DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 4-5, 7-8 and 10-31 are pending in this application.
Applicant’s amendment to the claims filed 02/13/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 02/13/2026 in response to the non-final rejection mailed on 11/13/2025 are acknowledged and have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is
Group I, corresponding to claims 1, 4-5, 7-8, and 13-20, drawn to the technical feature of a method for purifying blood comprising the steps of: (1) separating blood plasma from blood cells; (2) adjusting a pH of the blood plasma to a pH close to an isoelectric point of at least one predetermined protein; (3) treating the blood plasma by exchange chromatography; (4) neutralizing the pH of the blood plasma; and (5) pooling the blood plasma and the blood cells; wherein the pH to which the pH of the blood plasma is adjusted corresponds to the isoelectric point of the predetermined protein to within +1.5/+0.0 pH point,
elected without traverse in the reply filed 05/22/2024.
Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed 05/22/2024.
New claims 15-20 ultimately depend from claim 1, and therefore are drawn to the elected invention of Group I.
Newly submitted claims 21-31 are directed to an invention that lacks unity of invention with Groups I and II as set forth in the Office action mailed April 26, 2024 for the following reasons:
New claims 21-31 are drawn to the technical feature of a method of treating a human patient comprising separating blood plasma from blood cells of the human patient, adjusting a pH of the blood plasma to a pH of 7.0 or below, wherein the pH is adjusted by supplying protons to the blood plasma or dialysis of the blood plasma with an acidic buffer; treating the adjusted blood plasma by ion-exchange chromatography to remove one or more pathogenic substances from the adjusted blood plasma; neutralizing the pH of the treated adjusted blood plasma; pooling the treated neutralized blood plasma and the blood cells to produce purified blood; and administering the purified blood to the human patient, wherein adjusting the pH of the blood plasma reduces unwanted adsorption of at least one predetermined protein when treating the blood plasma by ion-exchange chromatography.
The invention of Group I and the invention of the newly submitted claims 21-31 listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
The inventions of Group I and of newly submitted claims 21-31 lack unity of invention because the groups do not share the same or corresponding technical feature. For example, the method of claim 21 requires the separation of blood plasma from blood cells of a human patient and the administration of purified blood to a human patient, while the invention of Group I is not required to separate blood plasma from blood cells of a human patient or to administer purified blood to a human patient.
The inventions of Groups I and II, and of newly submitted claims 21-31 lack unity of invention because even though the inventions of these groups require the technical feature of purifying blood comprising the steps of: (1) separating blood plasma from blood cells; (2) adjusting a pH of the blood plasma; (3) treating the blood plasma by exchange chromatography; (4) neutralizing the pH of the blood plasma; and (5) pooling the blood plasma and the blood cells, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Jain et al. (US 4,322,275; cited on the IDS submitted 10/08/2021; herein referred to as Jain) which discloses a method for the separation of protein mixtures comprising steps of pH adjustment, filtration and centrifugation [abstract] comprising filtering cell components from blood, sending the resulting plasma to an electrodialysis stack comprised of anion and cation exchange membranes [col 6, lns 13-25], adjusting the pH of the plasma to the pI of the least soluble protein [col 6, lns 36-37], restoring the original salt content of the mixture [col 6, lns 62-65] encompassing neutralization of plasma, and restoring blood cells previously separated from the plasma [col 6, ln 68 to col 7, ln 2].
As such, the shared same or corresponding technical feature among Groups I and II, and of newly submitted claims 21-31 is not a contribution over the prior art.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 21-31 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 1, 4-5, 7-8, and 13-20 are being examined on the merits.
Claim Objections
The objection to claim 13 is withdrawn in view of the instant claim amendments.
Claims 16 and 18 are objected to for the typo “Facture II”. In the interest of improving claim form, Applicant should consider an amendment to recite “Factor II”.
Claim Rejections - 35 USC § 112(b)
Claims 1, 4-5, 7-8, and 13-20 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The instant rejection is newly stated and is necessitated by claim amendment.
Claim 1 (claims 4-5, 7-8, and 13-20 dependent therefrom) is indefinite for the recitation of the phrase “adjusting the pH of the blood plasma reduces unwanted adsorption”. Without a reference to compare said reduction in adsorption, the term “reduces” is a relative term that renders the claim indefinite. The term “reduces” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, the limitation of the amount of unwanted adsorption of at least one predetermined protein is rendered indefinite by the use of the term.
Claim Rejections - 35 USC § 103
Claims 1, 4-5, 7-8 and 13-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al. (US 4,322,275; cited on the IDS submitted 10/08/2021; herein referred to as Jain) in view of Iberer et al. (J Chromatography A, 2002, 972:115; cited on the Form PTO-892 mailed 08/15/2024; herein referred to as Iberer).
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 1 is drawn to a method for purifying blood comprising the steps of:
separating blood plasma from blood cells;
adjusting a pH of the blood plasma to a pH of 7.0 or below, wherein the pH is adjusted by supplying protons to the blood plasma or dialysis of the blood plasma with an acidic buffer;
treating the adjusted blood plasma by ion-exchange chromatography to remove one or more pathogenic substances from the adjusted blood plasma;
neutralizing the pH of the treated adjusted blood plasma; and
pooling the treated neutralized blood plasma and the blood cells,
wherein adjusting the pH of the blood plasma reduces unwanted adsorption of at least one predetermined protein when treating the blood plasma by ion-exchange chromatograph (IEC).
Jain discusses the fractionation of protein mixtures [title] from biological fluids such as blood plasma [col 1, lines 9-15], wherein the method is adaptable for therapeutic plasma exchange as well as antihemophilic factor separation and purification [abstract].
Regarding claim 1, Jain discloses a method for the separation of protein mixtures [abstract] comprising filtering cell components from blood, sending the resulting plasma to an electrodialysis stack comprised of anion and cation exchange membranes [col 6, lines 13-25], adjusting the pH of the plasma to the pI of the least soluble protein [col 6, lines 36-37] which encompasses a pH value within 1.5 of the pI of a predetermined protein. Jain also discloses restoring the original salt content of the mixture [col 6, lines 62-65] which encompasses the neutralization of plasma. Jain additionally discloses restoring the blood cells previously separated from the plasma [col 6, line 68 to col 7, line 2] which encompasses the pooling of blood plasma and blood cells. Regarding the adjusting of plasma pH before treating the plasma by ion-exchange chromatography, Jain discloses "the combination of the techniques include the essential steps of electrodialysis of the protein mixture, (optionally combined with temperature and pH alteration) and separation of certain precipitated proteins" [col 5, lns 57-60], which is considered to correspond to the altering of pH before sending the resulting plasma to an electrodialysis stack comprised of anion and cation exchange membranes as stated in [col 6, lines 13-25].
Regarding claim 1 and the limitation of treating the adjusted blood plasma by IEC to remove one or more pathogenic substances from the adjusted blood plasma, Jain discloses a method of treating adjusted blood plasma by IEC as discussed above and discloses the method is meant to overcome problems previously present in the field such as the transmission of viruses to a patient receiving treated plasma [col 1, lns 42-56].
Jain does not teach the adjustment of pH to 7.0 or lower, and adjusting the blood plasma pH with the addition of protons or dialysis with an acidic buffer.
Iberer discusses purification of clotting factor IX [title], and discloses a chromatographic method for separating components from human plasma that has a large number of interfering proteins [p 116, col 1, para 3].
Regarding claim 1 and the limitation of adjusting the blood plasma pH wherein pH is adjusted by supplying protons to the blood plasma or dialysis of the blood plasma with an acidic buffer, the two options in the “wherein” clause of “supplying protons to the blood plasma” and “dialysis of the blood plasma with an acidic buffer” are considered to be alternative ways to adjust the blood plasma pH. In view of this interpretation, Iberer teaches purification of protein from plasma in a column equilibrated with Tris-HCl as well as the adjustment of pH with Tris-HCl [beginning p 119, col 2, para 2]. As the Tris-HCl was used in the column that contacted the plasma sample, and Iberer teaches the use of Tris-HCl to adjust pH which encompasses the supplying of protons, one of skill in the art would reasonably conclude that Tris-HCl can be used to directly adjust the pH of the plasma, as the addition of the plasma sample into the column equilibrated with Tris-HCl as taught by Iberer corresponds to the pH of the plasma being adjusted through the supplying of protons from said Tris-HCl.
Regarding claim 1 and the limitation of adjusting pH to 7.0 or below, Iberer teaches that the Factor IX protein is missing in haemophilia B patients it must be supplied by infusion, this protein can be separated from human plasma, and this protein has an apparent isoelectric point of 4.0-4.6 [p 116, col 1, final paragraph]. As stated above, Jain teaches adjusting plasma pH to the pI of the least soluble protein [col 6, lines 36-37] and the inclusion of electrodialysis of the protein mixture is optionally combined with temperature and pH alteration and separation of certain precipitated proteins [col 5, lns 57-60] that is considered to correspond to the altering of pH before sending the resulting plasma to an electrodialysis stack comprised of anion and cation exchange membranes as stated in [col 6, lines 13-25]. Jain also teaches methods of the disclosed invention can be used to recover coagulation factors such as Factor VIII from donors [col 2, lns 30-32]. In view of Jain and Iberer, one of ordinary skill in the art would be motivated to adjust the pH to the pI of Factor IX in order to separate this protein from the plasma before IEC, as taught by Jain, wherein the lowering of pH is carried out by the supplying of protons as implicitly taught by Iberer, and which corresponds to a pH of 7.0 or lower as recited in the claim, in order to remove the coagulation factor of Factor IX for infusion to haemophilia B patients as taught by Jain.
Regarding claim 1 and the limitation of adjusting the pH of the blood plasma reduces unwanted adsorption of at least one predetermined protein when treating the blood plasma by IEC, in addition to the teachings of Jain and Iberer above regarding lowering pH to the pI of a protein for its separation via IEC as discussed above, it is noted that this limitation is not a recited active step of the claimed method, but instead is an effect of one carrying out the recited active steps of adjusting the plasma pH and performing IEC. As one of ordinary skill in the art in carrying out the combined method of Jain and Iberer would perform these active steps as described above, the combined method is considered to have the effect of reducing unwanted adsorption of at least one predetermined protein when treating the blood plasma by ion-exchange chromatograph (IEC).
In view of Jain and Iberer, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the method of Jain by adjusting the plasma pH by adding protons, and reducing the pH to 7.0 or below, as taught by Iberer, to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to modify the method of Jain by adjusting the plasma pH by the addition of protons, because Jain teaches the adjustment of blood plasma pH, and Iberer teaches a chromatographic method for separating components from human plasma that has a large number of interfering proteins comprising the adjustment of pH.
One of ordinary skill in the art would have been motivated to modify the method of Jain by reducing the pH to 7.0 or below, because Jain teaches methods involving the separation of components from plasma can be used to recover or separate coagulation factors comprising altering plasma pH to the pI of a target protein in combination with IEC, and Iberer teaches the coagulation factor IX with a pI of 4.0-4.6 is needed from donors to supply to haemophilia B patients via infusion.
One of skill in the art would have had a reasonable expectation of success because Jain and Iberer both relate to methods for separating blood components via IEC.
Regarding claim 4, Iberer teaches the plasma-derived clotting Factor IX is a protein in the clotting cascade important to hemostasis, and must be supplied to patients suffering from haemophilia B [p 116, col 1, para 3], therefore identifying the role of Factor IX in blood coagulation. Iberer further teaches the separation of Factor IX from other blood components using anion-exchange chromatography [p 116, col 2, para 2].
Regarding claims 5, 15 and 16, Iberer teaches the isoelectric point of factor IX is 4.0 – 4.6 [p 116, col 1, para 3], and Jain teaches adjusting the pH of the plasma to the pI of the least soluble protein [col 6, lines 36-37], wherein the least soluble protein corresponds to a predetermined protein, which encompasses adjusting the pH to a value less than 5.5.
Regarding claim 7, Iberer teaches the addition of NaOH [p 120, col 1, para 1], which encompasses the supplying of hydroxide ions.
Regarding claim 8, Jain discloses the method comprising sending separated plasma to an electrodialysis stack comprised of anion and cation exchange membranes [col 6, lines 13-25].
Regarding claim 13, Iberer teaches the use of DEAE anion exchange chromatography to separate blood components [p 116, col 2, para 2].
Regarding claim 14, Jain teaches adjusting the pH of the plasma to the pI of the least soluble protein [col 6, lines 36-37], wherein the least soluble protein corresponds to a predetermined protein. Additionally, Jain discloses electrodialysis comprising desalting plasma using ion-exchange chromatography for precipitation and fractionation of plasma proteins, which can also can be used to restore electrolyte and water balance of processed protein mixtures resulting from fractionation for return of the protein to the patient with substantially its original salts [col 5, lines 34-56]. Jain further discloses in Example I the restoration of electrolyte and water balance of desalted plasma with fresh plasma in a dilute stream [col 7, lines 50-54], wherein the Table shows the concentrated desalted plasma corresponding to the fractionated protein to have a pH of 5.2 [col 8, lines 5-14], which indicates the adjustment of pH of the plasma to 5.2 for the desalting process via ion-exchange chromatography that produced the concentrated desalted plasma. The teaching of Jain corresponds to the adjustment of pH to within the range of 5.0 - 5.5 as recited by the claims.
Regarding claims 17-18, Iberer teaches the isoelectric point of factor IX is 4.0 – 4.6 [p 116, col 1, para 3], and Jain teaches adjusting the pH of the plasma to the pI of the least soluble protein [col 6, lines 36-37], wherein the least soluble protein corresponds to a predetermined protein, which encompasses adjusting the pH to a value less than 5.5. While Jain and Iberer do not teach the pH range of 5.0-5.5 as recited by the claims, MPEP 2144.05.II.A states where 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. One of ordinary skill in the art would be motivated to optimize the pH of the plasma to the claimed range in order to obtain the coagulation factor of Iberer, because Iberer teaches Factor IX is needed for infusions to haemophilia B patients and Jain teaches coagulation factors can be obtained from plasma using methods comprising plasma pH adjustment and IEC as discussed above.
Regarding claim 19, Jain teaches a method of treating adjusted blood plasma by IEC as discussed above and discloses the method is meant to overcome problems previously present in the field such as the transmission of viruses to a patient receiving treated plasma [col 1, lns 42-56], which is considered to correspond to the removal of pathogenic substances such as viruses.
Regarding claim 20, the method of claim 20 limits the endotoxins recited in claim 19, but does not limit the pathogenic substance recited in the method of claim 19 to comprise endotoxins. Therefore the method as recited in claim 20 still encompasses all of the alternatives pathogenic substances recited in claim 19, including viruses. If Applicant intends to limit the method of claim 19 to comprise the pathogenic substance of endotoxin, Applicant should consider an amendment to recite “The method of claim 19, wherein the pathogenic substance comprises endotoxin”.
Therefore the invention of claims 1, 4-5, 7-8 and 13-20 would have been obvious to one of skill in the art before the effective filing date.
Response to Remarks: beginning on page 7 of Applicant’s response to rejections under 35 USC 103; Applicant in summary contends that Jain does not discuss the problem of unwanted removal of coagulation factors when purifying blood; Applicant further contends Jain does not teach adjusting blood plasma to a pH of 7.0 or below and treating the plasma by IEC; Applicant further contends there is no reasonable expectation of success that one could successfully remove pathogenic substances from blood while avoiding unwanted adsorption of beneficial proteins such as coagulation factor.
Applicant’s remarks are considered and found not convincing.
Regarding the assertion that Jain does not discuss the problem of unwanted removal of coagulation factors when purifying blood, the limitation of “wherein adjusting the pH of the blood plasma reduces unwanted adsorption of at least one predetermined protein when treating the blood plasma by ion-exchange chromatograph (IEC)” recited in claim 1 is indefinite in the absence of a reference to compare said reduction in adsorption as described above. Moreover, given a broadest reasonable interpretation, the noted phrase is not a recited active step of the claimed method, but instead is interpreted as an effect of one carrying out the recited active steps of adjusting the plasma pH and performing IEC. As one of ordinary skill in the art in carrying out the combined method of Jain and Iberer would perform these active steps as described above, the combined method is considered to have the effect of reducing unwanted adsorption of at least one predetermined protein when treating the blood plasma by ion-exchange chromatograph (IEC).
Regarding the assertion that Jain does not teach adjusting blood plasma to a pH of 7.0 or below and treating the plasma by IEC, the details of the rejection are stated in the section above. Briefly, Jain teaches a method for the separation of protein mixtures comprising filtering cell components from blood, sending the resulting plasma to an electrodialysis stack comprised of anion and cation exchange membranes, adjusting the pH of the plasma to the pI of the least soluble protein, and adjustment of pH before IEC for the separation of proteins. Jain additionally teaches the method can be used to remove coagulation factors from donor plasma. Iberer teaches the coagulation factor of Factor IX is required by haemophilia B patients via infusion, and that Factor IX has a pI of 4.0-4.6. In view of Jain and Iberer, one of ordinary skill in the art would be motivated to adjust the pH of a donor plasma to the pI of Factor IX (e.g., below 7.0) to separate Factor IX for infusion to haemophilia B patients.
Regarding the assertion that there is no reasonable expectation of success that one could successfully remove pathogenic substances from blood while avoiding unwanted adsorption of beneficial proteins such as coagulation factor, Jain teaches a method disclosed to overcome the problems in the field of virus transmission, therefore one of ordinary skill in the art would have a reasonable expectation of success that carrying out the combined method of Jain and Iberer would result in the removal of pathogenic substances. Regarding the assertion of “avoiding unwanted adsorption”, it is noted the claims do not require “avoiding unwanted adsorption”, and instead recite “adjusting the pH of the blood plasma reduces unwanted adsorption of at least one predetermined protein when treating the blood plasma by IEC”. Therefore the claimed method is not required to adjust the pH to avoid unwanted adsorption.
Conclusion
Status of the Application:
Claims 1, 4-5, 7-8 and 10-31 are pending.
Claims 10-12 and 21-31 are withdrawn.
Claims 1, 4-5, 7-8, and 13-20 are rejected.
No claim is in condition for allowance.
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 JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
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