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 .
Priority
This application is a CON of 17/112,661 12/04/2020 PAT 12030918
17/112,661 has PRO 62/944,399 12/06/2019
Information Disclosure Statement
The information disclosure statements submitted on 02/17/2019, 03/30/2020 and 05/21/2020 have been considered by the examiner.
Claim Status
Claims 1-19 are being examined on the merits in this office action
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.
Claims 1-3, 5-20 are rejected under 35 U.S.C. 103 as being unpatentable over Vardar et al. (Acta Biomaterialia 67 (2018) 156–166) in view of Ishihara et al. (J. Chromatogr. B 995–996 (2015) 107–114) and Oakey et al. (US20070131622A1 – hereinafter “Oakey”).
Vardar teaches a method of producing fibrin microbeads (a type of particle), comprising loading into a microfluidic device a solution containing thrombin, fibrinogen, and a buffer (Section 2.2, on Page 157, right col.), that the mixture is further contacted with oil and a surfactant and teaches room temperature which is about 22 degrees (Section 2.2, on Page 158, left col., 1st paragraph; also see Fig. 1 reproduced below). Vardar teaches that the buffer comprises a thrombin inhibitor α2PI1-8 (Page 157, right col., last paragraph; Page 162, right col., 2nd paragraph).
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Vardar teaches that the fibrin micro-beads were obtained using a droplet microfluidics system as shown in Fig. 1 above, and that syringe pumps were used to adjust the flow rate (Section 2.2, on Page 157, right col.). Examiner notes that the teaching is equivalent to applying positive pressure to cause the flow of the fibrinogen droplets which were mixed with homogenized collagen, having different crosslinking degrees (Page 164, right col., last paragraph). Additionally, Vardar teaches the addition of FXIIIa, which is a known crosslink fibrinogen. Examiner notes that the teaching reads on gelling and crosslinking.
Vardar does not teach that the buffer comprises amino acids.
Ishihara teaches the use of buffers that comprise amino acids such as histidine and that improved clearance of impurity, high molecular weight species (HMW) and host cell proteins (HCP) was observed in the purification processes when using the amino acids as base-buffer constituents, additives or eluents compared with that of buffers without these amino acids (Abstract). Ishihara further teaches the addition of other amino acids such as glycine and glutamate, arginine (Abstract; Page 108, left col., 2nd paragraph).
Additionally, Oakey teaches a microfluidic flow device provides for separating a particle within a suspension flow in a microfluidic flow chamber, chamber includes a microfluidic channel comprising at least one inlet port for receiving a suspension flow under laminar conditions, a first outlet port and a second outlet port. The chamber further includes an interface for translating a particle within the channel. The first outlet port receives a first portion of the suspension exiting the said channel and the second outlet port receives the particle in a second portion of the suspension exiting the channel (Abstract). Oakley teaches Fig. 7 b, wherein the flow rate of the third inlet port 166 is less than the flow rate of the second inlet port 164 [0067]. Oakley teaches a means for connecting the pump or pressure differential means may also be provided [0057, 0083].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Vardar and use the buffer taught by Ishihara for improved clearance of impurity. It would have been obvious to adjust the flow rate of the different ports so as to prefocuses the inlet particle stream [0067]. One of ordinary skill in the art would have had a reasonable expectation of success in using a buffer as the one taught by Ishahara for enhanced impurity clearance. The disclosures render obvious claims 1, 13, and 20.
Regarding claim 2 and 17, Oakley teaches Fig. 7 b, wherein the flow rate of the third inlet port 166 is less than the flow rate of the second inlet port 164 [0067]. It would have been obvious to adjust the flow rate of the different ports to prefocuses the inlet particle stream [0067].
Regarding claim 3, 5, Vardar teaches that the buffer comprises a thrombin inhibitor α2PI1-8 (Page 157, right col., last paragraph; Page 162, right col., 2nd paragraph). Additionally, Ishihara teaches the use of buffers that comprise amino acids such as histidine and that improved clearance of impurity, high molecular weight species (HMW) and host cell proteins (HCP) was observed in the purification processes when using the amino acids as base-buffer constituents, additives or eluents compared with that of buffers without these amino acids (Abstract). Ishihara further teaches the addition of other amino acids such as glycine and glutamate, arginine (Abstract; Page 108, left col., 2nd paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Vardar and use the buffer taught by Ishihara for improved clearance of impurity.
Regarding claims 6-9, 14-16, and 18-19 Vardar teaches 200 U/mL of human thrombin, 10 mM of buffer, and 40 mg/mL of human fibrinogen (Section 2.2, on Page 157, right col.). Additionally, Ishihara teaches that the concentrations of amino acid in the buffer is 80mM glutamate and 20mM histidine (Table 1).
Regarding claim 10, Vardar teaches average diameter of the fibrin micro-beads was around 140 ± 11 μm (Abstract; page 159, right col., section 3.1).
Regarding claims 11-12, Vardar teaches about 6%fibrin (section 3.4 on Page 161).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Vardar et al. (Acta Biomaterialia 67 (2018) 156–166), Ishihara et al. (J. Chromatogr. B 995–996 (2015) 107–114) and Oakey et al. (US20070131622A1 – hereinafter “Oakey”) as applied to claim 1 above, and further in view of Carey et al. (Circ Cardiovasc Interv. 2011; 4: 171-179).
The teachings of Vardar, Ishihara and Oakey are disclosed above and incorporated herein by reference.
Vardar teaches that the buffer comprises a thrombin inhibitor α2PI1-8 (Page 157, right col., last paragraph; Page 162, right col., 2nd paragraph) but does not teach that the inhibitor is Bivalirudin as recited in claim 4.
However, bivalirudin is a known thrombin inhibitor as taught by Carey. Carey teaches that bivalirudin is a synthetic, direct thrombin inhibitor (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Vardar and use the thrombin inhibitor such as bivalirudin as taught by Carey since Bivalirudin effectively suppresses thrombin-dependent platelet activation (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in using other thrombin inhibitors such as bivalirudin since it is an effective thrombin inhibitor. The disclosures render obvious claim 4.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. US12030918B2 in view of Vardar et al. (Acta Biomaterialia 67 (2018) 156–166).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the patent recite A method of forming fibrin particles, comprising: (a) introducing a buffer, a fibrinogen solution, and a thrombin solution to a first end of a microfluidic device to form a mixture, the buffer comprising amino acids, the amino acids comprising: a first amino acid having a side chain group that is positively charged at a pH of 7; and a second amino acid having a side chain group that is negatively charged at a pH of 7;
(b) contacting the mixture with a fluorocarbon oil and a surfactant to form fibrinogen-containing particles; (c) applying positive pressure to the microfluidic device to cause the fibrinogen-containing particles to flow towards a second end of the microfluidic device;
performing (a), (b), and (c) at a temperature that is from about 15° C. to about 25° C.;
collecting the fibrinogen-containing particles from the second end of the microfluidic device; and polymerizing the fibrinogen-containing particles to form fibrin particles after the fibrinogen-containing particles are collected from the microfluidic device (claim 1).
The instant claims recite a method of forming fibrin particles, comprising: (a) introducing a buffer, a fibrinogen solution, and a thrombin solution to a first end of a microfluidic device to form a mixture, the buffer comprising: a first amino acid having a side chain group that is positively charged at a pH of 7; and a second amino acid having a side chain group that is negatively charged at a pH of 7; (b) contacting the mixture with a fluorocarbon oil and a surfactant to form fibrinogen-containing droplets; (c) applying positive pressure to the microfluidic device to cause the fibrinogen-containing droplets to flow towards a second end of the microfluidic device, wherein (a), (b), and (c) are performed at a temperature that is from about 15°C to about 25°C; collecting the fibrinogen-containing droplets from the second end of the microfluidic device; and gelling or crosslinking the fibrinogen of the fibrinogen-containing droplets to form fibrin particles after the fibrinogen-containing droplets are collected from the microfluidic device (claim 1).
The claims of the patent do not explicitly recite gelling or crosslinking.
However, this process is known to be done in fibrin particles as taught by Vardar et al.
Vardar teaches a method of producing fibrin microbeads (a type of particle), comprising loading into a microfluidic device a solution containing thrombin, fibrinogen, and a buffer (Section 2.2, on Page 157, right col.), that the mixture is further contacted with oil and a surfactant and teaches room temperature which is about 22 degrees (Section 2.2, on Page 158, left col., 1st paragraph; also see Fig. 1 reproduced below). Vardar teaches that the buffer comprises a thrombin inhibitor α2PI1-8 (Page 157, right col., last paragraph; Page 162, right col., 2nd paragraph).
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Vardar teaches that the fibrin micro-beads were obtained using a droplet microfluidics system as shown in Fig. 1 above, and that syringe pumps were used to adjust the flow rate (Section 2.2, on Page 157, right col.). Examiner notes that the teaching is equivalent to applying positive pressure to cause the flow of the fibrinogen droplets which were mixed with homogenized collagen, having different crosslinking degrees (Page 164, right col., last paragraph). Additionally, Vardar teaches the addition of FXIIIa, which is a known crosslink fibrinogen. Examiner notes that the teaching reads on gelling and crosslinking.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent to include the step of crosslinking so as to stabilize the fibrin. One of ordinary skill in the art would have had a reasonable expectation of success in including the step of crosslinking so as to stabilize the fibrin. The claims of the patent render obvious claims 1 and 20.
Regarding claim 2, the claims of the patent recite adjusting a flow rate of the buffer, a flow rate of the fibrinogen solution, a flow rate of the thrombin solution, or a combination thereof; adjusting a flow rate of the fluorocarbon oil and surfactant; or reducing the flow rate of the buffer while increasing the flow rate of the fibrinogen solution, the flow rate of the thrombin solution, or both (claim 2).
Regarding claim 3, the claims of the patent recite wherein: the first amino acid comprises arginine, lysine, histidine, or combinations thereof; the second amino acid comprises aspartic acid, glutamic acid, or combinations thereof; the fibrinogen solution, the buffer, or both, comprise an inhibitor, the inhibitor comprising a fibrinogen polymerization inhibitor, a thrombin inhibitor, or combinations thereof; or a combination thereof (claim 3).
Regarding claim 4, the claims of the patent recite wherein the inhibitor comprises bivalirudin (claim 4).
Regarding claim 5, 15, the claims of the patent recite wherein: the first amino acid comprises arginine, lysine, histidine, or combinations thereof; and the second amino acid comprises aspartic acid, glutamic acid, or combinations thereof (claim 5, 15, 19).
Regarding claim 6, the claims of the patent recite wherein: a concentration of the first and second amino acids in the buffer is from about 10 mM to about 100 mM; a concentration of thrombin in the thrombin solution is from about 0.5 IU/mL to about 2 IU/mL; or a combination thereof (claim 6).
Regarding claim 7, the claims of the patent recite wherein an amount of fibrinogen in the fibrinogen solution is 5% w/v or more (claim 7).
Regarding claim 8, the claims of the patent recite wherein: the amount of fibrinogen in the fibrinogen solution is from about 5% w/v to about 20% w/v; and a concentration of the first and second amino acids in the buffer is from about 25 mM to about 100 mM (claim 8).
Regarding claim 9, the claims of the patent recite wherein: concentration of the first and second amino acids in the buffer is from about 25 mM to about 75 mM; the first amino acid comprises arginine; and the second amino acid comprises glutamic acid (claim).
Regarding claim 10, the claims of the patent recite wherein median diameter of the fibrinogen-containing particles is from about 15 μm to about 125 μm (claim 10).
Regarding claim 11, the claims of the patent recite wherein the microfluidic device is substantially free of fibrin (claim 11).
Regarding claim 12, the claims of the patent recite wherein an amount of fibrin in the fibrin particles is greater than about 1% w/v (claim 12).
Regarding claim 13, the claims of the patent recite (a) co-flowing a buffer, a fibrinogen solution, and a thrombin solution into an introduction area of a fluidic channel to form an aqueous phase, the fluidic channel further comprising a contacting area and a mixing area, the contacting area disposed between the introduction area and mixing area, wherein: the buffer comprises amino acids, the amino acids comprising: a first amino acid having a side chain group that is positively charged at a pH of 7; and a second amino acid having a side chain group that is negatively charged at a pH of 7; and the fibrinogen solution, the buffer, or both, comprise an inhibitor, the inhibitor comprising a fibrinogen polymerization inhibitor, a thrombin inhibitor, or combinations thereof; (b) causing the aqueous phase to flow from the introduction area of the fluidic channel to the contacting area of the fluidic channel; contacting area in a location between the introduction area and mixing area; (c) contacting the aqueous phase with an oil phase comprising a fluorocarbon oil and a surfactant at the contacting area to form a dispersion of the aqueous phase in the oil phase, the dispersion comprising fibrinogen-containing particles; performing (a), (b), and (c) at a temperature that is from about 15° C. to about 25° C.; causing the dispersion to flow from the contacting area to the mixing area and to a fluidic channel exit; collecting the dispersion comprising the fibrinogen-containing particles from the fluidic channel exit; and heating the dispersion comprising the fibrinogen-containing particles under conditions effective to form fibrin particles after the fibrinogen-containing particles exit the fluidic channel (claim 13).
Regarding claim 14, the claims of the patent recite wherein an amount of fibrinogen in the fibrinogen solution is from about 2% w/v to about 25% w/v (claim 17).
Regarding claim 16, the claims of the patent recite wherein: a concentration of the first and second amino acids in the buffer is from about 25 mM to about 100 mM (claim 16).
Regarding claim 17, the claims of the patent recite further comprising: adjusting a flow rate of the buffer, a flow rate of the fibrinogen solution, a flow rate of the thrombin solution, or a combination thereof to flow rates of the buffer, the fibrinogen solution, and the thrombin solution, or a combination thereof that deviate from one another by less than about 10%; adjusting a flow rate of the fluorocarbon oil and surfactant; or reducing the flow rate of the buffer while increasing the flow rate of the fibrinogen solution, the flow rate of the thrombin solution, or both (claim 14).
Regarding claim 18, the claims of the patent recite a concentration of thrombin in the thrombin solution is from about 0.5 IU/mL to about 2 IU/mL (claim 16).
Regarding claim 19, the claims of the patent recite wherein an amount of fibrinogen in the fibrinogen solution is from about 2% w/v to about 25% w/v (claim 18).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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