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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 23, 2025, has been entered.
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 August 19, 2025, have been acknowledged. Claims 1-24, 26-28, 30, and 41 were cancelled. Claims 29, 32-33, and 42-47 were amended. Claims 25, 29, 31-40, and 42-47 are pending and examined on the merits.
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.
Withdrawn Claim Objections
The prior objection of claims 29 and 44-47 is withdrawn in light of the following changes:
In claim 29, line 1, the phrase “A fiber production method sing” was changed to read “A fiber production method using”.
In claims 44-47, line 2, the phrase flow was changed to flows.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claim 42 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in light of Applicant’s amendments to claims 42 to make it dependent on claim 29.
New 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 32-33 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 32-33 recite the limitation "The fiber production method" inline 1. There is insufficient antecedent basis for this limitation in the claim. There is no previously identified “A fiber production method” as these are independent claims and not dependent claims. As can be seen in independent claims 25 and 29, they use “A fiber production method” while dependent claims, such as claim 31, use “The fiber production”. Claims 32-33 should be amended to follow the same nomenclature as the other independent claims.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 32, 35, and 46 under 35 U.S.C. 102(a)(1) as being anticipated by JP2013074863 (Takeuchi), as evidenced by Onoe et al. (2010 IEEE 23rd International Conference on Micro Electro Mechanical Systems (MEMS): 248-251. 2010) is withdrawn in light of Applicant’s amendments to claim 32 to recite that delivery of the third fluid is stopped after delivery of the second fluid.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 29, 34, 40-41, and 45 under 35 U.S.C. 103 as being unpatentable over Onoe et al. (Nature Materials 12: 584-590. 2013) and JP2013074863 (Takeuchi, cited in IDS) is withdrawn in light of Applicant’s amendments to claim 29 to recite that 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.
The prior rejection of claims 33, 36, 43, and 47 under 35 U.S.C. 103 as being unpatentable over Onoe et al. (Nature Materials 12: 584-590. 2013) and JP2013074863 (Takeuchi, cited in IDS) is withdrawn in light of Applicant’s amendments to claim 33 to recite that at the stop stage of the production of the cell fiber, 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.
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 32, 35, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over JP2013074863 (Takeuchi, cited in IDS), as evidenced by Onoe et al. (2010 IEEE 23rd International Conference on Micro Electro Mechanical Systems (MEMS): 248-251. 2010). This is a new rejection made in response to Applicant’s amendment to claim 32. Applicant’s traversal has been considered but is moot in response to the new rejection.
Regarding claim 32, 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 stop stage of the production of the cell fiber, delivery of the second fluid is stopped after delivery of the first fluid is stopped, and delivery of the third fluid is stopped after the delivery of the first fluid is stopped. (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 bacteria 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 the delivery of the second and third fluid are stopped.
Takeuchi is silent as to the order of stopping the second and third fluids.
However, the ordinary artisan would have recognized that there are a finite number of identified, predictable potential solutions (i.e. the ordinary artisan would reasonably understand that there are only three known options for the order of ending the flow of the second and third fluids). Thus, it is considered that there is no great intellectual leap to conceive of and/or arrive at the instantly claimed combinations.
Furthermore, changing the order of steps was known to be obvious, see Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one of ordinary skill in the art could have chosen a method of fiber production of Takeuchi wherein they ended the flow of the third fluid after ending the flow of the second fluid, to arrive at the instantly claimed invention.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 35, as stated supra, Alginic acid gels by contact between sodium alginate (second flow path fluid) and calcium chloride (third flow path fluid). (paragraph 0031). As can be seen in Figure 1A, 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. Takeuchi, as stated supra, teaches that by flowing only sodium alginate and calcium chloride at the beginning and end, both ends of the tube were closed to prevent bacteria from flowing out (paragraph 0031). As such, the first fluid (the core flow with bacterial suspension) would only be delivered after the second fluid and third fluid have already reached the convergence point and gelled between the first and third flow paths.
Regarding claim 46, Takeuchi teaches that they formed a hydrogel tube containing a cellulose-producing bacterium using an apparatus of Onoe (2010) (page 4, paragraph 7 and page 9, paragraphs 1-4 of Examiner’s Machine Translation). Onoe (2010) identifies the device as a co-axial laminar flow device (Figure 2). Therefore, the fluids would undergo laminar flow.
Claims 25, 31, 39, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over JP2013074863 (Takeuchi, cited in IDS) and Yamada et al. (Soft Matter 8: 3122-3130. 2012), as evidenced by Onoe et al. (2010 IEEE 23rd International Conference on Micro Electro Mechanical Systems (MEMS): 248-251. 2010). This rejection is repeated with regards to the rejection in the Final Office Action mailed on October 23, 2025. Applicant’s traversal is addressed below.
Regarding claim 25, 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 bacteria 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.
Takeuchi is silent as to the order of delivering the second and third fluids.
However, Yamada teaches a microfluidic system for synthesizing calcium alginate hydrogel fibers comprising cells wherein the gelation solution (third fluid of Takeuchi) and the sodium alginate solutions (second fluid of Takeuchi) were introduced stepwise to avoid direct contact between them (Figure 1 and page 3124, column 1, paragraph 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one of ordinary skill in the art could have chosen a method of fiber production of Takeuchi wherein they started the flow of the second fluid after the third fluid as was done by Yamada, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the stepwise delivery of the third fluid then the second fluid as done by Yamada with a reasonable expectation of success because Yamada teaches that stepwise introduction avoids direct contact between the solutions. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Furthermore, the ordinary artisan would have recognized that there are a finite number of identified, predictable potential solutions (i.e. the ordinary artisan would reasonably understand that there are only three known options for the order of beginning the flow of the second and third fluids). Thus, it is considered that there is no great intellectual leap to conceive of and/or arrive at the instantly claimed combinations.
Additionally, changing the order of steps was known to be obvious, see Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the location of the delivery of the third fluid before beginning the delivery of the second fluid, as can be seen in Figure 1 of Takeuchi, the calcium chloride sheath fluid is introduced downstream of the first and second fluid delivery locations at the convergence point between the first and third flow paths. As this is the only location for starting delivery of the sheath fluid and Yamada identifies avoiding contact as an important consideration for the sequential delivery of the gelling and sodium alginate solutions, it would have been well understood that as part of delivering the sheath fluid first, it would need to be under a continuous flow at the point of convergence to prevent disruptive contact from occurring.
Regarding claim 31, Takeuchi teaches that 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 bacteria 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 the delivery of the second and third fluid are stopped.
Regarding claim 39, Takeuchi teaches that 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 bacteria 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 the delivery of the second and third fluid are stopped.
Takeuchi is silent as to the order of stopping the second and third fluids.
However, the ordinary artisan would have recognized that there are a finite number of identified, predictable potential solutions (i.e. the ordinary artisan would reasonably understand that there are only three known options for the order of ending the flow of the second and third fluids). Thus, it is considered that there is no great intellectual leap to conceive of and/or arrive at the instantly claimed combinations.
Furthermore, changing the order of steps was known to be obvious, see Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that one of ordinary skill in the art could have chosen a method of fiber production of Takeuchi wherein they ended the flow of the third fluid after ending the flow of the second fluid, to arrive at the instantly claimed invention.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 44, Takeuchi teaches that they formed a hydrogel tube containing a cellulose-producing bacterium using an apparatus of Onoe (2010) (page 4, paragraph 7 and page 9, paragraphs 1-4 of Examiner’s Machine Translation). Onoe (2010)identifies the device as a co-axial laminar flow device (Figure 2). Therefore, the fluids would undergo laminar flow.
Response to Arguments
Applicant's arguments filed August 19, 2025, are acknowledged.
Applicant argues that they disagree with the conclusions drawn from the Yamada reference. Applicant argues Yamada discloses as follows: "Initially, the buffer solution (10% dextran in DI water) was introduced into the channel, and the gelation solutions and the NaA solutions were introduced stepwise to avoid direct contact between them" (Figure 1 and page 3124, column 1, paragraph 1). This phrase merely means that the buffer solution (a solution flowed between the second solution (alginate solution) and the third solution (gelation solution)) is delivered prior to the second solution and the third solution. In Yamada, the buffer solution is interposed between the second solution (alginate solution) and the third solution (gelation solution), thereby preventing direct contact between the second solution and the third solution. For the purpose of preventing direct contact between the second solution (alginate solution) and the third solution (gelation solution), the order in which the second solution and the third solution are delivered is irrelevant. Therefore, the term "stepwise" in the above Yamada's excerpt can only be understood to mean that the buffer solution is delivered first, and the second solution and the third solution are delivered thereafter (page 9, paragraph 4-page 11, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
As best understood, Applicant is arguing that their interpretation of the statement from Yamada is the correct interpretation. However, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
Applicant has identified no evidence to suggest that their interpretation of the statement of Yamada is the correct one other than to recite aspects of the microfluidic system (the buffer solution is interposed between the second solution (alginate solution) and the third solution (gelation solution), thereby preventing direct contact between the second solution and the third solution). Although this aspect of the device of Yamada is also true based on the depiction in Figure 1, it does not provide any evidence regarding the timing of the introduction of the solutions into the device. A plain reading of the language of Yamada supports the interpretation provided by the Examiner in the October 23, 2025, rejection, restated in the rejection above, and restated here: Yamada teaches a microfluidic system for synthesizing calcium alginate hydrogel fibers comprising cells wherein the gelation solution (third fluid of Takeuchi) and the sodium alginate solutions (second fluid of Takeuchi) were introduced stepwise to avoid direct contact between them (Figure 1 and page 3124, column 1, paragraph 1). Under a plain reading of the language in Yamada, the first statement “Initially, the buffer solution (10% dextran in DI water) was introduced into the channel” would clearly be interpreted to mean that first, the buffer solution is introduced. Then the second statement recites “and the gelation solutions and the NaA solutions were introduced stepwise to avoid direct contact between them.” As the buffer solution has already been introduced to the device, the most reasonable interpretation is that introduced stepwise is in regards to the gelation solutions and the NaA solutions. Therefore, Applicant’s interpretation is not considered to be the correct interpretation and Yamada is considered to provide motivation for introducing the sodium alginate and gelation solutions in a stepwise manner as identified by Yamda.
Furthermore, even if Yamada were not considered to provide a specific order, as stated in the rejection above, the ordinary artisan would have recognized that there are a finite number of identified, predictable potential solutions (i.e. the ordinary artisan would reasonably understand that there are only three known options for the order of beginning the flow of the second and third fluids). Thus, it is considered that there is no great intellectual leap to conceive of and/or arrive at the instantly claimed combinations.
Additionally, changing the order of steps was known to be obvious, see Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Applicant argues that, as described above, the concept of intentionally offsetting the timing of stopping the supply of the second fluid and the third fluid cannot be derived from Yamada or from any other cited reference (page 11, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
As best understood, Applicant is describing the arguments previously used against the previous 102 rejections (page 8, paragraph 1-page 9, paragraph 2 of Applicant’s remarks filed on December 23, 2025). As stated in the rejection above, although Takeuchi is silent as to the order of stopping the second and third fluids, the ordinary artisan would have recognized that there are a finite number of identified, predictable potential solutions (i.e. the ordinary artisan would reasonably understand that there are only three known options for the order of ending the flow of the second and third fluids). Thus, it is considered that there is no great intellectual leap to conceive of and/or arrive at the instantly claimed combinations. Furthermore, changing the order of steps was known to be obvious, see Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959). Therefore, Applicant’s arguments are considered unpersuasive.
Claims 25 and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over JP2013074863 (Takeuchi, cited in IDS) and Yamada et al. (Soft Matter 8: 3122-3130. 2012) as applied to claim 25 above and further in view of Onoe et al. (Nature Materials 12: 584-590. 2013; referenced in IDS). This rejection is repeated with regards to the rejection in the Final Office Action mailed on October 23, 2025. Applicant’s traversal has been addressed above.
The teachings of Takeuchi and Yamada are as discussed above.
The combined teachings of Takeuchi and Yamada do not teach wherein a cleaning fluid is delivered in the device.
However, Onoe (2013) teaches a microfluidic system for synthesizing calcium alginate hydrogel fibers comprising cells wherein 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).
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 Takeuchi by including a step of delivering a saline solution before delivering the calcium chloride gelling solution and a step of delivering a saline solution before delivering the calcium chloride gelling solution, as identified by Onoe (2013) 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 (2013) teaches that delivering the saline solution prevents clogging at the merge point of the shell and sheath streams. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 29, 34, 40, 42, and 45 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 made in response to Applicant’s amendment to claim 29. Applicant’s traversal has been considered but is moot in response to the new rejection.
Regarding claims 29 and 42, 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.
Claims 33, 36, 43, and 47 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 made in response to Applicant’s amendment to claim 33. Applicant’s traversal has been considered but is moot in response to the new rejection.
Regarding claims 33 and 43, 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