nozzle” (see Figure 1 description)
Therefore, Applicants’ arguments are not found persuasive and the rejection is maintained.
The rejection of claims 32-34 under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 584 586 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004) and Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49) as applied to claims 1, 4, 12, 13, 21, 31, 39, and 40 above, and further in view of Dorfman et al. (Analytical Chemistry, 2005, vol. 77, pages 3700-3704), made in the Office Action mailed on June 1, 2023 is maintained for the reasons of record.
Applicants do not present any new arguments in the Amendment, but rely solely on their arguments presented for the rejection over Cho et al., Kumacheva et al. and Bhagat et al. which have been fully responded to above.
Because no additional arguments are presented for the instant rejection, the rejection is maintained for the reasons already of record.
The Rejection:
The teachings of Cho et al., Kumacheva et al. and Bhagat et al. have been discussed above.
Cho et al., Kumacheva et al. and Bhagat et al. do not teach that the immiscible fluid oil should be fluorinated (claim 32) or comprise a fluorosurfactant (claims 33 and 34).
Dorfman et al., much like Cho et al., disclose a method of performing a continuous PCR reaction in aqueous droplets surrounded by immiscible oil (“[p]erforming continuous flow PCR for high-throughput clinical and quantitative applications require encapsulating the sample and preventing contamination between them … this can be accomplished in two ways: either the sample can be a droplet entrained in an immiscible solvent …”, page 3700, 2nd column).
Dorfman et al. disclose the use of fluorinated oil as the immiscible medium when performing the continuous emulsion PCR (“an improvement system for performing continuous flow PCR using droplets in an immiscible fluorinated solvent …”, page 3701, 1st column, 2nd paragraph; “primed with either the bulk fluorinated oil FC-40”, page 3701, 1st column, 3rd paragraph) or oil comprising a fluorosurfactant (“or FC-40 containing various amounts of fluoro alcohol surfactant”, page 3701, 1st column, 3rd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cho et al., Kumacheva et al. and Bhagat et al. with the teachings of Dorfman et al., thereby arriving at the invention as claimed for the following reasons.
Dorfman et al. discuss potential problems associated with performing emulsion droplet PCR in an immiscible medium:
“wall treatment [of the channel] are necessary to prevent adsorption of DNA to the walls and subsequent transfer between samples … wall contamination problem is a significant drawback … bubbles in the stream may introduce irregularities in the thermal history of the droplets, making the technique less attractive … flowing droplet system does not suffer from either of these drawbacks … However, the initial work on this system suffered from contamination between droplets” (page 3701, 1st column, 1st paragraph)
In solving this drawback, Dorfman et al. disclose that immiscible solvent, “prevent[ed] the droplet breakage … thereby eliminating the contamination between droplets” (page 3701, 1st column, 2nd paragraph), producing “adequately reproducible amplification between different drops without any detectable contamination between them” (page 3701, 1st column, 2nd paragraph).
Based on such findings, one of ordinary skill in the art would have been motivated to utilize a fluorinated immiscible oil or oil comprising fluorosurfactants into the teachings of Cho et al., Kumacheva et al. and Bhagat et al., for the same recognized benefit of producing reproducible amplification reaction between emulsion droplets as well as preventing contamination therebetween.
Given that Cho et al., in combination with Kumacheva et al. performed emulsion amplification reaction in a flowing oil medium, said one of ordinary skill in the art would have also expected that the addition of fluorosurfactants or using fluorinated oil in the method of Cho et al./Kumacheva et al. would have yielded the same predictable benefit as observed by Dorfman et al.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id.  at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
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 extension fee 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.
Inquiries

APPLICANT REBUTTAL: Remarks
With entry of this amendment, claims 1, 4, 12, 13, 21, 31-34, 39, and 40 are pending, with claim 1 being the only independent claim. Claims 1 is amended. Support for the amendments may be found in the original application at least at lines 5-23 on page 29 and lines 1-10 on page 86.
No new matter is added.
Supplemental Amendment
The Office may enter a supplemental reply as provided for by 37 CFR 1.111, which gives examples of permissible amendments in an open list. MPEP 714.03(A) provides that, "This list is not exhaustive. The examiner has the discretion to approve the entry of a supplemental reply that is not listed above."
Applicant hereby asks the Examiner to enter this amendment. For completeness of the
written record, and to make every effort, in good faith, to advance prosecution of this application to allowance, Applicant offers the following remarks given below to address those grounds of rejection that were set forth in the previous Office Action that was mailed on June 1, 2023.
Rejections under 35 U.S.C.
Q
The Office Action on page 3 stated that claims 3 and 21 are rejected under 35 U.S.C. 112 (pre-AIA), second paragraph, as indefinite.
Claim 3 was cancelled, rendering the rejection as to that claim moot. Claim 21 was
amended for consistency with base claim 1. Applicant submits that the rejections under § 11 2 2 have been overcome.
Rejections under 35 U.S.C.
Q
The Office Action, at page 4, stated that claim 1, 3, 4, 12, 13, 21, 31, 39, and 40 are
rejected under §103 over EP 1574586A2 to Cho in view of WO 2005/103106 to Kumacheva and Bhagat, 2007, Re-usable quick-release interconnect for characterization of microfluidic systems, J Micromech Microeng 17:42-39. At page 9, claims 32-34 are so rejected over Cho, Kumacheva, and Bhagat and further in view of Dorfman, 2005, Anal Chem 77:3700-3704.
Applicant submits that the claims of this supplemental amendment are not obvious.
A determination of obviousness requires basic factual inquiries into the scope and content of the prior art as well as the differences between the claimed invention and the prior art. Graham v. John Deere Co., 383 U.S. 1 (1966). When a patent claim includes a limitation that is wholly missing from the prior art, then that prior art does not support a conclusion of obviousness. Arendi S.A.R.L. v. Apple, Inc., 832 F.3d 1355, 1366-67 (Fed. Cir. 2016).
Independent claim 1 recites a method for forming droplets of an aqueous sample fluid. The method includes flowing an immiscible carrier fluid into a nozzle that is immersed within the immiscible carrier fluid and into a main channel within the nozzle and adjusting pressure of the aqueous sample fluid in an inlet channel to produce a plurality of droplets of the aqueous sample fluid. Claim 1-as amended-recites that the nozzle is immersed, by design, within the immiscible carrier fluid, thereby preventing the aqueous sample fluid from wetting surfaces of the nozzle or the main channel.
The prior art does not teach or suggest a droplet formation nozzle that is immersed in oil and that therefore does not undergo any aqueous phase wetting.
Cho only reports injecting an aqueous solution of PCR reactants and a second fluid via different inlet channels into a channel to form aqueous droplets in which amplification is performed. EP 1574586 A2, [0015]. In Cho, amplification occurs in a reaction channel with a serpentine shape passing between two temperature areas. Id., [0045]. Cho never mentions any nozzle, much less any significance to the concept of phase wetting of surface, and thus does not teach or suggest a droplet-formation nozzle designed to avoid aqueous wetting.
Kumacheva reports producing polymer particles with pre-selected shapes by injecting a polymerizable fluid and an immiscible second fluid into a channel long enough that droplets have time to polymerize or harden into the intended shapes. WO 2005/103106, Abstract. Kumacheva shows an example in which silicone oil was inserted in a central channel while an aqueous solution was supplied to the outer channels, in which when the two liquids were forced through an orifice, a thread of silicone oil broke up into oil droplets dispersed within the aqueous continuous phase. Id., page 30, lines 16-21. Kumacheva does not teach or suggest any mechanism by which to form aqueous droplets surrounded by an immiscible carrier fluid. In fact, because Kumacheva forms droplets of silicone
oil surrounded by aqueous solution,
Kumacheva teaches and requires that the droplet formation mechanism be wetted by the aqueous phase, which teaches away from the subject matter of claim 1.
Bhagat only reports re-usable quick-release compression-based fluidic connections for microfluidic systems based on using O-rings to form a compression seal against a surface of the microfluidic device and around the inlet/outlet tubing, thus establishing connections to the macroworld and preventing any leaks at the ports. Bhagat 2007, Abstract. There is no mention of droplets or emulsions or immiscible liquids. Lacking any disclosure of immiscible liquids, Bhagat does not teach or suggest any droplet formation nozzle designed to avoid aqueous wetting.
Dorfman reports PCR in droplets flowing in an immiscible solvent. Dorfman, Abstract. Dorfman uses droplets in the immiscible solvent flowing in Teflon capillaries through zones of a compact heating system. Id., 3701. Dorfman reports aspirating droplets from a fluid reservoir into a capillary tube. Id., 3702. Dorfman explores variability in PCR results among droplets and observes that, even when the tip of the aspiration capillary is wetted with oil/surfactant mixture prior to aspiration, "variability in the amount of wetting fluorocarbon mixture of the tip" leads to different PCR droplet sizes. Id., 3703. Dorfman does not teach or suggest fully wetting a nozzle with an oil phase by having the nozzle immersed in the oil phase as a mechanism by which to avoid aqueous wetting of the nozzle. In fact, Dorfman explicitly states that the aspiration capillary experiences "variability in the amount of wetting fluorocarbon mixture of the tip". Id [which means that some amount is wetted by the oil and that another amount
is wetted by the aqueous phase
and that those amounts vary].
The Office has not found a droplet formation nozzle with a design that prevents aqueous fluid from wetting surfaces of the nozzle or a channel therein.
Because that element of claim 1, as amended, is missing from the prior art, claim 1 is not obvious. Because the only independent claim is not obvious, none of the claims are obvious. Applicant submits that the rejections under § 103 are overcome.
Conclusion

NEXT OFFICE ACTION: DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application is being examined under the pre-AIA  first to invent provisions.
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 January 31, 2024 has been entered.
Preliminary Remark
Claims 2, 3, 5-11, 14-20, 22-30, and 35-38 are canceled.
Claims 41-43 are new.
Claim Objections – Necessitated by Amendment
Claim 41 is objected to because of the following informalities: claim 41 recites the words, “de-stabilizing.”  The hyphen should be removed.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Necessitated by Amendment
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.
Claim 40 is 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 40 recites the phrase, “the one droplet of the plurality of droplets”.  It is unclear which of the many (plurality) of droplets, “the one droplet” is referring to.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 4, 12, 13, 21, 31, 39, and 40 under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 574 5861 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004) and Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49), made in the Office Action mailed on October 31, 2023 is withdrawn in view of the Amendment received on January 31, 2024.
The rejection of claims 32-34 under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 584 586 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004) and Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49) as applied to claims 1, 4, 12, 13, 21, 31, 39, and 40 above, and further in view of Dorfman et al. (Analytical Chemistry, 2005, vol. 77, pages 3700-3704), made in the Office Action mailed on October 31, 2023 is withdrawn in view of the Amendment received on January 31, 2024.
Rejection – New Grounds, Necessitated by Amendment
The following is a quotation of pre-AIA  35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 4, 12, 13, 21, 31, 39, and 40 are rejected under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 574 5862 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004), Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49), and Leamon et al. (US 2006/0040297 A1, published February 23, 2006, priority August 2003).
With regard to claim 1, Cho et al. teach a method of performing nucleic acid amplification reaction (“a method and apparatus for amplifying nucleic acids”, Abstract), the method comprising:
providing a first aqueous fluid from a first reservoir into a first inlet channel on a microfluidic substrate, the first aqueous fluid comprising a biological material (see Fig. 6, Target DNA reservoir 442);
providing via a second inlet channel, a second aqueous fluid comprising primer (see Fig. 6, see primer reservoir 444);
coalescing the first aqueous fluid with the second aqueous fluid to form an aqueous sample fluid (see Fig. 6, channel where the aqueous droplets merge therein prior to entry into main channel);
providing an immiscible carrier fluid via at least one oil supply line (see Fig. 6, see oil 152),
applying a pressure to flow the immiscible fluid into a main channel (“oil 131 … inserted into the reaction channel 130 via the respective inlet channels … 151 at a constant flow rate”, section [0053] evidences the presence of a source of pressure driven flow), and
copying the nucleic acid by extending the at least one primer (PCR copies the nucleic acid template).
With regard to claims 12 and 13 the aqueous fluids further comprise reagents for conducting an amplification (see Fig. 6, element 446, “for example, polymerase, dNTPs, and buffer”, section [0076]).
With regard to claim 21, the oil flow is constant flow (see section [0053]).
With regard to claim 31, the immiscible fluid is oil (“oil introduction”, section [0076]).
With regard to claims 39 and 40, the microfluidic substrate is a chip that includes a heating and cooling lines (see Figure 7, T1, T2, and T3, wherein the PCR reaction is performed as the droplets travel past the different temperature zones of heating and cooling (also, “substrate 110 has two areas having different temperatures, for example, 65oC area and 95oC area … heating unit 120 may also be comprised of three or more heaters having different temperatures”, section [0050]).
Cho et al. do not disclose that the device comprises a nozzle disposed within the immiscible carrier fluid which leads into the main channel where emulsion droplets enter for nucleic acid amplification reaction, wherein the nozzle comprises a ferrule immersed in oil thereby inhibiting the aqueous droplets to wet the surfaces of the nozzle or the main channel (claims 1 and 3), wherein the nozzle has complete isolation from any continuous aqueous phase (claim 4).
Cho et al. do not explicitly state that the emulsion droplets containing the amplification products are transferred from the oil carrier fluid into a droplet-destabilizing second fluid, and the aqueous sample fluid is removed from the plurality of droplets.
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Kumacheva et al. teach a device for producing droplets within a channel, wherein in an embodiment, aqueous droplets are generated and enters a main channel that is prefilled with immiscible fluid, so as to prevent the aqueous droplets from contacting the main channel and its entry (see below Figure 21b, reproduced below):
“present invention discloses a versatile strategy of synthesis of polymeric particles using a ‘lab on chip’ with pre-designed size shape, morphology and composition” (page 9, lines 18-30)
“Figures 21a and 21b is a schematic illustration of the formulation of droplets by two different mechanism using the microfluidic reactor 120 … Immiscible liquids L1 and L2 (e.g., oil and aqueous phases) are forced into the narrow orifice …” (page 20, lines 23-26)
Bhagat et al. teach a prior art known means of coupling a channel to another channel via a ferrule (see Figure 1).
Leamon et al. teach a method of amplifying nucleic acid molecules in an emulsion droplet, wherein the artisans teach that the amplification products can be sequenced:
“After encapsulation, the template nucleic acid may be amplified by any suitable method of DNA amplification … DNA amplification is performed by PCR … by exposing the emulsion to any suitable thermocycling regimen known in the art … Following amplification of the template, the emulsion is ‘broken’ (also referred to as ‘demulsification’ in the art).  There are many methods of breaking an emulsion … one preferred method of breaking the emulsion is to add additional oil to cause the emulsion to separate into two phases.  The oil phase is then removed, and a suitable organic solvent (e.g., hexane) is added.  After mixing, the oil/organic solvent phase is removed … Finally, the aqueous layers above the beads are removed.  The beads are then washed with an organic solvent/annealing buffer mixture … Suitable organic solvents include alcohols such as methanol, ethanol, and the like” (section [0192]).
“integrated system, comprising … nucleic acid sample preparation, … nucleic acid amplification, and … DNA sequencing” (section [0016])
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cho et al. with the teachings of Kumacheva et al., Benett et al., and Leamon et al., thereby arriving at the invention as claimed.
As discussed above, Cho et al. already teach a microfluidic device comprising separate reservoirs that provide template nucleic acids and reagents for amplification reaction, which are connected to a main channel flowing with oil.  The resulting configuration produces individual droplets of amplification reaction reagents that are surrounded by flowing oil which are flowed past different sections of the microfluidic chip zones having different temperatures.
While Cho et al. did not explicitly teach that the single channel which coalesces the template nucleic acid and amplification reagents leads into the main channel is completely surrounded by oil, such a configuration has been taught by Kumacheva et al. as shown above that result in the same result of providing an emulsified droplet of precisely controlled size (see page 9, lines 29-35).
As to connecting the main channel to the portion where the aqueous droplets are dispersed (see below left region where droplets are formed and the right region (b) the main channel where emulsion droplets flow through in the figure from
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Kumacheva et al.), use of any such prior known coupling means, such as ferrule would have been an obvious implementation, who use does not provide any perceivable functional advantage over that of Kumacheva et al.
In addition, Cho et al. explicitly state that nucleic acid amplification typically precedes analysis such as nucleic acid sequence analysis:
“To disclose the genetic information of nucleic acids such as DNAs and RNAs for the purpose of sequence analysis and disease diagnosis, amplification of trace amounts of nucleic acids to a desired level is required.” (section [0002])
Therefore, one of ordinary skill in the art would have recognized as well as would have been motivated to employ the droplets containing the amplification products of Cho et al. in a nucleic acid sequencing analysis.  Indeed, this motivation in the art is evidenced by Leamon et al. who explicitly teach that nucleic acid templates amplified in droplets should be sequenced (see above).
Leamon et al. also teach the common conclusion that in order to sequence the amplified nucleic acids in the droplets, droplets must first be “broken”.  Leamon et al. teach that this process can be performed by transferring the plurality of droplets and immersing them into a droplet-destabilizing second fluid (additional oil is added as well as a suitable organic solvent), allowing for the amplification products to be liberated and purified from the droplets and subsequently sequenced.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id.  at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the invention as claimed is prima facie obvious over the cited references.
Claims 32-34  are rejected under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 574 5863 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004), Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49), and Leamon et al. (US 2006/0040297 A1, published February 23, 2006, priority August 2003) as applied to claims 1, 4, 12, 13, 21, 31, 39, and 40 above, and further in view of Dorfman et al. (Analytical Chemistry, 2005, vol. 77, pages 3700-3704).
The teachings of Cho et al., Kumacheva et al., Bhagat et al., and Leamon et al. have been discussed above.
Cho et al., Kumacheva et al., Bhagat et al., and Leamon et al. do not teach that the immiscible fluid oil should be fluorinated (claim 32) or comprise a fluorosurfactant (claims 33 and 34).
Dorfman et al., much like Cho et al., disclose a method of performing a continuous PCR reaction in aqueous droplets surrounded by immiscible oil (“[p]erforming continuous flow PCR for high-throughput clinical and quantitative applications require encapsulating the sample and preventing contamination between them … this can be accomplished in two ways: either the sample can be a droplet entrained in an immiscible solvent …”, page 3700, 2nd column).
Dorfman et al. disclose the use of fluorinated oil as the immiscible medium when performing the continuous emulsion PCR (“an improvement system for performing continuous flow PCR using droplets in an immiscible fluorinated solvent …”, page 3701, 1st column, 2nd paragraph; “primed with either the bulk fluorinated oil FC-40”, page 3701, 1st column, 3rd paragraph) or oil comprising a fluorosurfactant (“or FC-40 containing various amounts of fluoro alcohol surfactant”, page 3701, 1st column, 3rd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cho et al., Kumacheva et al. and Bhagat et al. with the teachings of Dorfman et al., thereby arriving at the invention as claimed for the following reasons.
Dorfman et al. discuss potential problems associated with performing emulsion droplet PCR in an immiscible medium:
“wall treatment [of the channel] are necessary to prevent adsorption of DNA to the walls and subsequent transfer between samples … wall contamination problem is a significant drawback … bubbles in the stream may introduce irregularities in the thermal history of the droplets, making the technique less attractive … flowing droplet system does not suffer from either of these drawbacks … However, the initial work on this system suffered from contamination between droplets” (page 3701, 1st column, 1st paragraph)
In solving this drawback, Dorfman et al. disclose that immiscible solvent, “prevent[ed] the droplet breakage … thereby eliminating the contamination between droplets” (page 3701, 1st column, 2nd paragraph), producing “adequately reproducible amplification between different drops without any detectable contamination between them” (page 3701, 1st column, 2nd paragraph).
Based on such findings, one of ordinary skill in the art would have been motivated to utilize a fluorinated immiscible oil or oil comprising fluorosurfactants into the teachings of Cho et al., Kumacheva et al. and Bhagat et al., for the same recognized benefit of producing reproducible amplification reaction between emulsion droplets as well as preventing contamination therebetween.
Given that Cho et al., in combination with Kumacheva et al. performed emulsion amplification reaction in a flowing oil medium, said one of ordinary skill in the art would have also expected that the addition of fluorosurfactants or using fluorinated oil in the method of Cho et al./Kumacheva et al. would have yielded the same predictable benefit as observed by Dorfman et al.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id.  at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 41-43  are rejected under pre-AIA  35 U.S.C. 103(a) as being unpatentable over Cho et al. (EP 1 574 5864 A2, published 2005) in view of Kumacheva et al. (WO 2005/103106 A1, published November 2005, priority April 2004), Bhagat et al. (Journal of Micromechanics and Microengineering, 2007, vol. 17, pages 42-49), and Leamon et al. (US 2006/0040297 A1, published February 23, 2006, priority August 2003) as applied to claims 1, 4, 12, 13, 21, 31, 39, and 40 above, and further in view of Viovy et al. (WO 2006/027757 A2, published March 2006, priority September 2004).
The teachings of Cho et al., Kumacheva et al., Bhagat et al., and Leamon et al. have been discussed above.
While Leamon et al. teach that the droplets should be broken for sequencing the amplified products therein, the artisans do not explicitly teach all types of means which could be used for the purpose, and consequently do not teach that oil comprising surfactant (claim 41) is used, wherein said surfactant promote coalescence of the droplets (claim 42), wherein the surfactant comprises a perfluorinated alcohol (claim 43).
Viovy et al. teach that when adding various wt% of a fluorosurfactant, perfluorodecam-1-ol, (Fluorochem), the surfactant reduced the interfactial tension between the droplets, resulting in the destabilization of the droplets and their break (page 35, lines 11-14).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cho et al., Kumacheva et al. and Bhagat et al. with the teachings of Viovy et al., thereby arriving at the invention as claimed for the following reasons.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id.  at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
The use of surfactants in disrupting emulsion particles had been well-known in the art, as well as evidenced by Viovy et al.  Given that Leamon et al. explicitly suggested that, “one of ordinary skill in the art be able to select the proper method of ... breaking the emulsion” (Leamon et al., section [0192]), employing art known means to disrupt the emulsion particles, such as those disclosed by Viovy et al., would have been obvious to said ordinary skill in the art.
Conclusion
No claims are allowed.
Applicant’s arguments with respect to the previous rejections of record have been considered but are moot in view of the present rejections based on additional references.
Inquiries

CITED REFERENCE SUMMARIES: Ref WO2005103106A1: Claims:
A process for producing polymer particles of predetermined size and/or shape, and /or morphology, comprising the steps of: a) injecting a first fluid comprising a constituent which can harden into a microfluidic channel; b) injecting at least a second fluid into the microfluidic channel for causing the first fluid to forms into fluidic droplets within the at least second fluid causing the fluidic droplets to flow through the microfluidic channel, the microfluidic channel being sufficiently long so that the fluidic droplets harden into particles of predetermined size and/or shape while flowing through the channel; and c) collecting the hardened particles of predetermined size and/or shape from the microfluidic, channel.
The process according to claim 1 , wherein the fluidic droplets harden by any one of ionic crosslinking, hydrogen bonding, chelation, complexation and combinations thereof.
The process according to claim 1 , wherein the first fluid comprises a polymerizable constituent, and wherein said fluidic droplets harden by polymerizing into polymer particles.
The process according to claims 1 , 2 or 3 wherein the microfluidic channel is constructed and configured to produce fluidic droplets having a pre-selected size and or shape.
The process according to claims 1 , 2, 3 or 4 wherein the microfluidic channel has a cross-sectional shape being any one of circular, oval, triangular, irregular, square, and rectangular.
The process according to claims 1 , 2, 3, 4 or 5 wherein the microfluidic channel has an aspect ratio (length to average cross sectional dimension) of at least about 10:1.
The process according to claims 1 , 2, 3, 4 or 6 wherein the first and second fluids are each injected with a controlled flow rate into the microfluidic channel.
The process according to claims 1 , 2, 3, 4, 5, 6 or 7 wherein a diameter of the fluidic droplets formed in step b) is controlled by controlling flow rates and flow rate ratios of the first and second fluids, controlling dimensions of said microfluidic channel, properties of said first and second fluids including viscosity and interfacial tension between the first and second fluids, controlling properties of the polymerizable constituent, and wherein said microfluidic channel includes a portion constructed with pre-selected cross-sectional shape and dimensions to give a desired shape to said fluidic droplets upon transit of said fluidic droplets through said portion of said fluidic channel.
The process according to any one of claims 1 to 8 wherein said fluidic droplets have a diameter d, and wherein said portion of the microfluidic channel is constructed with pre-selected cross-sectional shape and dimensions selected so that d is larger than at least one of the dimensions of the microfluidic channel so that fluidic droplets with non-spherical shapes are formed upon transit through said portion of the microfluidic channel with preselected cross-sectional shape and dimensions so that said collected polymer particles have a non-spherical shape.
The process according to claim 9 wherein an aspect ratio for said non- spherical droplets is varied by changing a ratio between fluidic droplet volume and said dimensions of the microfluidic channel.
The process according to any one of claims 1 to 8 wherein said fluidic droplets have a diameter d, and wherein said portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the  microfluidic channel is constructed so that w > d and h > d, and a flow rate of the fluidic droplets through the microfluidic channel is selected to be slow enough so that the fluidic droplets maintain a spherical shape so that said collected polymer particles have a spherical shape.
The process according to ' any one of claims 1 to 8 wherein said fluidic droplets have a diameter d, and wherein said portion of the microfluidic channel has a width wand a height h, and wherein when said portion of the microfluidic channel is constructed so that w > d and h > d, and a flow rate of the fluidic droplets through the microfluidic channel is selected to be high enough so that the fluidic droplets acquire an ellipsoidal shape so that said collected polymer particles have an ellipsoidal shape.
The process according to any one of claims 1 to 8 wherein said fluidic droplets have a diameter d, and wherein said portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the microfluidic channel is constructed so that w < d and h > d the droplets acquire a discoid shape so that said collected polymer particles have a discoid shape shape.
The process according to any one of claims 1 to 8 wherein said fluidic droplets have a diameter d, and wherein said portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the microfluidic channel is constructed so that w < d, h < d the droplets acquire a rod shape so that said collected polymer particles have a rod shape.
The process according to any one of claims 1 to 8, and 11 to 14 wherein said at least a second fluid includes at least two immiscible fluids, and wherein said two immiscible fluids and said first fluid are injected into adjacent microfluidic channel inlets, and wherein one of said two immiscible fluids envelops the first fluid mixed with the other immiscible fluid thereby forming a coaxial stream which during passage through said microfluidic channel breaks up into segments, and wherein said segments form spherical fluidic cores enveloped by a shell which form core/shell particles.
The process according to claim 15 including adjusting flow rates of each of said first fluid and said at least two immiscible fluids to selectively control a size of the cores, a thickness of shells, and a size of core-shell particles, and a number of cores per particle.
The process according to claim 16 wherein there are at least five adjacent microfluidic channel inlets including a middle microfluidic channel inlet, two inner microfluidic channels with said middle microfluidic channel inlet being located between said two inner microfluidic channel inlets, and two outer microfluidic channel inlets with one outer outer microfluidic channel inlet being located adjacent to one of the inner microfluidic channel inlets and the other outer microfluidic channel inlet being located adjacent to the other inner microfluidic channel inlet, and wherein said first fluid is injected into said middle microfluidic channel inlet, one of the at least two immiscible fluids being injected into the two inner microfluidic channel inlets and the other of the at least two immiscible fluids being injected into the two outer microfluidic channel inlets.
The process according to claim 17 wherein the immiscible fluid injected into the two inner microfluidic channel inlets is an oil, and wherein the immiscible fluid injected into the two outer microfluidic channel inlets is an aqueous fluid.
The process according to claim 17 wherein said coaxial stream becomes unstable to perturbations with wavelengths larger than a circumference of said coaxial stream which causes the coaxial stream to break up into segments,
The process according to claim 16, 17, 18 or 19 including controlling a number of cores per fluid droplet by adjusting relative flow rates of the first fluid and the at least two fluids, and by varying interfacial capillary wavelengths Î» m and Î» 0 , where Î» m is an interfacial capillary wavelength of said monomer, and Î» 0 is an interfacial capillary wavelength of said second fluid.
The process according to any one of claims 1 to 20 wherein the constituent which can harden is a polymerizable constituent including a mixture of two or more monomers, oligomers, liquid polymers or combinations thereof such that said polymer particles are copolymer particles.
The process according to any one of claims 1 to 20 wherein the constituent which can harden is a polymerizable constituent including a monomer or oligomer or liquid polymer.
The method according to any one of claims 1 to 22 wherein the second fluid is immiscible with the first fluid so that the first fluid forms fluidic droplets.
The process according any one of claims 1 to 23 wherein the collected hardened particles of pre-selected size and/or shape and /or morphology are formed into a product.
The process according to any one of claims 1 to 24 wherein said microfluidic channel is formed in a microreactor.
The process according to claim 25 wherein said microreactor comprises a hydrophobic material, and wherein said first and second fluids exhibit different degrees of hydrophobicity, and wherein the less hydrophobic of the first and second fluids forms the fluidic droplets in the other.
The process according to claim 25 wherein said microreactor comprises a hydrophilic material, and wherein said first and second fluids exhibit different degrees of hydrophilicity and wherein the less hydrophilic of the first and second fluids forms the fluidic droplets in the other.
The process according to claim 25 wherein said microreactor comprises a moderately hydrophobic material.
The process according to any one of claims 1 to 28, wherein said first  fluid comprises one or more of organic dyes, chromophores, nonlinear optical compounds, fluorescent dyes, inorganic chemicals, inorganic particles, inorganic pigments, fluorescent inorganic particles, semiconductor nanoparticles (quantum dots), inorganic particles having pre-selected magnetic properties, inorganic particles having pre-selected anti-magnetic properties, inorganic particles having pre-selected electrically conductive and/or semiconducting properties, carbon nanotubes, liquids such as liquid crystal, which are incorporated into said hardened particles, wherein said hardened particles are composite hardened particles.
The process according to any one of claims 1 to 29 wherein said hardened particles of predetermined size and/or shape and /or morphology are monodisperse.
The process according to claim 30 wherein no more- than about 5% of the hardened particles have a dimension greater than about 5% of the average dimension.
The process according to claim 30 wherein no more than about 3% of the hardened particles have a dimension greater than about 10% of the average dimension.
The process according to any one of claims 1 to 32, wherein the hardened particles have an average dimension of less than about 100 micrometers.
The process according to any one of claims 1 to 32, wherein the hardened particles have a shape selected from the group consisting of spherical, disk, rod, oval, ellipsoidal, plates, truncated spheres, hemispheres and bowls.
The process according to any one of claims 1 to 34, wherein the hardened particles are hollow.
The process according to any one of claims 1 to 34, wherein the hardened particles have a core/shell structure with a controlled number of cores.
The process according to any one of claims 1 to 36, wherein the first fluid comprises a polymerizable constituent including carbon or carbon-wall nanotubes so that the hardened particles are polymer particles having carbon or carbon-wall nanotubes incorporated therein.
The process according to any one of claims 1 to 37, including injecting an unpolymerizable liquid into the microfluidic channel along with the first and second fluids wherein some of said unpolymerizable liquid is incorporated into the polymer particles.
The process according to any one of claims 1 to 37, wherein said first fluid comprises a polymerizable constituent which includes an unpolymerizable liquid wherein some of said unpolymerizable liquid for producing polymer particles having unpolymerizable liquids incorporated into the polymer particles.
The process according to claim 38 or 39, wherein the unpolymerizable liquid is any one of a liquid crystal, a porogen, a dispersion of inorganic or organic particles.
The process according to any one of claims 1 , including injecting an unpolymerizable fluid into the microfluidic channel along with the first and second fluids wherein said hardened particles has unpolymerizable fluid incorporated into the polymer particles for producing porous polymer particles.
The process according to any one of claims 1 to 41 , wherein said first fluid includes two or more monomers, and wherein said polymer particles include a core formed by polymerization of one of said two ore more polymers and a shell enveloping said core formed by polymerization of at least one of the other of said two ore more polymers.
The process according to claim 25, wherein said first fluid includes two or more monomers includes two or more monomers, and wherein said polymer particles include one or more polymer cores formed by polymerization of one or more of said polymers, and a shell enveloping said core formed by polymerization of at least one of the other of said two ore more polymers.
The process according to any one of claims 1 to 43, wherein said first fluid comprises a biocompatible product including one or more of starch, derivatives, polymers containing 3-hydroxybutyrate and its derivatives, polymers containing 3-hydroxyvalerate and its derivatives, protein, nucleic acids (DNA, RNA), amino acid (peptide), liposomes, agaroze and its derivatives, chitosane and it's derivatives, alginate and its derivatiives, pectin and its derivatives, cellulose derivatives, drugs and their derivatives which are incorporated into said hardened particles, wherein said hardened particles are composite particles.
The process according to any one of claims 1 to 43 including exposing said fluidic droplets in said microfluidic channel to a polymerizing agent for polymerizing said fluidic droplets.
The process according to claim 45 wherein said polymerizing agent is one of heat, ultra-violet light (UV), plasma, irradiation.
The process according to any one of claims 1 to 46 including exposing said fluidic droplets in said microfluidic channel to an external field including any one or more of a magnetic field, an electric field, light or other form of radiation.
The process according to any one of claims 1 to 47 wherein said first fluid includes a gel precursor material that hardens upon chemical or physical crosslinking so that upon hardening the fluidic droplets gel to form microgel particles.
The process according to any one of claims 1 to 48 wherein said first fluid includes biological cells so that said hardened particles contain biological cells.
The process according to any one of claims 1 to 49 wherein said first fluid includes two or more monomeric, polymeric or oligomeric constituents, and wherein the microfluidic droplets harden in a stepwise manner, including exposing said microfluidic droplets to at least polymerizing agents at different positions along said microfuidic channel in a pre-selected sequence to sequentially polymerize the different constituents at different times.
The process according to any one of claims 1 to 50 wherein production of hardened particles is done in a continuous throughput process.
The process according to anyone of claims 15 to 20 wherein the cores are solid.
The process according to anyone of claims 15 to 20 wherein the cores are liquids encapsulated by said shell.
The process according to anyone of claims 1 to 53 wherein the step c) of collecting the hardened particles of predetermined size and/or shape from the microfluidic channel includes producing a lattice structure with said hardened particles.
The process according to any one of claims 1 to 43 wherein said hardened particles include two or more monodisperse populations of hardened particles of predetermined size and/or shape and/or morphology, and wherein each population has a size different from the other populations.
The process according to claim 55 wherein the step c) of collecting the two or more monodisperse populations of hardened particles includes producing a lattice structure with said two or more monodisperse populations of hardened particles.
The process according to any one of claims 1 to 33, wherein the hardened particles are porous.
The process according to any one of claims 1 to 57 wherein said first fluid includes a gel material, and including controlling flow conditions of said first and second fluids in said microfluidic channel that said first fluid is sheared by the second fluid such that it undergoes shear thinning, liquifies and brakes in droplets which harden and form microgel particles in said microfluidic channel.
The process according to any one of claims 1 to 58 wherein said , microfluidic channel is formed in a microfluidic reactor made of a polyurethane material, and wherein said polyurethane material is synthesized from a polyol or a combination of polyols and polyisocyanate or a combination of polyisocyanates using organometallic or/and amine-containing catalysts.
An apparatus for producing polymer particles with pre-determined sizes and or shapes, comprising: a microreactor having an input end including one or more fluid inlets inputs and a microfluidic channel, said microfluidic channel being sufficiently long so that fluidic droplets located in the microfluidic channel have a long enough residence time to polymerize within the microfluidic channel; and the microreactor being made of a suitable material such that upon injecting a fluid comprising a polymerizable constituent into the microreactor the fluid forms into droplets within the microfluidic channel.
The apparatus according to claim 60, wherein the microreactor is produced by soft lithography.
The apparatus according to claim 60 or 61 wherein the suitable material is a hydrophobic material, and wherein a hydrophilic polymerizable constituent is injected into the apparatus which forms droplets which are polymerized.
The apparatus according to claim 60, 61 or 62 wherein the suitable material is a hydrophobic material, and wherein a hydrophilic polymerizable constituent is injected into the apparatus which forms droplets which are polymerized.
The apparatus according to claim 63 wherein the hydrophobic material is one of polysiloxane and polyurethane.
The apparatus according to claim 64 where said polyurethane material is synthesized from a polyol or a combination of polyols and polyisocyanate or a combination of polyisocyanates using organometallic or/and amine- containing catalysts.
A polyurethane material synthesized from a polyol or a combination of polyols and polyisocyanate or a combination of polyisocyanates using organometallic or/and amine-containing catalysts.