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 .
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Claims 1-11 are pending and examined on the merits.
Applicant’s remarks filed on 12/22/2025 in response to the Non-Final Rejection mailed on 9/24/2025 have been fully considered and are not deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Maintained Claim Rejections - 35 USC § 103
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 rejection of claims 1-11 under 35 U.S.C. 103 as being unpatentable Hall et al (2016, WO 2016/162308 A1, International Publication Date: 13 October 2016, cited on PTO-892 filed 9/25/2024) {herein Hall} in view of Tabarzad et al (2018, JABFM, Examiner Cited) {herein Tabarzab} as evidenced by Wang et al (2011, Biomaterials, Examiner cited) {herein Wang} is maintained.
Previously presented claims 1-11 are drawn to a method for purification of plasma protein(s) from a crude sample, comprising binding of desired plasma protein(s) to ligands on magnetic beads and eluting said plasma protein(s), wherein the binding and eluting is performed in batch mode, and wherein elution (i) yields 92-100% Factor VIII (FVIII) from a cryoprecipitate and/or (ii) at least 85% Factor IX (FIX) and a ratio of active Factor IX (FIXa) to FIX of less than 1 % from a cryosupernatant.
With respect to claims 1-6, 10, Hall teaches a method wherein Factor VIII is purified from a cryoprecipitate of plasma using a matrix comprising an inner porous core and outer porous lid surrounding said core (page 3, lines 3-6), which are referred to as agarose beads (page 6, lines 21) with anion exchange ligands attached (page 4, lines 28-29; page 6, lines 20). Examiner is interpreting the cryoprecipitate of plasma taught by Hall to be a crude sample taken directly, without further purification besides settlement of the cells, as Hall does not teach any purification of the sample before column chromatography. Hall further teaches a method comprising a step of adsorbing FVlll/vWF on said anion exchange ligands (page 4, lines 28-29). The anion exchange ligands are preferably selected from diethylaminoethyl (DEAE), quaternary aminoethyl (QAE) or quaternary ammonium (Q), most preferably the anion exchange ligands are Q-ligands (page 4, lines 34-36). Since said ligands bind FVIII, Examiner is interpreting that it would be obvious to one of ordinary skill in that art that said ligands would necessarily have affinity for the light chain of FVIII since said ligands bind FVIII. In addition, Hall teaches a method wherein large proteins (eg FVlll/vWF) can be separated from smaller plasma proteins (HSA, lgG, FIX) (page 4, lines 11-13). Examiner is interpreting IgG and FIX to be ‘desired proteins’ as they can be separated from the larger proteins FVIII/vWF.
With respect to claim 8, Hall teaches the sample was dissolved cryoprecipitate from human plasma (page 8, lines 21).
With respect to claim 9, Hall teaches porous agarose beads for the purification of FVIII (claims 10 and page 5, lines 7-15).
However, Hall does not teach the method of claim 1, wherein desired plasma protein(s) to ligands on magnetic beads and wherein elution (i) yields 92-100% Factor VIII (FVIII) from a cryoprecipitate and/or (ii) at least 85% Factor IX (FIX) and a ratio of active Factor IX (FIXa) to FIX of less than 1 % from a cryosupernatant (claim 1). The method of claim 7 the sample being taken from cell culture of recombinant plasma proteins (claim 7). The method of claim 8, of a) adding a plasma protein fraction, such as a cryosupernatant or dissolved cryoprecipitate comprising at least one plasma protein, to a container or bag; b) adding magnetic beads provided with anion ligands by pouring or pumping said beads into said container or bag; c) incubating preferably at least 30 minutes with mixing; d) binding plasma protein(s) to ligands on the magnetic beads; and e) retaining the magnetic beads with a magnetic field and washing away undesired material from the magnetic beads (claim 8). The method of claim 9, wherein the bead is embedded magnetic particles (claim 9). The method of claim 11, wherein the magnetic beads are 8-300 um in diameter (claim 11).
With respect to claim 1, Tabarzad teaches a method wherein magnetic nanoparticles are used for the binding and purification of FVIII (abstract). It is known by those of ordinary skill in the art that magnetic nanoparticles are the same as magnetic beads as they have the same structure and function. The nanoparticles were silica coated and magnetized (page 162, column 2, para 3).
With respect to claim 7, Tabarzad teaches FVIII is a valuable therapeutic protein that has been
purified from plasma or recombinant sources by different chromatography processes, especially affinity chromatography (page 167, column 2, para 1).
With respect to claim 8, Tabarzad teaches a method wherein lyophilized FVIII is reconstituted in a vial (page 162, column 2, para 4). Magnetic nanoparticles are added to the vial and incubated, with mixing, for 2 hours (page 163, column 1, para 1). Magnetic separation was applied to separate the unbound FVIII from the bound FVIII (page 163, column 1, para 1). Unbound FVIII was washed using PBS (page 163, column 1, para 1).
With respect to claim 9, Tabarzad teaches magnetic nanoparticles comprised of agarose (page 162, column 1, para 2). Tabarzad further teaches functionalized FVIII coated Fe3O4@ SiO2 nanoparticles, of which Examiner is interpreting as silica coated nanoparticles embedded with magnetic particles Fe3O4 (page 162, column 2, para 3).
With respect to claim 11, Tabarzab teaches functionalized Fe3O4@ SiO2 nanoparticles for the purification of FVIII (abstract). Evidentiary reference of Wang is cited to demonstrate that Fe3O4@ SiO2 nanoparticles have a diameter of 200 ± 4 µm (abstract). As such. Examiner is interpreting the recited 8 – 300 µm to be inherent to the Fe3O4@ SiO2 nanoparticles taught by Tabarzab.
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Hall et by of a method, wherein Factor VIII is purified from a cryoprecipitate of plasma using a matrix comprising an inner porous core and outer porous lid surrounding said core (page 3, lines 3-6), which are referred to as agarose beads (page 6, lines 21) or combine the teachings of Tabarzab because Tazarzab teaches a method wherein magnetic nanoparticles are used for the binding and purification of FVIII (abstract).
One of ordinary skill in the art would be motivated to either use the teachings of Hall et al. by itself or combine the teachings of Tazarzeb because Tazarzeb provides the motivation for Hall to utilize FVIII coated Fe3O4@ SiO2 nanoparticles for the purification of FVIII as said magnetic particle are one of the more useful particulate systems in analytical application and said magnetic particles successfully immobilized FVIII with no significant particle aggregation (abstract). One of ordinary skill in the art knowing the benefit of purified FVIII based on the teachings of Hall and Tazareb would have a reasonable expectation of success that purifying FVIII utilizing FVIII coated Fe3O4@ SiO2 nanoparticles would result in a yield between 92% - 100%. Especially since Tazareb teaches Fe3O4@ SiO2 nanoparticles with added functional groups for FVIII result in maintenance of protein activity after attachment (page 162, column 1, para 2), which is useful if purified FVIII is utilized in studies requiring functional FVIII. As such, it would be obvious to one of ordinary skill in the art that Hall would increase the yield of FVIII if utilizing FVIII coated Fe3O4@ SiO2 nanoparticles as said nanoparticles have a binding efficiency at a mass ratio of 0.5% (w/w) FVIII to magnetic nanoparticles (page 164, column 2, para 3). Furthermore, Tabarzad teaches FVIII release from FVIII-coated MNPs was less than 10% mass of coated protein after 72 h incubation (page 166, column 2, para 1), which is an indication of the binding efficiency of the FVIII coated Fe3O4@ SiO2 to FVIII sample. In addition, utilizing FVIII coated Fe3O4@ SiO2 for the purification of FVIII is more time efficient that traditional methods such as column chromatography as said method would specifically bind FVIII in a sample, thereby resulting in a high yield of protein with high purity.
One of skill in the art would have a reasonable expectation of success to make and use the claimed magnetic beads for the purification of FVIII because Hall provides the basic method of purifying FVIII from a crude sample and its uses and methods of making it. Reference of Tabarzab provides the teachings for making and using FVIII coated Fe3O4@ SiO2 nanoparticles for the purification of FVIII and the molecular tools needs for making such a magnetic nanoparticle. Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding the limitation in claim 1 ‘wherein elution (i) yields 92-100% Factor VIII (FVIII) from a cryoprecipitate and/or (ii) at least 85% Factor IX (FIX) and a ratio of active Factor IX (FIXa) to FIX of less than 1 % from a cryosupernatant,’ this language does not require steps to be performed or limit the claim to a particular structure and does not limit the scope of the claim. See MPEP 2106.C and 2111.04. Instead, the “wherein” clause merely recites a correlation between the magnetic beads and its usefulness in purifying FVIII. It would be obvious to one of ordinary skill in the art that Hall utilizing the FVIII coated Fe3O4@ SiO2 nanoparticles taught by Tazareb for the purification of FVIII would yield between 92% - 100% FVIII as Tazareb teaches said magnetic particles immobilize FVIII with no significant particle aggregation. In addition, Tazareb teaches FVIII release from FVIII-coated MNPs was less than 10% mass of coated protein after 72 h incubation (page 167, column 2, para 1), which would result in a high yield of protein and high purity of said protein.
Response to Remarks: Beginning on page 4 of Applicant’s remarks, Applicant contends that the proposed combination of Hall and Tabarzad does not disclose or suggest elution yielding (i) 92-100%o FVIII and/or (i) at least 85%o FIX and a ratio of FIXz to FIX of less than l1%.
This argument is found to be not persuasive. Examiner contends that Applicant has not provided sufficient evidence that the magnetic nanoparticles taught by Tabarzad would not necessarily result in elution (i) yields 92-100% Factor VIII (FVIII) from a cryoprecipitate as recited in the instant application claim 1. Especially since Hall in view of Tabarzad teaches the structure Nanoparticles aggregated extensively at high protein concentration (FVIII) (page 164, column 2, para 3). Applicant contends that Tabarzad is silent regarding elution yields of FVIII. Applicant contends one of ordinary skill in the art would recognize that binding efficiency is not the same as an elution yield. Applicant contends the Office Action fails to articulate how the increased binding efficiency of Tabarzad translates to improved FVIII elution during a purification process.
This argument is found to be not persuasive. Examiner contends that based on Applicants own admission, Tabarzad teaches that FVIII release from FVIII-coated nanoparticles was less than 10%, which indicates that FVIII has a 90% or greater binding efficiency. Additionally, it is well-known in the art and by those of ordinary skill in the art that a higher amount of bound protein ("load") often results in a higher concentration of eluted protein ("eluate"). Furthermore, Tabarzad teaches investigations focusing on selection of processes for the binding and purification of protein (FVIII) utilizing MNP’s (page 167, column 2, para 1). Absent evidence otherwise, it is the Examiner’s position that the teaching of ‘purification’ by Tabarzad is the same as ‘elution,’ in this context, as both result in the separation/purification of protein (FVIII). MPEP 2144.05 states"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05 IIA)." One of ordinary skill would desire to optimize the yield either by increasing the magnetic beads concentration or increase the elution profile etc. depending on the particular application. It would be routine for one to arrive at the magnetic beads concentration and elution profile for the application they intend on using the method. Therefore, the above invention would have been prima facie obvious.
Conclusion
Claims 1-11 are pending and examined on the merits.
Claims 1-11 are rejected.
No claims are in condition for allowance.
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 ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
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, Manjunath Rao can be reached at 571-272-0939. 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.
/ERICA NICOLE JONES-FOSTER/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656