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 .
Withdrawal of Rejections
The response and amendments filed on 11/24/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by Applicant’s amendments.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
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 1-7, 10, 15-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Bal (EP0549964; Date of Publication: July 7, 1993 – previously cited) in view of Brgles (Selectivity of monolithic supports under overloading conditions and their use for separation of human plasma and isolation of low abundance proteins; 2011 – cited in the IDS filed on 01/23/2023 – previously cited) and Branovic (Application of monoliths for downstream processing of clotting factor IX; 2000 – cited in the IDS filed on 01/23/2023 – newly cited).
Bal’s general disclosure relates to a method for producing virus-inactivated Prothrombin Complex Concentrate (PCC) and blood plasma fractions (see, e.g., Bal, English Translation, pg. 2). Moreover, Bal discloses anion exchange chromatography for obtaining fractions enriched in PCC, such as prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, “Description”, pg. 2). Additionally, Bal teaches the use of “so-called low-cryogenic plasma in the method” (see, e.g., Bal, English Translation, “Description”, pg. 2)
Regarding claim 1 pertaining to purification of PCC from plasma by means of chromatography, Bal teaches obtaining plasma and performing a first anion exchange chromatography step to obtain PCC (see, e.g., Bal, English Translation, claims page 1 & “Description” pg. 2). Bal does not teach a dilution process of the plasma; therefore, one of ordinary skill in the art would readily understand that the plasma is undiluted.
Regarding claim 2 pertaining to the anion exchanger, Bal teaches QAE modified dextran (see, e.g., Bal, English Translation, “Description”, pg. 2), which one of ordinary skill in the art would recognize is a strong anion exchanger.
Regarding claim 3 pertaining to the second chromatography step, Bal teaches obtaining the flow-through or elution product from the first chromatography step and performing a second chromatography step with DEAE-modified dextran to obtain a second fraction enriched in PCC (see, e.g., Bal, English Translation, claims page 1 & “Description” pg. 2).
Regarding claim 7 pertaining to the virus inactivation step, Bal teaches that the PCC is treated with detergents for virus inactivation (see, e.g., Bal, English Translation, “Description”, pg. 2).
Regarding claims 10 and 16 pertaining to the virus filtration step, Bal teaches that the virus filtration step is performed to the elution product from the first anion exchange chromatography step (see, e.g., Bal, English Translation, “Description”, pg. 2), which one of ordinary skill in the art would recognize is the first fraction.
Regarding claim 18 pertaining to the cryo-poor plasma, Bal teaches the use of low-cryogenic plasma (see, e.g., Bal, English Translation, “Description”, pg. 2). Moreover, Bal does not teach a dilution process of the low-cryogenic plasma; therefore, one of ordinary skill in the art would readily understand that the low-cryogenic plasma is undiluted.
Regarding claim 19 pertaining to components of the PCC, Bal teaches fractions enriched in PCC, such as prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, Abstract & “Description”, pg. 2).
However, Bal does not teach: a monolithic stationary phase (claim 1); or sample displacement chromatography (claim 1); or wherein the monolithic stationary phase with an anion exchanger is performed with an undiluted sample (claim 1); or a third chromatography step with a cation exchanger to obtain a fraction comprising enriched FIX, and in which other components of the PCC are depleted or removed (claim 4); or wherein the cation exchanger is -SO3 (claim 5); or wherein the anion exchanger of the second chromatography step is a bulk material or monolithic material (claim 6); or wherein the cation exchanger of the third chromatography step is a bulk material or a monolithic material (claim 15).
Brgles’ general disclosure relates to “the characterization of ion-exchange monolithic supports under overloading conditions was performed by use of sample displacement chromatography (SDC)” (see, e.g., Brgles, abstract). Moreover, Brgles discloses the use of monolithic material for anion and cation exchange chromatography because monolithic material has “good mechanical strength, high porosity and dynamic capacity for large molecules, high separation speed and high flow rates at a very low pressure drop enable rapid processing of large volumes of complex biological mixtures” and “their pH resistance makes possible cleaning and sanitation under harsh conditions such as high and low pH, and repeating use of monolithic support also for isolation and high-throughput analysis of proteins for therapeutic use” (see, e.g., Brgles, Introduction, pg. 2). Furthermore, Brgles discloses the use of these methods for obtaining low abundance proteins from plasma, such as plasminogen, clotting factor XII, and clotting factor IX (see, e.g., Brgles, Discussion, pg. 7).
Regarding claim 1 pertaining to the monolithic stationary phase and sample displacement chromatography, Brgles teaches the use of sample displacement chromatography for separation of human plasma (see, e.g., Brgles, abstract). Moreover, Brgles teaches that anion exchange chromatography was performed using DEAE and QA monoliths (see, e.g., Brgles, pg. 3, Section 2.2).
Regarding claim 4 pertaining to the cation exchanger, Brgles teaches the use of cation exchange chromatography for obtaining fractions from human plasma (see, e.g., Brgles, pg. 3, Section 2.2 & pg. 6, section 3.2). Moreover, Brgles teaches obtaining a fraction concentrated in factor IX (see, e.g., Brgles, Discussion, pg. 7).
Regarding claim 5 pertaining to the cation exchanger, Brgles teaches that the cation exchanger is -SO3 (see, e.g., Brgles, pg. 3, Section 2.2).
Regarding claim 6 pertaining to the anion exchanger, Brgles teaches that for anion-exchange chromatography monolithic, disk-shaped columns with DEAE and QA CIM monoliths were used (see, e.g., Brgles, pg. 3, Section 2.2).
Regarding claim 15 pertaining to the cation exchanger, Brgles teaches that “cation-exchange chromatography monolithic disk and cylinder-shaped columns” with SO3 were used (see, e.g., Brgles, pg. 3, Section 2.2).
Branovic’s general disclosure relates to “the application of monolithic columns for downstream processing of different clotting factor IX concentrates is shown. Determination of basic chromatographic conditions as well as investigations on the regeneration of disk- and tube-shaped monolithic columns using human serum albumin as a model protein, were performed. Separation of factor IX and vitronectin, a possible impurity in commercial factor IX concentrates was accomplished using disk-shaped monolithic columns” (see, e.g., Branovic, abstract).
Regarding claim 1 pertaining to the undiluted sample, Branovic teaches using “CIM disk monolithic columns bearing strong (quaternary amine – QA) and weak (diethylaminoethyl – DEAE) anion groups were used throughout the experimental work (BIA Separations, Ljubljana, Slovenia)” (see, e.g., Branovic, section 2.3, page 23). Furthermore, Branovic teaches that samples containing plasma proteins can be prepared and run through the monolithic anion exchange columns in order to separate proteins (see, e.g., Branovic, section 3, pg. 24). Moreover, Branovic does not teach that these samples need to be diluted before running them through the monolithic anion exchange columns; therefore, one of ordinary skill in the art would readily understand that samples do not need to be diluted in order to perform chromatography with monolithic anion exchange columns.
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform Bal’s method of purifying PCC by means of chromatography from plasma, wherein the method comprises the use of a monolithic stationary phase with anion exchangers, as taught by Brgles. One would have been motivated to do so because Brgles teaches that “monoliths made of polyglycidyl methacrylate polymers have been successfully used for separation of proteins from human plasma” (see, e.g., Brgles, Introduction, pg. 2). Additionally, Brgles teaches that monoliths have “good mechanical strength, high porosity and dynamic capacity for large molecules, high separation speed and high flow rates at a very low pressure drop enable rapid processing of large volumes of complex biological mixtures”, and “their pH resistance makes possible cleaning and sanitation under harsh conditions such as high and low pH, and repeating use of monolithic support also for isolation and high-throughput analysis of proteins for therapeutic use” (see, e.g., Brgles, Introduction, pg. 2). Moreover, Bal teaches the use of anion exchange chromatography columns with QAE-modified dextran and DEAE in order to obtain purified plasma enriched in prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, “Description”, pg. 2). Therefore, based on the teachings of Bal and Brgles, it would have been obvious to perform anion exchange chromatography using a monolithic stationary phase in order to purify PCC from plasma.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform Bal’s method of purifying PCC by means of chromatography from plasma, wherein the method comprises the use of sample displacement chromatography, as taught by Brgles. One would have been motivated to do so because Brgles teaches “When this chromatographic separation mode is applied, during loading, there is competition among the sample components for the binding sites of the hydrophobic surface of the stationary phase. The more molecules compete for these sites, the more components with lower affinity to the surface will be displaced and eluted from the column” (see, e.g., Brgles, Introduction, pg. 2). Moreover, Brgles teaches that sample displacement chromatography can be performed for purification of proteins in ion-exchange mode (see, e.g., Brgles, Introduction, pg. 2). Furthermore, Bal teaches the use of anion exchange chromatography columns with QAE-modified dextran and DEAE in order to obtain purified plasma enriched in prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, “Description”, pg. 2). Therefore, based on the teachings of Bal and Brgles, it would have been obvious to perform sample displacement chromatography in ion-exchange mode in order to purify PCC from plasma.
It would have been thirdly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform Bal’s method of purifying PCC by means of anion exchange chromatography from plasma, wherein the method comprises performing cation exchange chromatography, as taught by Brgles. One would have been motivated to do so because Brgles teaches that the cation-exchange chromatography monolithic disk and cylinder-shaped columns has strong anion exchanger ligands (see, e.g., Brgles, pg. 3, Section 2.2), which one of ordinary skill in the art would understand results in the binding and purification of positively charged amino acids and proteins. Moreover, Bal teaches the use of anion exchange chromatography columns with QAE-modified dextran and DEAE in order to obtain purified plasma enriched in prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, “Description”, pg. 2). Therefore, based on the teachings of Bal and Brgles, it would have been obvious to perform cation exchange chromatography on the second fraction enriched in PCC because this would allow for one to obtain a final plasma fraction enriched specifically in factor IX. One would have expected success because Bal and Brgles both teach chromatography methods for the purification of PCC from plasma samples.
It would have been fourthly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform Bal’s method of purifying PCC by means of anion exchange chromatography from a plasma sample, wherein the sample is ran using a monolithic stationary phase and is undiluted, as taught by Branovic. One would have been motivated to do so because Branovic teaches that proteins within plasma are at very low concentrations; therefore, isolating them from the impurities within samples is often difficult (see, e.g., Branovic, Introduction, pg. 22). Furthermore, Branovic teaches “Chromatography with compact, porous units such as monolithic columns is being used increasingly for analytical and preparative separations of biopolymers with apparent molecular masses (Mr) ranging from several thousand to up to several million” (see, e.g., Branovic, Introduction, pg. 22). Moreover, Bal teaches the use of anion exchange chromatography columns with QAE-modified dextran and DEAE in order to obtain purified plasma enriched in prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, “Description”, pg. 2). Therefore, based on the teachings of Bal and Branovic, it would have been obvious for one of ordinary skill in the art to separate proteins in an undiluted plasma sample using monolithic station phase chromatography with an anion exchanger since this will allow protein separation in samples that have very low concentrations of proteins. Furthermore, since there are very low concentrations of some plasma proteins (see, e.g., Branovic, Introduction, pg. 22), this is motivation for one of ordinary skill in the art to perform chromatography with undiluted plasma samples. One would have expected success because Bal and Branovic both teach anion exchange chromatography for separation and/or isolation of plasma proteins.
Claims 8-9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bal, Brgles, and Branovic as applied to claims 1-7, 10, 15-16, and 18-19 above, and further in view of Lim (US 2007/0297982; Date of Publication: December 27, 2007 – previously cited).
The teachings of Bal, Brgles, and Branovic herein referred to as modified-Bal-Brgles-Branovic, is discussed above as it pertains to purification of PCC from plasma.
However, modified-Bal-Brgles-Branovic does not teach: wherein a stabilizer is added to at least one of the first, second and third fractions (claim 8); or wherein the stabilizer is a positively charged amino acid (claim 9); or wherein the positively charged amino acid comprises lysine (claim 20).
Lim’s general disclosure relates to the purification of inter-alpha inhibitor proteins, which are plasma-associated serine protease inhibitors, from human plasma samples (see, e.g., Lim, [0003], [0006]). Moreover, Lim discloses that inter-alpha inhibitor proteins are present in side-fractions generated during the purification of factor IX (see, e.g., Lim, [0045]). Lim discloses the use of anion-exchange chromatography by monolithic support, for example, CIM with immobilized anion-exchange ligands such as DEAE-CIM or Q-CIM, for the purification of inter-alpha inhibitor proteins (see, e.g., Lim, [0073]). Additionally, Lim discloses the use of stabilizers during the purification or isolation steps in order to inactivate any viruses present (see, e.g., Lim, [0089]-[0090]).
Regarding claims 8-9 and 20 pertaining to the stabilizer, Lim teaches that stabilizers can be added to the blood plasma fractions, wherein the stabilizer can be lysine (see, e.g., Lim, [0090]). Moreover, Lim teaches that “stabilizers may be sufficient to inactivate any viruses present” (see, e.g., Lim, [0089]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform modified-Bal-Brgles-Branovic’s method of obtaining a purified PCC sample from human plasma by means of chromatography, wherein the samples (i.e., fractions) are treated with a stabilizer, as taught by Lim. One would have been motivated to do so because Lim teaches that the addition of a stabilizer, such as lysine, can inactivate any viruses present without significant loss of activity (see, e.g., Lim, [0089]-[0090], [0143]). Moreover, modified-Bal-Brgles-Branovic teaches that PCC fractions are treated with detergents for virus inactivation (see, e.g., Bal, English Translation, “Description”, pg. 2). Moreover, modified-Bal-Brgles-Branovic teaches that the virus-inactivated PCC samples are administered in a variety of medical applications, such as hemophilia patients, accident victims who are to be treated surgically, intensive care patients, and patients are risk of severe blood loss during dental treatments (see, e.g., Bal, English Translation, “Description”, pg. 2). Therefore, based on the teachings of modified-Bal-Brgles-Branovic and Lim, it would have been obvious to produce a purified PCC sample that is virus-inactivated by detergent and lysine because this PCC sample is to be used in a variety of medical applications. One would have expected success because modified-Bal-Brgles-Branovic and Lim both teach purification of plasma proteins using chromatography methods.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Bal, Brgles, Branovic, and Lim as applied to claims 1-10, 15-16, and 18-20 above, and further in view of Griffin (US 2016/0289299; Date of Publication: October 6, 2016 – previously cited).
The teachings of Bal, Brgles, Branovic, and Lim, herein referred to as modified-Bal-Brgles-Branovic-Lim, are discussed above as it pertains to purification of PCC from plasma, wherein plasma fractions obtained during the purification process contain lysine as a stabilizer.
However, modified-Bal-Brgles-Branovic-Lim does not teach: wherein heparin is added to at least one of the first, second and third fraction (claim 11).
Griffin’s general disclosure relates to methods of treating bleeding and/or hypocoagulation disorders in patients in need thereof through administration of factor Va in combination with Factor VIIa (see, e.g., Griffin, abstract). Moreover, Griffin discloses that factor Va, Factor VIIa, a PCC (containing factor VII, factor II, factor IX and/or factor X), or a combination thereof synergistically improves thrombin generation and hemostasis potential (see, e.g., Griffin, [0039]). Additionally, Griffin discloses the use of heparin as an anticoagulant in order to prevent blood coagulation (see, e.g., Griffin, [0028]-[0029], [0140]).
Regarding claim 11 pertaining to the addition of heparin, Griffin teaches the use of heparin as an anticoagulant (see, e.g., Griffin, [0028], [0140]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform modified-Bal-Brgles-Branovic-Lim’s method of obtaining a purified PCC sample from human plasma by means of chromatography, wherein the samples (i.e., fractions) are treated with heparin, as taught by Griffin. One would have been motivated to do so because Griffin teaches that heparin is an anticoagulant that is used in order to prevent blood coagulation (see, e.g., Griffin, [0028]-[0029], [0140]). Moreover, modified-Bal-Brgles-Branovic-Lim teaches the purification of PCC (see, e.g., Bal, English Translation, Abstract & “Description”, pg. 2), which one of ordinary skill in the art would readily understand contains fractions used to reverse the effects of anticoagulants. Therefore, based on the teachings of modified-Bal-Brgles-Branovic-Lim and Griffin, it would have been obvious to add heparin to the plasma samples during the chromatography purification process in order to prevent blood clotting during the PCC purification process. Moreover, based on the teachings of modified-Bal-Brgles-Branovic-Lim and Griffin, it would have been obvious to add heparin to the samples in order to prevent hyper-coagulation. One would have expected success because modified-Bal-Brgles-Branovic-Lim and Griffin both teaches the use of PCC in medical applications.
Examiner’s Response to Arguments
Applicant's arguments filed 11/24/2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that amended claim 1 is not taught by the prior art of Bal, Brgles, Lim, and Griffin (remarks, pages 7-9), this is not persuasive because, as discussed above, Bal was used to teach the limitation of “undiluted complete plasma or undiluted cryo-poor plasma” and Bal does not teach a dilution process as it pertains to the plasma; therefore, one of ordinary skill in the art would readily understand that the plasma is not diluted. Furthermore, Branovic was added to teach that monolithic stationary phase chromatography with an anion exchanger does not require dilution because Branovic teaches separation of plasma proteins using monolithic stationary phase chromatography with an anion exchanger and does not teach dilution of the sample when loading it onto the chromatography column (see, e.g., Branovic, sections 2-3). Therefore, based on the teachings of Branovic, monolithic stationary phase chromatography does not require dilution. Furthermore, Branovic teaches that proteins within plasma are at very low concentrations; therefore, isolating them from the impurities within samples is often difficult (see, e.g., Branovic, Introduction, pg. 22). Furthermore, Branovic teaches “Chromatography with compact, porous units such as monolithic columns is being used increasingly for analytical and preparative separations of biopolymers with apparent molecular masses (Mr) ranging from several thousand to up to several million” (see, e.g., Branovic, Introduction, pg. 22). Moreover, Bal teaches the use of anion exchange chromatography columns with QAE-modified dextran and DEAE in order to obtain purified plasma enriched in prothrombin (factor II), proconvertin (factor VII), Stuart Prower factor (factor X) and hemophilia B factor (factor IX) (see, e.g., Bal, English Translation, “Description”, pg. 2). Therefore, based on the teachings of Bal and Branovic, it would have been obvious for one of ordinary skill in the art to separate proteins in an undiluted plasma sample using monolithic station phase chromatography with an anion exchanger since this will allow protein separation and/or isolation in samples that have very low protein concentrations. Furthermore, one of ordinary skill in the art would understand dilution of plasma samples with already very low protein concentrations would result in even lower protein concentrations; therefore, this is motivation for using undiluted plasma samples for chromatography.
Conclusion
Claims 1-11, 15-16, and 18-20 are rejected.
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653