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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/10/2026 has been entered.
Applicant’s claims filed on 6/10/2026 in response to the Final Rejection mailed on 3/19/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1-11 are pending and examined on the merits.
Applicant’s remarks filed on 6/10/2026 in response to the Final Rejection mailed on 3/19/2026 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 4/22/2024) {herein Hall} in view of Tabarzad et al (2018, JABFM, Examiner Cited) {herein Tabarzab} as evidenced by Wang et al (2011, Biomaterials, cited on PTO-892 dated 9/24/2025) {herein Wang} is maintained. The rejection has been modified to address Applicant’s Remarks regarding the % yield of FVIII.
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 Fe3O4@ SiO2 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). Fe3O4@ SiO2 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 Fe3O4@ SiO2 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 Fe3O4@ SiO2 nanoparticles are used for the binding and high-yield 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 Fe3O4@ SiO2 nanoparticles are one of the more useful particulate systems in analytical application and said Fe3O4@ SiO2 nanoparticles successfully immobilized FVIII with no significant particle aggregation (abstract). As such, it would be obvious for Hall to the substitute the agarose beads with anion exchange ligands for the Fe3O4@ SiO2 nanoparticles taught by Tabarzab as Tabarzab teaches after binding, less than 10% mass of the coated protein was release the Fe3O4@ SiO2 nanoparticles after 72 h incubation (page 166, column 2, para 1). As such, it would be obvious to one of ordinary skill in the art that substituting the agarose beads that have anion exchange ligands attached, taught by Hall, with Fe3O4@ SiO2 nanoparticles, taught by Tabarzad, would yield predicable results of a high elution yield. Especially since Tabarzad teaches the release of less than 10% mFVIII from Fe3O4@ SiO2 nanoparticles, which equates to ~90% retention of FVIII (page 166, column 2, para 1). Supporting the Examiner’s position is MPEP 2143.I.B which states “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” Therefore, one of ordinary skill in the art knowing the benefit of purified FVIII based on the teachings of Hall and Tabarzad would have a reasonable expectation of success that purifying FVIII utilizing Fe3O4@ SiO2 nanoparticles would result in a high yield of FVIII, such as a yield between 92% - 100%, as recited in the instant application claim 1. Furthermore, Tabarzad 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, therefore provided additional motivation for Hall to the substitute the agarose beads with anion exchange ligands for the Fe3O4@ SiO2 nanoparticles taught by Tabarzab. In addition it would be obvious to one of ordinary skill in the art that said substitution would increase the yield of FVIII, 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). In addition, utilizing FVIII coated Fe3O4@ SiO2 nanoparticles 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 Fe3O4@ SiO2 nanoparticles 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 one of ordinary skill in the art would not have had any reason to believe that the high binding affinity of FVIII disclosed in Tabarzad could in any way be predictive of high elution yields should the methods of Tabarzad be combined with those described in Hall. Applicant contends One of ordinary skill in the art would actually expect that FVIII bound to MNPs, as taught in Tabarzad, would be difficult to elute (i.e., would have a low elution yield) given the inverse relationship between binding affinity and elution yields.
The argument is not persuasive. Examiner contends that the low elution taught by Tabarzad is in the absence of elution buffer. Tabarzad’s teaching of ‘FVIII release from FVIII-coated MNPs was less than 10% mass of coated protein after 72 h incubation’ (page 166, column 2, para 1) is in the presence of binding buffer. As such, the ‘binding’ taught by Tabarzad is not indicative of FVIII being ‘difficult’ to elute from the MNPs.
Applicant contends that Rather than provide any scientific or factual evidence to support the present rejections, it is clear that the Examiner instead is relying on hindsight cleaned from Applicant's disclosure to support the alleged motivation to combine Hall and Tabarzad. Applicant contends that nothing in either reference would provide one of ordinary skill in the art with (1) any reason to make the proposed combination or (2) a reasonable expectation of success in such a combination. The rejections are entirely based on hindsight.
The argument is not persuasive. Examiner contends that Tazarzeb provides the motivation for Hall to utilize FVIII coated Fe3O4@ SiO2 nanoparticles for the purification of FVIII as said Fe3O4@ SiO2 nanoparticles are one of the more useful particulate systems in analytical application and said Fe3O4@ SiO2 nanoparticles successfully immobilized FVIII with no significant particle aggregation (abstract). As such, it would be obvious for Hall to the substitute the agarose beads with anion exchange ligands for the Fe3O4@ SiO2 nanoparticles taught by Tabarzab as Tabarzab teaches after binding, less than 10% mass of the coated protein was release the Fe3O4@ SiO2 nanoparticles after 72 h incubation (page 166, column 2, para 1). As such, it would be obvious to one of ordinary skill in the art that substituting the agarose beads that have anion exchange ligands attached, taught by Hall, with Fe3O4@ SiO2 nanoparticles, taught by Tabarzad, would yield predicable results of a high elution yield. Especially since Tabarzad teaches the release of less than 10% mFVIII from Fe3O4@ SiO2 nanoparticles, which equates to ~90% retention of FVIII (page 166, column 2, para 1). Furthermore, Tabarzad 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, therefore providing scientific evidence and motivation for Hall to the substitute the agarose beads with anion exchange ligands for the Fe3O4@ SiO2 nanoparticles taught by Tabarzab.
Conclusion
Claims 1-11 are pending and examined on the merits.
Claims 1-11 are rejected.
No claims are in condition for allowance.
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.
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/ERICA NICOLE JONES-FOSTER/ Examiner, Art Unit 1656
/MANJUNATH N RAO/ Supervisory Patent Examiner, Art Unit 1656 (nr)
