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 .
Election/Restrictions
Applicant’s election with traverse of Group VI (Claims 25 and 28-33; drawn to a fiber production method) in the reply filed on March 21, 2025, is acknowledged.
DETAILED ACTION
The amended claims filed on June 26, 2026, have been acknowledged. Claims 1-28, 30-32, 35, 37-39, 41, 44, and 46 were cancelled. Claim 33 was amended. Claims 48-49 are new. Claims 29, 33-34, 36, 40, 42-43, 45, and 47-49 are pending and examined on the merits.
Applicant’s response has been considered. Rejections and/or objections not reiterated from the previous office action mailed March 26, 2026, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from JP2019-132257 filed on July 17, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received January 12, 2022. While a certified copy of the foreign patent application JP2019-132257 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Information Disclosure Statement
The information disclosure statement (IDS) filed on April 6, 2026, has been considered.
Claim Rejections - 35 USC § 112
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.
Claims 29, 33-34, 36, 40, 42-43, 45, and 47-49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 29 and 33 recite "A fiber production method using a device that includes..." and the phrases “are sent”, “is sent”, and “is delivered” of claim 29 and “is stopped”, “is started”, and “are stopped” are not considered to constitute active method steps as this type of language is considered passive present and not active language. Therefore, in claim 29, the claim limitations following the phrase “at the state of the production of the cell fiber” and in claim 33, the claim limitations following the phrase “at the stop stage of the production of the cell fiber” are not considered active, positively recited steps and do not clearly define a method limitation. As such, the claims fail to positively recite any active steps of how the use of the device is actually practiced. See MPEP 217305 (q). MPEP 2173.05 states that attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b). For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parteErlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).
It is worth noting that the “is sent” language of claim 29 is not found in the instant specification and that claim 34 switches to “stopping the delivery” language. As such, the claims use inconsistent language and should be amended to ensure consistent language is used throughout.
Claims 34, 40, 42, 45, and 48 are also rejected because of their dependence on claim 29. Claims 36, 43, 47, and 49 are also rejected because of their dependence on claim 33.
The same issues of using passive language and lacking active, positively recited steps are also identified in the dependent claims, such as claim 36 (is delivered) and claim 40 (is stopped).
Applicant is recommended to amend the claims to use similar language to what was used in claim 25 of the claims set of March 21, 2025 which is considered to use active, positively recited methods steps. For example, the language of the method comprising: delivering (an active method step) the first fluid and the second fluid so that the first fluid starts to join the second fluids after the second fluid joins the third fluid for gelling the second fluid at a start stage of production would not have the same indefiniteness issues as the current claim language (i.e. is delivered).
Claim 33 recites “after delivery of the first fluid is stopped, a delivery of the third fluid is stopped … and then the delivery of the second fluid and delivery of the cleaning fluid are stopped.” No step of delivering the first, second, or third fluid is positively recited in the claim. It is unclear what active step the limitation is referencing
Claim 34 recites “stopping the delivery of the second fluid after delivery of the first fluid is stopped”; however, claim 34 depends from claim 29, and the claims do not positively recite any active delivery steps. It is unclear what the recited stoppage limitation is referencing.
Claims 48 and 49 use the term “the periods”. However, there is insufficient antecedent basis for this limitation in the claim. Claims 48 is dependent on claim 29 and claim 49 is dependent on claim 33. Claims 29 and 33 use the term “a period”. It is not clear the periods correspond to a period of claims 29 and 33 as a period suggests one period or one or more while the periods suggests two or more periods.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 29, 33-34, 36, 40, 42-43, 45, and 47-49 rejected under 35 U.S.C. 101 because Claims 29 and 33 recite "A fiber production method using a device that includes..." and the phrases “are sent”, “is sent”, and “is delivered” of claim 29 and “is stopped”, “is started”, and “are stopped” are not considered to constitute active method steps as this type of language is considered passive present and not active language. Therefore, in claim 29, the claim limitations following the phrase “at the state of the production of the cell fiber” and in claim 33, the claim limitations following the phrase “at the stop stage of the production of the cell fiber” are not considered active, positively recited steps and do not clearly define a method limitation. As such, the claims fail to positively recite any active steps of how the use of the device is actually practiced.
Claims 34, 40, 42, 45, and 48 are also rejected because of their dependence on claim 29. Claims 36, 43, 47, and 49 are also rejected because of their dependence on claim 33.
Applicant is recommended to amend the claims to use similar language to what was used in claim 25 of the claims set of March 21, 2025 which is considered to use active, positively recited methods steps. For example, the language of the method comprising: delivering (an active method step) the first fluid and the second fluid so that the first fluid starts to join the second fluids after the second fluid joins the third fluid for gelling the second fluid at a start stage of production would not have the same indefiniteness issues as the current claim language (i.e. is delivered).
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.
Claims 29, 34, 40, 42, 45, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Onoe et al. (Nature Materials 12: 584-590. 2013), JP2013074863 (Takeuchi, cited in IDS), Ghorbanian et al. (Biomed Microdevices 16:387–395. 2014), and Meng et al. (Lab Chip 16: 2673-2681. 2016). This is a new rejection that is substantially similar to a previous rejection of record. Applicant’s traversal is addressed below.
As an initial matter, in regards to the 112b issues identified above, the claim limitations after “at the start stage of production” are treated as active method steps for the purpose of prior art based rejections.
Regarding claims 29, 42, and 48, Onoe (2013) teaches a method of producing a fiber comprising cells using a device, wherein the device comprises:
A first flow path (core flow, Figure 1) through which a first fluid containing a cell flows (ECM protein with cells),
a second flow path (shell flow of sodium alginate, Figure 1) for allowing a second fluid for preparing a hydrogel to flow along a flow of the first fluid around the first fluid,
a third flow path (calcium chloride as a sheath flow, Figure 1) for allowing a third fluid that gels (Alginic acid gelled by contact between sodium alginate and calcium chloride, paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation) the second fluid to join the first flow path on a downstream side with respect to a convergence point between the first flow path and the second flow path (the third flow path joins the first flow downstream of the convergence point of the core flow and shell flow for gelation, Figure 1)
an ejection port (right hand end of Figure 1a and b allowing rapid extrusion of the hydrogel core-shell fiber) through which at least the first fluid, the second fluid, and the third fluid are discharged together,
and a cleaning flow path for allowing a cleaning fluid to flow into a third flow path (Onoe (2013) teaches that they deliver saline as part of the third flow path before delivering the calcium chloride gelling solution and after forming desired length of the fibers in the tube, switch the calcium chloride gelling fluid flow to the saline fluid flow to avoid clogging at the merge point of the shell and sheath streams (Figure 1 and Supp Infor page 5, paragraph 4-page 6, paragraph 1))
the method comprising:
at a start stage of the production of the cell fiber, the second fluid and cleaning fluid are sent toward the ejection port, after the second fluid reaches a confluence of the second flow path and the first flow path, the cleaning fluid is stopped and the third is sent (the device was operated as follows. (1) Load core and shell solution in the device and introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. (2) Start syringe pumps to infuse the core, shell and sheath solutions to generate double coaxial laminar flow in the device. The flow rates of each stream, core, shell and sheath, were Qcore = 25 μL/min, Qshell = 75 μL/min and Qsheath = 3.6 mL/min, respectively. (3) Switch the saline stream to 100 mM CaCl2 stream while keeping the flow rate at 3.6 mL/min. A core-shell hydrogel fiber is continuously generated and collected in a tube filled with saline (4) After forming desired length of the fibres in the tube, switch the CaCl2 stream to the saline stream again, and stop the pumps. (Supp Infor page 5, paragraph 4-page 6, paragraph 1)).
Regarding the third fluid is sent after the second fluid reaches a confluence of the second flow path and the first flow path limitation, Onoe teaches that they introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. Therefore, the saline solution would be maintained until the shell (second fluid) has reached a confluence of the third and first flow path which is downstream of the second and first flow path convergence point and would also reach confluence.
Onoe does not teach wherein the core fluid is delivered after the second and third fluid reach a convergence point between the third and first flow paths.
However, Takeuchi teaches a method of producing a fiber with comprising cells using a device, wherein the device comprises:
A first flow path (core flow, Figure 1) through which a first fluid containing a cell flows (bacterial suspension),
a second flow path (shell flow of 1.5 wt% sodium alginate, Figure 1) for allowing a second fluid for preparing a hydrogel to flow along a flow of the first fluid around the first fluid,
a third flow path (100 mM calcium chloride as a sheath flow, Figure 1) for allowing a third fluid that gels (Alginic acid gelled by contact between sodium alginate and calcium chloride, paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation) the second fluid to join the first flow path on a downstream side with respect to a convergence point between the first flow path and the second flow path (the third flow path joins (just before gelation point) the first flow downstream of the convergence point of the core flow and shell flow (before coaxial laminar flow marker) for gelation, Figure 1 and paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation)
and an ejection port (right hand end of Figure 1A allowing rapid extrusion of the hydrogel core-shell fiber) through which at least the first fluid, the second fluid, and the third fluid are discharged together,
the method comprising:
at a start stage of the production of the cell fiber, the first fluid is delivered after the second fluid reaches the convergence point between the third flow path and the first flow path (Alginic acid gelled by contact between sodium alginate (second fluid) and calcium chloride (third fluid), and a hydrogel tube was formed. In addition, by flowing only sodium alginate and calcium chloride at the beginning and end, both ends of the tube were closed to prevent cells from flowing out (paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation). Therefore, the delivery of the cell suspension (first fluid) is started after the delivery of the second and third fluid reach the convergence point and gel.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the cell fiber production method of Onoe by including a step of flowing only sodium alginate and calcium chloride at the beginning and end so that both ends of the tube were closed to prevent cells from flowing out, as identified by Takeuchi to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Takeuchi teaches that flowing only sodium alginate and calcium chloride at the beginning and end so that both ends of the tube were closed prevents cells from flowing out of the hydrogel fiber. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Onoe (2013) and Takeuchi do not teach wherein after the second fluid reaches at least a confluence of the second flow path and the first flow path, the cleaning fluid is stopped and the third fluid is sent so that a period in which a flow rate of the third fluid increases overlaps with a period in which a flow rate of the cleaning fluid decreases.
However, Ghorbanian teaches a method of producing a fiber comprising cells using a microfluidic device, wherein the device comprises:
A sodium alginate + cells flow, a calcium chloride flow, and an EDTA flow along the same path as the calcium chloride flow (Figure 1). Ghorbanian teaches that the EDTA, a Ca2+chelator, is used to remove clogs within the system to dissolve the hydrogel clogging the channel. The EDTA shares a common microchannel with the CaCl2 (Fig. 1). Since alginate is initially crosslinked due to the presence of calcium, the removal of calcium by EDTA leads to the alginate getting dissolved. Upon observation of blockage within the MFDW head, EDTA was delivered to the conduit to dissolve the solid gel. Once the clogged gel was removed, the writing process was resumed. For this declogging mechanism to work efficiently, early injection of the EDTA was required, the longer the clogging had occurred the more difficult it was to remove the gel with this mechanism. Even though this declogging mechanism addressed the clogging issue to a great extent, there were instances that large cloggings occurred which required the disassembly of the device. This occurred very rarely when a declogging was not flushed out immediately (Figure 1, page 390, column 1, paragraph 2-column 2, paragraph 1, and page 392, column 1, paragraph 1).
Meng teaches a method of producing a fiber using a microfluidic device, wherein the device comprises:
four aqueous solutions (W1, W2, W3, and W4) W1 = DI water + 0.5% (w/v) Sodium carboxymethyl cellulose (CMC); W2= DI water + 2% (w/v) Na-Alg + 0.1% (w/v) bromoeosin; W3 = DI water + 2% (w/v) PEG20000; W4 = DI water + 2% (w/v) CaCl2. An aqueous flow of polyethylene glycol (PEG20000) is used as a buffer solution to separate the Ca2+-containing and alginate-containing flows. The buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate, and enabling continuous fabrication of hollow Ca-alginate microfibers (page 2674, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the cell fiber production method of Onoe and Takeuchi by gradually increasing the flow rate of the calcium chloride while decreasing the flow rate of the cleaning fluid to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Onoe specifically identifies that they introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. Therefore, Onoe clearly understood the risk of clogging in their device. Furthermore, Ghorbanian and Meng are focused on getting rid of clogs and preventing clogs in their devices, respectively. As shown by Ghorbanian, an anti-clogging solution can share a common microchannel with the CaCl2 and be operated under a separate pump. This would allow for the flow rate of the calcium chloride and the buffer solution to be modified independently, thus, allowing for the rate of the cleaning fluid to be gradually decreased while the calcium chloride solution flow rate increases. Additionally, Meng identifies that flow of a buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate. As such, it would have been obvious to gradually reduce the flow of the cleaning solution while increasing the flow of the calcium chloride solution at the start of production of the cell fiber as this will limit the potential of clogging to occur. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 34, as stated supra, it would have been obvious to stop the core flow with cells before stopping the flow of the shell fluid to ensure both ends of the fiber are closed, preventing cells from flowing out of the hydrogel fiber.
Regarding claim 40, as stated supra, it would have been obvious to stop the core flow with cells before stopping the flow of the shell fluid to ensure both ends of the fiber are closed, preventing cells from flowing out of the hydrogel fiber. As stated supra, Onoe (2013) teaches that (4) After forming desired length of the fibres in the tube, switch the CaCl2 stream to the saline stream again (i.e. starting the cleaning fluid after delivery of the first fluid is stopped), and stop the pumps (i.e. stopping the second fluid and cleaning fluid).
Regarding claim 45, Figure 1 of Onoe (2013) that they used a double-coaxial laminar-flow microfluidic device which would cause the fluids to be under laminar flow.
Response to Arguments
Applicant's arguments filed June 26, 2026, are acknowledged.
Applicant argues that the claims require that the third fluid is replaced with the cleaning fluid or vice versa in a synchronized manner such that the replacement is performed while both fluids are being transitions. In other words, the cleaning fluid or third fluid is not supplied after the third fluid or the cleaning fluid has been completely stopped. Applicant argues that Onoe and Takeuchi and specifically Ghorbanian and Meng do not teach or suggest these features. The Office admits that Onoe and Takeuchi do not teach this limitation but attempts to remedy the deficiencies of Onoe and Takeuchi by relying on Ghorbanian and Meng.
Ghorbanian merely discloses the concept that, when a blockage is observed within the MFDW head, EDTA is delivered into the conduit to dissolve the solidified gel. In such a case, once a blockage is observed, it is sufficient simply to deliver EDTA (the cleaning fluid). One of ordinary skill in the art would not have any need to replace the cleaning fluid with the third fluid after the cleaning fluid has been supplied. Furthermore, Ghorbanian does not disclose the concept of gradually changing the flow rate of EDTA (the cleaning fluid), nor does Ghorbanian disclose the concept of gradually changing the flow rate of the third fluid.
Ghorbanian discloses that a pump for the calcium chloride solution (third fluid) and a pump for the EDTA (buffer solution) are provided separately. However, Ghorbanian neither teaches nor suggests operating these pumps so as to "gradually increase the flow rate of the third fluid while gradually decreasing the flow rate of the EDTA (cleaning fluid)."
Therefore, Ghorbanian fails to disclose that, during replacement between the EDTA (the cleaning fluid) and the third fluid, a decrease/increase in the flow rate of the cleaning fluid is synchronized with an increase/decrease in the flow rate of the third fluid.
Meng does not disclose the concept of gradually changing the flow rate of PEG20000 (Buffer fluid), nor does it disclose the concept of gradually changing the flow rate of the third fluid. Therefore, Meng fails to disclose that, during replacement between the PEG20000 (Buffer fluid) and the third fluid, a decrease/increase in the flow rate of the cleaning fluid is synchronized with an increase/decrease in the flow rate of the third fluid.
Meng's buffer solution (the inner flow of the alginate-containing stream) adjusts the diffusion rate of Ca2+ into the alginate-containing stream for crosslinking. Meng' s teaching is directed to adjusting the diffusion rate of Ca2+ in the CaCh solution (see Fig. 1), and not to adjusting (or varying) the flow rates. Meng does not mention any variation in the flow rates of the respective fluids.
Therefore, Meng fails to disclose that, during replacement between the PEG20000 (Buffer fluid) and the third fluid, a decrease/increase in the flow rate of the PEG20000 (Buffer fluid) is synchronized with an increase/decrease in the flow rate of the third fluid (page 6, paragraph 1-page 10, paragraph 5).
Applicant's arguments have been fully considered but they are not persuasive.
As identified in the rejection above, Ghorbanian teaches a method of producing a fiber comprising cells using a microfluidic device, wherein the device comprises:
A sodium alginate + cells flow, a calcium chloride flow, and an EDTA flow along the same path as the calcium chloride flow (Figure 1). Ghorbanian teaches that the EDTA, a Ca2+chelator, is used to remove clogs within the system to dissolve the hydrogel clogging the channel. The EDTA shares a common microchannel with the CaCl2 (Fig. 1). Since alginate is initially crosslinked due to the presence of calcium, the removal of calcium by EDTA leads to the alginate getting dissolved. Upon observation of blockage within the MFDW head, EDTA was delivered to the conduit to dissolve the solid gel. Once the clogged gel was removed, the writing process was resumed. For this declogging mechanism to work efficiently, early injection of the EDTA was required, the longer the clogging had occurred the more difficult it was to remove the gel with this mechanism.
Meng teaches an aqueous flow of polyethylene glycol (PEG20000) is used as a buffer solution to separate the Ca2+-containing and alginate-containing flows. The buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate, and enabling continuous fabrication of hollow Ca-alginate microfibers (page 2674, column 1, paragraph 2).
Regarding delivering the cleaning and third fluid at the start stage of production, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the cell fiber production method of Onoe and Takeuchi by gradually increasing the flow rate of the calcium chloride while decreasing the flow rate of the cleaning fluid because Onoe specifically identifies that they introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. Therefore, Onoe clearly understood the risk of clogging in their device. Furthermore, Ghorbanian and Meng are focused on getting rid of clogs and preventing clogs in their devices, respectively. As shown by Ghorbanian, an anti-clogging solution can share a common microchannel with the CaCl2 and be operated under a separate pump. This would allow for the flow rate of the calcium chloride and the buffer solution to be modified independently, thus, allowing for the rate of the cleaning fluid to be gradually decreased while the calcium chloride solution flow rate increases. Additionally, Meng identifies that flow of a buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate. As such, it would have been obvious to gradually reduce the flow of the cleaning solution while increasing the flow of the calcium chloride solution at the start of production of the cell fiber as this will limit the potential of clogging to occur.
Therefore, there is a clear scientific rationale for gradually reducing the flow of the cleaning solution while increasing the flow of the calcium chloride solution at the start stage of production of the cell fiber as this will limit the potential of clogging to occur.
Similarly, at the stop stage of production, Onoe teaches that they introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. Therefore, Onoe clearly understood the risk of clogging in their device. Furthermore, Ghorbanian and Meng are focused on getting rid of clogs and preventing clogs in their devices, respectively. As shown by Ghorbanian, an anti-clogging solution can share a common microchannel with the CaCl2 and be operated under a separate pump. This would allow for the flow rate of the calcium chloride and the buffer solution to be modified independently, thus, allowing for the rate of the calcium chloride solution to be gradually decreased while the cleaning fluid flow rate increases. Additionally, Meng identifies that flow of a buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate. Takeuchi teaches that flowing only sodium alginate and calcium chloride at the beginning and end so that both ends of the tube were closed prevents cells from flowing out of the hydrogel fiber. As such, it would have been obvious to gradually reduce the flow of the calcium chloride solution while increasing the flow of the cleaning solution at the end of production of the cell fiber as this will allow for the end of the cell fiber tube to enclose to prevent cells from flowing out of the hydrogel fiber while also limiting the potential of clogging to occur by gradually reducing the flow rate and concentration of calcium chloride.
Therefore, there is a clear scientific rationale for gradually reducing the flow of the calcium chloride solution while increasing the flow of the cleaning solution at the stop stage of production of the cell fiber as this will limit the potential of clogging to occur.
Claims 33, 36, 43, 47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Onoe et al. (Nature Materials 12: 584-590. 2013), JP2013074863 (Takeuchi, cited in IDS), Ghorbanian et al. (Biomed Microdevices 16:387–395. 2014), and Meng et al. (Lab Chip 16: 2673-2681. 2016). This is a new rejection that is substantially similar to a previous rejection of record. Applicant’s traversal has been addressed above.
As an initial matter, in regards to the 112b issues identified above, the claim limitations after “at the start stage of production” are treated as active method steps for the purpose of prior art based rejections.
Regarding claims 33, 43, and 49, Onoe (2013) teaches a method of producing a fiber comprising cells using a device, wherein the device comprises:
A first flow path (core flow, Figure 1) through which a first fluid containing a cell flows (ECM protein with cells),
a second flow path (shell flow of sodium alginate, Figure 1) for allowing a second fluid for preparing a hydrogel to flow along a flow of the first fluid around the first fluid,
a third flow path (calcium chloride as a sheath flow, Figure 1) for allowing a third fluid that gels (Alginic acid gelled by contact between sodium alginate and calcium chloride, paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation) the second fluid to join the first flow path on a downstream side with respect to a convergence point between the first flow path and the second flow path (the third flow path joins the first flow downstream of the convergence point of the core flow and shell flow for gelation, Figure 1)
an ejection port (right hand end of Figure 1a and b allowing rapid extrusion of the hydrogel core-shell fiber) through which at least the first fluid, the second fluid, and the third fluid are discharged together,
and a cleaning flow path for allowing a cleaning fluid to flow into a third flow path (Onoe (2013) teaches that they deliver saline as part of the third flow path before delivering the calcium chloride gelling solution and after forming desired length of the fibers in the tube, switch the calcium chloride gelling fluid flow to the saline fluid flow to avoid clogging at the merge point of the shell and sheath streams (Figure 1 and Supp Infor page 5, paragraph 4-page 6, paragraph 1))
the method comprising:
at a stop stage of the production of the cell fiber, a delivery of the third fluid is stopped and a delivery of the cleaning fluid is started, and then the delivery of the second fluid and the delivery of the cleaning fluid are stopped (the device was operated as follows. (1) Load core and shell solution in the device and introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. (2) Start syringe pumps to infuse the core, shell and sheath solutions to generate double coaxial laminar flow in the device. The flow rates of each stream, core, shell and sheath, were Qcore = 25 μL/min, Qshell = 75 μL/min and Qsheath = 3.6 mL/min, respectively. (3) Switch the saline stream to 100 mM CaCl2 stream while keeping the flow rate at 3.6 mL/min. A core-shell hydrogel fiber is continuously generated and collected in a tube filled with saline (4) After forming desired length of the fibres in the tube, switch the CaCl2 stream to the saline stream again, and stop the pumps. (Supp Infor page 5, paragraph 4-page 6, paragraph 1)).
Regarding the third fluid is sent after the second fluid reaches a confluence of the second flow path and the first flow path limitation, Onoe teaches that they introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. Therefore, the saline solution would be maintained until the shell (second fluid) has reached a confluence of the third and first flow path which is downstream of the second and first flow path convergence point and would also reach confluence.
Onoe does not teach wherein the core fluid is stopped before the second and third are stopped.
However, Takeuchi teaches a method of producing a fiber comprising cells using a device, wherein the device comprises:
A first flow path (core flow, Figure 1) through which a first fluid containing a cell flows (bacterial suspension),
a second flow path (shell flow of 1.5 wt% sodium alginate, Figure 1) for allowing a second fluid for preparing a hydrogel to flow along a flow of the first fluid around the first fluid,
a third flow path (100 mM calcium chloride as a sheath flow, Figure 1) for allowing a third fluid that gels (Alginic acid gelled by contact between sodium alginate and calcium chloride, paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation) the second fluid to join the first flow path on a downstream side with respect to a convergence point between the first flow path and the second flow path (the third flow path joins (just before gelation point) the first flow downstream of the convergence point of the core flow and shell flow (before coaxial laminar flow marker) for gelation, Figure 1 and paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation)
and an ejection port (right hand end of Figure 1A allowing rapid extrusion of the hydrogel core-shell fiber) through which at least the first fluid, the second fluid, and the third fluid are discharged together,
the method comprising:
at a start stage of the production of the cell fiber, the first fluid is delivered after the second fluid reaches the convergence point between the third flow path and the first flow path (Alginic acid gelled by contact between sodium alginate (second fluid) and calcium chloride (third fluid), and a hydrogel tube was formed. In addition, by flowing only sodium alginate and calcium chloride at the beginning and end, both ends of the tube were closed to prevent cells from flowing out (paragraph 0031 of Applicant’s machine translation of JP2013074863, page 9, paragraphs 1-4 of Examiner’s machine translation). Therefore, the delivery of the cell suspension (first fluid) is stopped before delivery of the second and third fluids are stopped.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the cell fiber production method of Onoe by including a step of flowing only sodium alginate and calcium chloride at the beginning and end so that both ends of the tube were closed to prevent cells from flowing out, as identified by Takeuchi to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Takeuchi teaches that flowing only sodium alginate and calcium chloride at the beginning and end so that both ends of the tube were closed prevents cells from flowing out of the hydrogel fiber. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Onoe (2013) and Takeuchi do not teach wherein
after delivery of the first fluid is stopped, a delivery of the third fluid is stopped and a delivery of the cleaning fluid is started so that a period in which a flow rate of the cleaning fluid increases overlaps with a period in which a flow rate of the third fluid decreases.
However, Ghorbanian teaches a method of producing a fiber comprising cells using a microfluidic device, wherein the device comprises:
A sodium alginate + cells flow, a calcium chloride flow, and an EDTA flow along the same path as the calcium chloride flow (Figure 1). Ghorbanian teaches that the EDTA, a Ca2+chelator, is used to remove clogs within the system to dissolve the hydrogel clogging the channel. The EDTA shares a common microchannel with the CaCl2 (Fig. 1). Since alginate is initially crosslinked due to the presence of calcium, the removal of calcium by EDTA leads to the alginate getting dissolved. Upon observation of blockage within the MFDW head, EDTA was delivered to the conduit to dissolve the solid gel. Once the clogged gel was removed, the writing process was resumed. For this declogging mechanism to work efficiently, early injection of the EDTA was required, the longer the clogging had occurred the more difficult it was to remove the gel with this mechanism. Even though this declogging mechanism addressed the clogging issue to a great extent, there were instances that large cloggings occurred which required the disassembly of the device. This occurred very rarely when a declogging was not flushed out immediately (Figure 1, page 390, column 1, paragraph 2-column 2, paragraph 1, and page 392, column 1, paragraph 1).
Meng teaches a method of producing a fiber using a microfluidic device, wherein the device comprises:
four aqueous solutions (W1, W2, W3, and W4) W1 = DI water + 0.5% (w/v) Sodium carboxymethyl cellulose (CMC); W2= DI water + 2% (w/v) Na-Alg + 0.1% (w/v) bromoeosin; W3 = DI water + 2% (w/v) PEG20000; W4 = DI water + 2% (w/v) CaCl2. An aqueous flow of polyethylene glycol (PEG20000) is used as a buffer solution to separate the Ca2+-containing and alginate-containing flows. The buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate, and enabling continuous fabrication of hollow Ca-alginate microfibers (page 2674, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the cell fiber production method of Onoe and Takeuchi by gradually increasing the flow rate of the cleaning fluid while decreasing the flow rate of the calcium chloride fluid to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Onoe teaches that they introduce saline to the sheath channel instead of the 100 mM CaCl2 solution to avoid clogging at the merge point of the shell and sheath streams. Therefore, Onoe clearly understood the risk of clogging in their device. Furthermore, Ghorbanian and Meng are focused on getting rid of clogs and preventing clogs in their devices, respectively. As shown by Ghorbanian, an anti-clogging solution can share a common microchannel with the CaCl2 and be operated under a separate pump. This would allow for the flow rate of the calcium chloride and the buffer solution to be modified independently, thus, allowing for the rate of the calcium chloride solution to be gradually decreased while the cleaning fluid flow rate increases. Additionally, Meng identifies that flow of a buffer solution adjusts the diffusion rate of Ca2+ into the alginate-containing flow for crosslinking, thus effectively preventing the clogging of microchannels resulting from rapid gelation of alginate. Furthermore, Takeuchi teaches that flowing only sodium alginate and calcium chloride at the beginning and end so that both ends of the tube were closed prevents cells from flowing out of the hydrogel fiber. As such, it would have been obvious to gradually reduce the flow of the calcium chloride solution while increasing the flow of the cleaning solution at the end of production of the cell fiber as this will allow for the end of the cell fiber tube to enclose to prevent cells from flowing out of the hydrogel fiber while also limiting the potential of clogging to occur by gradually reducing the flow rate and concentration of calcium chloride. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 36, as stated supra, it would have been obvious to start the core flow with cells after starting the flow of the shell fluid and sheath fluid to ensure both ends of the fiber are closed, preventing cells from flowing out of the hydrogel fiber.
Regarding claim 47, Figure 1 of Onoe (2013) that they used a double-coaxial laminar-flow microfluidic device which would cause the fluids to be under laminar flow.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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