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 .
This action is responsive to papers filed 06/11/2026.
Claims 1, 22, and 27 have been amended. Claims 33-34 have been newly added and no claims have been newly canceled.
Claims 1-5, 7, 21-34 are currently pending and have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 7, 21-34 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al (WO 2015/102726 A2) in view of Martin-Ramirez et al ( Nature Protocols, 2012) and (Ecklu-Mensah et al (PLOS One 2018-from IDS filed 08/30/2021).
Regarding claims 1, 3, 7, 21-24, 27-30, 33-34, Jain teach and suggest a microfluidic device that comprises a substrate (body) with microchannels formed enclosed therein between the fluid inlet and fluid outlet and wherein the surface of the microchannels is treated with collagen and/or endothelial cells as a first or second treatment (pages 31-32 para 77-78, pages 36-37 para 88-91). Including an imaging device to collect information is also taught and suggested as well (page 13 para 38, page 14 para 41, pages 18-19 para 50-51, page 27 para 71). Jain disclose wherein the microchannel has a same cross-section geometry between the fluid inlet and the fluid outlet (provide a geometry that allows fluid to pass through microchannels of substantially constant cross-sectional area) (page 18, para 50).
Jain are silent with regard to how the microchannels are coated with endothelial cells and what type of endothelial cells to use.
Martin-Ramirez disclose that blood outgrowth endothelial cells are important tools when investigating diagnostic and therapeutic approaches for vascular disease (abstract). HUVECs are disclosed as extensively used as a model but have the disadvantage of a limited life span and drift of phenotype as experimental limitations (page 1709). Owing to their unique phenotypic stability, BOECs have emerged as a powerful tool for monitoring pathophysiological changes in patients with vascular abnormalities. BOECs have been successfully used to survey for possible genetic differences in endothelial gene expression (page 1709). Owing to their angiogenic potential, BOECs (termed ECFCs in many studies) are excellent candidates for cell therapy in vascular regeneration. It has been shown that ECFCs manifest the ability to form de novo vessels in vivo, as opposed to the so-called EPCs of hematopoietic origin, which do not have this property (page 1710).
Ecklu-Mensah disclose that blood outgrowth endothelial cells (BOECs) offer a convenient means to study endothelium of clinically relevant populations (page 2). Ecklu-Mensah disclose that these BOECs are seeded onto micro surfaces pre-coated with collagen type I and grown to confluences for greater than 48 hours (a period of at least 18 hours) and then RPMI growth medium is flowed over the cells at microvascular wall shear stress 1 dyn/cm2 (pages 3-4).
One of ordinary skill in the art would have been motivated to select BOECs (blood-derived endothelial cells) for the type of endothelial cell seeded on a collagen coated surface and used to coat the microchannels of Jain because Martin-Ramirez and Ecklu-Mensah teach and suggest that this is a beneficial and advantageous type of endothelial cell to use and on collagen when looking to recreate and represent the in vivo vascular environment. One of ordinary skill in the art would have been motivated to use the pump for at least 18 hours to perfuse the BOECs and the growth media through the microfluidic channel because Ecklu-Mensah disclose that these BOECs are seeded onto micro surfaces pre-coated with collagen type I with RPMI growth medium and grown for greater than 48 hours with growth media flowed at microvascular wall shear stress 1 dyn/cm2 (pages 3-4). One of ordinary skill in the art would have had a reasonable expectation of success because Jain teach and suggest that a microfluidic device containing a plurality of parallel microchannels that mimic blood vessels and permit real-time analysis of clotting dynamics will retain a laminar flow (page 13 para 39).
Jain do not specifically describe wherein the plurality of endothelial cells are aligned with a flow axis of the microfluidic channel. However, they do indicate that it is desirable to provide a constant (continuous) flow of fluid into the microfluidic channels and that this flow can be induced in the channel through the use of a pump (page 32 para 80, page 35 para 86).
Applicant’s disclosure indicates that the majority of BOECs will align with a flow axis in the microfluidic channel when culture medium is flowed continuously through the microchannel (Specification page 16 para 68, page 20 para 81).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to apply a continuous flow of culture medium to the microchannels of the microfluidic device of Jain because Jain teach and suggest that a constant flow is desirable and beneficial. This process would have inherently provided wherein the cells lining the microchannel (BOECs) would then align with a flow axis in the microfluidic channel as evidenced by Applicant’s disclosure (Specification page16 para 68, page 20 para 81).
Jain teach and suggest that a microfluidic device containing a plurality of parallel microchannels that mimic blood vessels and permit real-time analysis of clotting dynamics will retain a laminar flow (page 13 para 39).
This laminar flow through the microfluidic channels would then inherently produce the alignment of the endothelial cells within 30 degrees of the flow axis of the microfluidic channel as evidenced by the fact that this is the type of flow that Applicant uses in their device to create the alignment of BOECs in the microchannel (Specification page 16 para 68, page 20 para 81).
Regarding claims 1, 2, 22, 27, Jain teach that it is suitable and beneficial to include a pump configured to withdraw blood from a patient from a fluid conduit connected to a fluid inlet of the channel and perfused through the channel to the outlet (page 32 para 78, page 39 para 100).
Regarding claims 1, 4, 22, 25, 27 and 31, Jain teach that it is suitable and beneficial to include a computer system configured to provide a readout comprising information associated with the function of the device and thus associated with the endothelial cells lining the channels of the device as well (pages 33-34 para 83-84). The computer system includes a controller including one or more processors for communicating information and a main memory and/or other dynamic storage device for storing information and instructions to be executed by the processor and further integrated with a pump operation and sensory data collection (page 33 para 83).
Regarding claims 5, 26 and 32, Jain teach that it is suitable and beneficial to include microchannel diameters that mimic the diameter of blood vessels (page 13 para 39) and include a maximal hydraulic diameter between about 25 µm- 5mm (page 42 claim 5).
One of ordinary skill in the art would have been motivated to include microchannels that mimic the diameter of blood vessels and include a maximal hydraulic diameter between about 25 µm- 5mm in the microfluidic system because Jain teach that it is suitable and beneficial to include microchannel diameters that mimic the diameter of blood vessels (page 13 para 39) and include a maximal hydraulic diameter between about 25 µm- 5mm (page 42 claim 5). This diameter range disclosed by Jain overlaps and thus renders obvious Applicant’s claimed range. One of ordinary skill in the art would have had a reasonable expectation of success because Jain are seeding microfluidic channels with endothelial cells from a patient.
Regarding claim 27, Jain teach and suggest that a shear rate of a microfluidic device containing endothelial cells is properly within the range of 75-2500 sec-1 (page 17 para 48 and page 18 para 50) which overlaps with the range of a shear rate that is less than 100 inverse seconds) and thus renders the claimed range obvious.
In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists. In re Wertheim (MPEP 2144.05).
Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use a shear rate of 75-100 inverse seconds in the microfluidic device of Jain because Jain teach and suggest that this is a suitable and beneficial feature of a microfluidic device system designed to enhance and assess patient or subject care.
Therefore, the combined teachings of Jain et al, Martin-Ramirez et al and Ecklu-Mensah et al render obvious Applicant’s invention as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 7, 21-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending US Patent 12,387,622 (previously US Application No. 18/739567) in view of Jain et al (WO 2015/102726 A2) in view of Martin-Ramirez et al ( Nature Protocols, 2012) and (Ecklu-Mensah et al (PLOS One 2018-from IDS filed 08/30/2021).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of copending Application ‘567 are drawn to a microfluidic chip for modeling blood through a vein comprising a body comprising a microchannel coated with endothelial cells that form a vascular lumen, wherein the endothelial cells are coated over a layer of extracellular matrix, with a flow channel width between 25 µm and 200 µm.
Regarding claims 1, 3, and 7, While the copending claims do not recite wherein the endothelial cells are blood outgrowth endothelial cells (BOECs), it would have been obvious to substitute or add BOECs to the endothelial cells coating the channel because Martin-Ramirez and Ecklu-Mensah teach that BOECs are a suitable type of endothelial cell to line the surface of a device to model in vivo blood flow.
Regarding claims 1, 3, 7, 21-24, 27-30, 33-34, Jain teach and suggest a microfluidic device that comprises a substrate (body) with microchannels formed enclosed therein between the fluid inlet and fluid outlet and wherein the surface of the microchannels is treated with collagen and/or endothelial cells as a first or second treatment (pages 31-32 para 77-78, pages 36-37 para 88-91). Including an imaging device to collect information is also taught and suggested as well (page 13 para 38, page 14 para 41, pages 18-19 para 50-51, page 27 para 71). Jain disclose wherein the microchannel has a same cross-section geometry between the fluid inlet and the fluid outlet (provide a geometry that allows fluid to pass through microchannels of substantially constant cross-sectional area) (page 18, para 50).
Jain are silent with regard to how the microchannels are coated with endothelial cells and what type of endothelial cells to use.
Martin-Ramirez disclose that blood outgrowth endothelial cells are important tools when investigating diagnostic and therapeutic approaches for vascular disease (abstract). HUVECs are disclosed as extensively used as a model but have the disadvantage of a limited life span and drift of phenotype as experimental limitations (page 1709). Owing to their unique phenotypic stability, BOECs have emerged as a powerful tool for monitoring pathophysiological changes in patients with vascular abnormalities. BOECs have been successfully used to survey for possible genetic differences in endothelial gene expression (page 1709). Owing to their angiogenic potential, BOECs (termed ECFCs in many studies) are excellent candidates for cell therapy in vascular regeneration. It has been shown that ECFCs manifest the ability to form de novo vessels in vivo, as opposed to the so-called EPCs of hematopoietic origin, which do not have this property (page 1710).
Ecklu-Mensah disclose that blood outgrowth endothelial cells (BOECs) offer a convenient means to study endothelium of clinically relevant populations (page 2). Ecklu-Mensah disclose that these BOECs are seeded onto micro surfaces pre-coated with collagen type I and grown to confluences for greater than 48 hours (a period of at least 18 hours) and then RPMI growth medium is flowed over the cells at microvascular wall shear stress 1 dyn/cm2 (pages 3-4).
One of ordinary skill in the art would have been motivated to select BOECs (blood-derived endothelial cells) for the type of endothelial cell seeded on a collagen coated surface and used to coat the microchannels of Jain because Martin-Ramirez and Ecklu-Mensah teach and suggest that this is a beneficial and advantageous type of endothelial cell to use and on collagen when looking to recreate and represent the in vivo vascular environment. One of ordinary skill in the art would have been motivated to use the pump for at least 18 hours to perfuse the BOECs and the growth media through the microfluidic channel because Ecklu-Mensah disclose that these BOECs are seeded onto micro surfaces pre-coated with collagen type I with RPMI growth medium and grown for greater than 48 hours with growth media flowed at microvascular wall shear stress 1 dyn/cm2 (pages 3-4). One of ordinary skill in the art would have had a reasonable expectation of success because Jain teach and suggest that a microfluidic device containing a plurality of parallel microchannels that mimic blood vessels and permit real-time analysis of clotting dynamics will retain a laminar flow (page 13 para 39).
Jain do not specifically describe wherein the plurality of endothelial cells are aligned with a flow axis of the microfluidic channel. However, they do indicate that it is desirable to provide a constant (continuous) flow of fluid into the microfluidic channels and that this flow can be induced in the channel through the use of a pump (page 32 para 80, page 35 para 86).
Applicant’s disclosure indicates that the majority of BOECs will align with a flow axis in the microfluidic channel when culture medium is flowed continuously through the microchannel (Specification page 16 para 68, page 20 para 81).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to apply a continuous flow of culture medium to the microchannels of the microfluidic device of Jain because Jain teach and suggest that a constant flow is desirable and beneficial. This process would have inherently provided wherein the cells lining the microchannel (BOECs) would then align with a flow axis in the microfluidic channel as evidenced by Applicant’s disclosure (Specification page16 para 68, page 20 para 81).
Jain teach and suggest that a microfluidic device containing a plurality of parallel microchannels that mimic blood vessels and permit real-time analysis of clotting dynamics will retain a laminar flow (page 13 para 39).
This laminar flow through the microfluidic channels would then inherently produce the alignment of the endothelial cells within 30 degrees of the flow axis of the microfluidic channel as evidenced by the fact that this is the type of flow that Applicant uses in their device to create the alignment of BOECs in the microchannel (Specification page 16 para 68, page 20 para 81).
Regarding claims 1, 2, 22, 27, Jain teach that it is suitable and beneficial to include a pump configured to withdraw blood from a patient from a fluid conduit connected to a fluid inlet of the channel and perfused through the channel to the outlet (page 32 para 78, page 39 para 100).
Regarding claims 1, 4, 22, 25, 27 and 31, Jain teach that it is suitable and beneficial to include a computer system configured to provide a readout comprising information associated with the function of the device and thus associated with the endothelial cells lining the channels of the device as well (pages 33-34 para 83-84). The computer system includes a controller including one or more processors for communicating information and a main memory and/or other dynamic storage device for storing information and instructions to be executed by the processor and further integrated with a pump operation and sensory data collection (page 33 para 83).
Regarding claims 5, 26 and 32, Jain teach that it is suitable and beneficial to include microchannel diameters that mimic the diameter of blood vessels (page 13 para 39) and include a maximal hydraulic diameter between about 25 µm- 5mm (page 42 claim 5).
One of ordinary skill in the art would have been motivated to include microchannels that mimic the diameter of blood vessels and include a maximal hydraulic diameter between about 25 µm- 5mm in the microfluidic system because Jain teach that it is suitable and beneficial to include microchannel diameters that mimic the diameter of blood vessels (page 13 para 39) and include a maximal hydraulic diameter between about 25 µm- 5mm (page 42 claim 5). This diameter range disclosed by Jain overlaps and thus renders obvious Applicant’s claimed range. One of ordinary skill in the art would have had a reasonable expectation of success because Jain are seeding microfluidic channels with endothelial cells from a patient.
Regarding claim 27, Jain teach and suggest that a shear rate of a microfluidic device containing endothelial cells is properly within the range of 75-2500 sec-1 (page 17 para 48 and page 18 para 50) which overlaps with the range of a shear rate that is less than 100 inverse seconds) and thus renders the claimed range obvious.
In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists. In re Wertheim (MPEP 2144.05).
Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use a shear rate of 75-100 inverse seconds in the microfluidic device of Jain because Jain teach and suggest that this is a suitable and beneficial feature of a microfluidic device system designed to enhance and assess patient or subject care.
Therefore, the combined teachings of the patent claims, Jain et al, Martin-Ramirez et al and Ecklu-Mensah et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant’s amendment to the claims has overcome the previous rejection under 35 USC 103 and therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Jain in view of Martin-Ramirez and Ecklu-Mensah as described above.
Applicant argues that the teaching of Jain does not remedy the deficiencies of Vulto to render obvious the claimed invention. This is not found persuasive because the current rejection does not rely on the Vulto reference.
Applicant requests that the provisional double patenting rejections be held in abeyance until claims are allowed.
This request cannot be granted at this time. The “provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in one of the applications. See MPEP 822.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Srigunapalan et al., “A microfluidic membrane device to mimic critical components of the vascular microenvironment”, Biomicrofluidics, 2011, Vol. 5, pp. 013409-1 013409-9 , pages 1-9.
(Discloses effects on endothelial function in a device.)
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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, James (Doug) Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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