DETAILED ACTION
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 submission filed on November 24, 2025 has been entered and considered. Rejections and/or objections not reiterated from the previous action mailed August 25, 2025 are hereby withdrawn.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.
Claims 8-9 were previously withdrawn after the finalization of the restriction requirement in the office action dated August 25, 2025.
The amended claims filed on November 24, 2025 are acknowledged. Claims 1, 2, 5, and 7 have been amended to recite megakaryocytes in plural form. Claim 1 has been amended to incorporate features of previously dependent claims 2-4. Claim 2 has been amended to recite specific formulas for the height and width of the channel. Claims 3 and 4 have been canceled.
Claims 1-2 and 5-7 are examined on the merits.
Priority
The instant application is a 35 U.S.C 371 national stage filing of the International Application No. PCT/JP2021/006177 filed on February 18, 2021. The instant application claims foreign priority under 35 U.S.C 119(a)-(d) to Japanese Patent Application JP2020-027289, filed on February 20, 2020. Receipt is acknowledged of a certified copy of the foreign patent application in the original language as required by 37 CFR 1.55. Thus, the earliest possible priority for the instant application is February 20, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 17, 2022 are in compliance with the provisions of 37 CFR 1.97 and have been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, “the list may not be incorporated into the specification but must be submitted in a separate paper.” Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawn Objections to the Specification
In light of Applicant’s amendment to the Specification to include generic terminology for the trademark Teflon and the correction of typographical and translation errors, the objections to the specification have been withdrawn.
Withdrawn Claim Objections
In light of Applicant’s amendment of claim 1 to remove the word “cell” from the phrase “megakaryocytes to be injected”, the objection to claim 1 has been withdrawn.
Withdrawn Claim Rejections – 35 USC § 112
Applicant has amended claim 2 to remove recitations of “diameter distribution” and “correlates” rendering the rejection of claim 2 moot.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-7 under 35 U.S.C. 103 as being unpatentable over Sakuma et al. (WO 2017/061528A1) in view of Eto et al. (WO 2018/164040A1) and Sicot et al. (US2018/0104692A1) and as evidenced by Ito et al. (2018, Turbulence activates platelet biogenesis to enable clinical scale ex vivo production, Cell, 174, 636-648, found in IDS) is withdrawn in light of Applicant’s amendment to claim 1 to incorporate limitations of previously dependent claims 3 and 4, amendment of claim 2 to include formulas representing the height and depth, and cancelation of claims 3 and 4.
New Claim Rejections - 35 USC § 112
Claims 1 and 2 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.
Claim 1 recites the phrase “determined to change” in line 24. As claimed, the meaning of the phrase determined to change is not defined thus rendering the claim indefinite. Appropriate correction is required. It is recommended that Applicant amend to either recite “w(x) is determined…” as recited in the original claim language or “w(x) changes…”.
Claim 1 recites that “the method comprises a plurality of pillars…” in lines 27-28. As instantly claimed, the phrase regarding the plurality of pillars does not comprise an additional method step beyond those recited in claim 1 as steps (a) and (b) and instead appear to be additional structural features of the previously recited platelet production device, thus rendering the claim indefinite. Appropriate correction is required. It is recommended that Applicant amend to incorporate the original claim language which recites “the method according to claim 1, wherein the platelet production device comprises…”
Claim 2 recites formulas which are intended to further define the height, h(x), and width, w(x), of the channel at any given distance of x. However, the limitations required to use the formulas as recited in claim 2 are based on variable values which are not defined by the claim, thus rendering the claim indefinite. As instantly claimed, the limitations of the domains of the values used to calculate the dimensions of the channel are undefined, rendering the metes and bounds of the invention unclear. For example, if the value of the slope at distance x was high enough, the instantly claimed formula would generate a negative value for height of the channel h(x). Further, it is not clear how one of ordinary skill in the art would know whether any given value of h(x) or w(x) for any given channel are consistent with the variable descriptions as instantly claimed. Appropriate correction is required.
New Claim Rejections - 35 USC § 103
Claims 1-2 and 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sakuma et al. (WO 2017/061528A1, found in IDS, Espacenet translation attached for clarity, hereafter “Sakuma”) in view of Eto et al. (WO 2018/164040A1, found in IDS, Espacenet translation attached for clarity, hereafter “Eto”) and Sicot et al. (US2018/0104692A1, hereafter “Sicot”) and as evidenced by Ito et al. (2018, Turbulence activates platelet biogenesis to enable clinical scale ex vivo production, Cell, 174, 636-648, found in IDS, hereafter “Ito”). Claim 2 has been included in the rejection by virtue of it’s dependency on claim 1.
This is a new rejection necessitated by Applicant’s amendment in the response filed November 24, 2025. However, this rejection shares substantial similarity with the rejection over Sakuma in view of Eto and Sicot and as evidenced by Ito as put forth in the office action dated August 25, 2025. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection
With regard to claim 1, Sakuma teaches a method for producing platelets comprising culturing megakaryocytes by “known methods” (Pg. 29, lines 17-18) and introducing the megakaryocytes and a liquid into a flow path of a device for producing platelets (Pg. 7, lines 6-7) wherein the platelet production device comprises a first member comprising an “input hole” for megakaryocytes (Pg. 5, lines 12-13) and second member which, when combined with the first member, forms a “flow channel” through which liquid can flow to apply shear force to the megakaryocytes (which is considered to read on laminar flow) and which includes an outlet for produced platelets and wherein the depth of the flow channel at one end is deep enough for megakaryocytes to pass through and the depth of the flow channel at the “platelet outlet” on the other end of the channel is shallower than at the input (Pg. 5, lines 4-11). Additionally, Sakuma teaches that the flow channel of the platelet production device has a depth on the inlet side that allows megakaryocytes to pass through (Pg. 10, lines 12-13) and that the depth at the platelet outlet must prevent megakaryocytes from flowing out (Pg. 12, line 7) but allow platelets to pass through (Pg. 12, lines 14-15 and Figs. 3-6). Further, in reference to the input hole depth, Sakuma teaches that there are “no particular restrictions” on the depth of the megakaryocyte input hole as long as megakaryocytes can pass through without difficulty and that the input hole should be at least 25 µm or more (e.g. 160 µm, 200 µm, 250 µm, 300 µm or more) since megakaryocyte size is approximately 25 µm – 160 µm (Pg. 11, lines 18-21 and Pg. 12, lines 1-2). In reference to the platelet outlet depth, Sakuma teaches that it is preferable to set the depth such that megakaryocytes are unlikely to flow out and that the lower limit of the depth may be any size that allows platelets to pass through (Pg. 12, lines 11 and 15-16). Sakuma teaches an embodiment wherein the platelet outlet depth is greater than 3 µm but less than 9 µm (Pg. 13, lines 3-4) since platelets produced in vitro have a maximum diameter of 8 µm (Pg. 12, line 17). As the instant specification discloses that the height of the channel at the megakaryocyte injection port is based on a maximum diameter of a megakaryocyte and the height of a channel at the platelet collection point is based on a minimum diameter of a megakaryocyte and discloses an example in Para. [0081] and FIG. 5B wherein the maximum diameter of a megakaryocyte was determined to be 50 µm and the minimum diameter of a megakaryocyte was determined to be 5 µm, Sakuma’s teachings of a depth of greater than 25 µm at the megakaryocyte input hole and a depth between 3 µm and 9 µm at the platelet outlet are considered to reasonably read on the claims of the instant application. Sakuma teaches that by using a channel wherein the depth is adjusted such that the depth of the channel where produced platelets flow out is shallower than the depth of the channel where megakaryocytes are introduced, megakaryocytes can be “held” in the channel regardless of megakaryocyte size while maintaining the ability to apply shear force to the megakaryocytes thus continuing to produce platelets (Pg. 4, lines 2-13). Sakuma also teaches that the platelet production device comprises “capture pillars” which are formed on the first (top) or second (bottom) member and are positioned on the platelet outlet side of the flow path (Pg. 6, lines 20-21 and Pg. 7, lines 1-3)
Sakuma teaches that megakaryocytes may be cultured by “known methods” (Pg. 29, lines 17-18) but does not specifically teach culturing megakaryocytes for at least 6 days in a platelet production medium in which turbulent flow is generated.
Eto teaches a method of producing platelets comprising a step of culturing megakaryocytes in a platelet production medium in the presence of “physical stimulation” (Para. [0008], lines 2-3). Additionally, Eto teaches that “culturing in the presence of a physical stimulus means that an external force is applied to a fluidic medium”, exposing the megakaryocytes to “physical stimuli such as vortex flow and shear strain rate” (Para. [0037], lines 1-3) and wherein the culture period is preferably “about 3 to 7 days.” (Para. [0033], line 2). Further, Eto teaches an exemplary embodiment wherein immortalized megakaryocytes were cultured for 6 days using platelet production medium in VerMES shaking culture (Para. [0058], lines 2-4) which is capable of generating physical stimuli such as vorticity and shear stress (Para. [0058], lines 10-11). Eto also teaches use of a platelet production apparatus wherein medium containing megakaryocytes is injected into an inlet which leads to a flow path wherein the height of the flow channel gradually decreases along the flow of the sample and wherein the flow path ends at an outlet from which the sample containing platelets can be recovered (Para. [0070], lines 6-17 and FIG 13).
Therefore, it would have been obvious to one having ordinary skill in the art, prior to the effective filing date of the claimed invention, to combine Saukma’s the method of platelet production wherein megakaryocytes are cultured via known methods prior to use of a platelet production device comprising a first member including an input hole for megakaryocytes and a second member, wherein when combined with the first member, forms a flow channel for liquid and which includes an outlet for produced platelets and wherein the flow channel is configured such that the depth at the input end is deep enough for megakaryocytes to pass through and the depth at the “platelet outlet” on the other end of the channel is shallower, and also wherein megakaryocytes can be retained in the channel during transport thereby allowing platelets to flow to the channel outlet with Eto’s method of producing platelets wherein megakaryocytes are cultured for six days in platelet production medium subjected to physical stimuli including vortex flow and shear strain. Since Eto teaches that other methods of platelet production generate platelets which are not able to be used for blood products due to their longevity after administration (Para. [0007], lines 8-12) and that application of a physical stimulus during culture increases production of platelets which are healthy and suitable for transfusion preparations (Para. [0007], lines 14-15), a skilled artisan would have been motivated to combine Eto’s method of megakaryocyte culture with Sakuma’s platelet production device because one would have recognized that use of Eto’s method of megakaryocyte culture would lead to platelets having longer longevity after administration and which are more readily used for blood products. One having ordinary skill in the art would have had a reasonable expectation of success as both Sakuma and Eto teach methods of platelet production using cultured megakaryocytes and platelet production devices comprising inlet portions for megakaryocytes, a flow path wherein the channel depth decreases along the flow path, leading to an outlet to capture produced platelets and wherein the platelets may be recovered.
Sakuma teaches a platelet production device wherein the width of the channel changes from the megakaryocyte injection hole toward the platelet outlet and wherein the density of megakaryocytes at a particular portion of the channel increases as the channel width increases (Figs. 16 and 19(1)). Additionally, Sakuma teaches a platelet production device comprising a “depth adjusting member” which could be a “wall or pillar” formed on the first member of the device (Pg. 5, line 17) and wherein the depth of the channel can be optimized in order to maintain a constant flow rate in the channel and order to create a uniform shear force to which megakaryocytes are subjected regardless of location in the flow path (Pg. 4, lines 13-16; Pg. 19, lines 12-14). Thus, Sakuma teaches optimization of the platelet production device with the goal of standardizing shear force on the megakaryocyte population and also that megakaryocyte populations vary in size (Pg. 11, lines 18-21 and Pg. 12, lines 1-2) .
Sakuma is silent as to the adjustment of the width of the channel based on megakaryocyte diameter.
Sicot teaches a method of producing platelets via a platelet production device having features which contribute to high yield and high-quality platelet production (Abstract). Sicot teaches a method of producing platelets from megakaryocytes (Para. [0014]) comprising providing a suspension of megakaryocytes (Para. [0015]), introducing the suspension of megakaryocytes in channel of a fluidic device (Para. [0016]), and subjecting the megakaryocyte suspension in the channel to a flow having a shear rate suitable for platelet release (Para. [0017], lines 1-4). Additionally, Sicot teaches the fluidic device comprises at least one channel having at least two openings, described as the “inlet” and the “outlet” of the channel wherein megakaryocytes flow from the inlet to the outlet (Para. [0164], lines 1-6) and wherein platelets can be collected from the outlet (Para. [0165], lines 6-7). Further, Sicot teaches that the dimensions of the channel height, width, and length (Para. [0185]) may be optimized depending on the average size of megakaryocytes that could be used for platelet production (Para. [0183], lines 1-3). Sicot teaches that in order to optimize the channel dimensions, the mean megakaryocyte diameter in the suspension can be measured (Para. [0183], lines 5-7), which is considered to reasonably read on a measurement of the frequency of megakaryocyte diameters within a population of megakaryocytes. Additionally, Sicot teaches that the diameter may vary based on the source of the precursor cells and megakaryocyte production method and that the platelet production device can be optimized for various mean diameters of megakaryocytes (Para. [0184]).
Therefore it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Sakuma wherein the depth of the platelet production device channel is optimized in order to create uniform shear stress on megakaryocytes with the teachings of Sicot wherein the dimensions of the channel, including width, may be optimized based on the frequency of a megakaryocyte diameter. As Sakuma teaches that adjusting channel depth can be used to standardize the flow rate and resultant shear force applied to megakaryocytes which standardizes platelet quality (Pg. 4, lines 15-16) and Sicot teaches that channel dimensions including width can be optimized based on frequency of a megakaryocyte diameter, a skilled artisan would have recognized that increasing the channel width in a platelet production device when the frequency of megakaryocytes having a particular diameter increases would result in the ability to control flow rate through the channel and the resultant shear force to which megakaryocytes are subjected the predictable result of standardizing the platelet quality of platelets. One having ordinary skill in art would have had a reasonable expectation of success as both Sakuma, Eto, and Sicot teach use of microfluidic devices for platelet production.
With regard to claim 5, while Sakuma teaches use of megakaryocytes cultured by known methods, Sakuma does not teach forcibly expressing an oncogene, a polycomb gene, and an apoptosis-inhibiting gene prior to megakaryocyte differentiation. However, Eto’s method of platelet production as combined with Sakuma and detailed above, teaches a method comprising, prior to culturing megakaryocytes, a step of “forcibly expressing an oncogene, a polycomb gene, and an apoptosis-inhibiting gene in cells less differentiated than megakaryocyte cells to obtain immortalized megakaryocyte cells.” (Para. [0014]).
Therefore, one having ordinary skill in the art, before the effective filing date of the claimed invention, would have been motivated to combine step of expressing an oncogene, a polycomb gene, and an apoptosis-inhibiting gene in cells less differentiated than megakaryocyte cells to obtain immortalized megakaryocyte cells as taught by Eto with Sakuma’s method of platelet production (as detailed above) because, since Eto teaches that these cells proliferate indefinitely (Para. [0015], line 5), one would have recognized that first generating immortalized megakaryocytes would lead to the ability to produce a greater number of platelets from the same group of megakaryocytes. A skilled artisan would have had a reasonable expectation of success as both Sakuma and Eto teach methods of platelet generation from cultured megakaryocytes.
With regard to claim 6, Sakuma teaches a method of producing platelets wherein platelets that have flowed out of the flow path into the platelet outlet are recovered (Pg. 7, lines 9-10).
With regard to claim 7, as detailed in claim 1 above, Sakuma teaches use of megakaryocytes cultured by known methods, and Eto teaches method of producing platelets comprising culturing megakaryocytes in the presence of “physical stimulation” (Para. [0008], lines 2-3) thereby exposing the megakaryocytes to “physical stimuli such as vortex flow and shear strain rate” (Para. [0037], lines 1-3) and wherein the culture period is preferably “about 3 to 7 days.” (Para. [0033], line 2). Further, as detailed above in claim 1, Eto teaches an exemplary embodiment wherein immortalized megakaryocytes were cultured for 6 days using platelet production medium in VerMES shaking culture (Para. [0058], lines 2-4). Eto is silent as to whether the VerMES shaking culture includes use of a shaking flask or a culture vessel comprising an unsteadily operable blade. However, Ito evidences the VerMES “bioreactor” is a culture vessel comprising mixing blades which move in a vertical motion (Experimental Model and Subject Details, “VerMES bioreactors” and Figs. 3A and S3A). Therefore, one having ordinary skill in the art would have recognized that the VerMES shaking culture as taught by Eto comprises an unsteadily operating blade.
Response to Arguments
Applicant's arguments filed November 24, 2025 have been fully considered but they are not persuasive.
Applicant traverses starting at para. 2 of Pg. 16 that the combination of Sakuma, Eto, and Sicot does not teach the recitations of newly amended claim 1. Specifically, that Sakuma does not teach or suggest a platelet production device wherein the width of the channel changes according to a frequency of megakaryocytes having a specific diameter and that the teachings of Sicot do not remedy the deficiency. Applicant asserts that the device of Sicot, in which the channel dimensions are optimized based on the average size of megakaryocytes, is not configured to be adjusted based on the frequency of megakaryocytes having a particular size. Applicant asserts that, in the device as instantly claimed, the width of the channel changes from injection port to the collection station such that the change in channel width correlates with the frequency distribution of the diameter of the megakaryocyte population. Further, Applicant asserts that Eto and Ito are silent as to changes in channel width based on frequency of megakaryocyte diameter. Applicant traverses that the combination of Sakuma, Sicot, Eto, and Ito would not have led a skilled artisan to the instantly claimed invention in which the width of the channel is determined by the frequency of megakaryocytes having a particular size which allows constant fluid flow in the device and maintenance of constant shear stress on the megakaryocytes.
Applicant’s arguments have been fully considered but are not persuasive.
As instantly claimed, that distance of the channel in Applicant’s platelet production device is measured at a single point of x and width of the channel is similarly based on measurement at a single point of x, identified as w(x) which reads on a channel having a single width. As instantly claimed, dynamic adjustment of the channel width along a continuum of distances (i.e., x-2, x-1, x, x+1, x+2, etc.) is not required. Applicant’s claims recite that the width of the channel w(x) at a single distance x is based on a measurement of a frequency of megakaryocytes having a specific diameter, which one having ordinary skill in the art could reasonably understand to mean the mean diameter of a megakaryocytes in a population. Thus, as Sicot teaches optimization of the channel width in a platelet production device based on the mean diameter of megakaryocytes in the population, a skilled artisan could have readily envisioned use of platelet production device having a channel where the width is increased in order to accommodate a megakaryocyte population having a larger average diameter, particularly in view of the teachings of Sakuma where channel dimensions can be optimized in order to maintain a constant flow rate in the channel thereby creating a uniform shear force on megakaryocytes and improving overall platelet quality.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIN V PAULUS/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631