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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/04/2025 has been entered.
Election/Restrictions
Newly submitted claim 40 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: Claim 40 is drawn to a FVIII (anti-haemophilic factor or AHF) high-concentrate with a specific activity of at least 2.5 units AHF and a fibrinogen content of less than 0.25 mg/mg protein, wherein the concentrate comprises about 95%, 98%, 99% or at least about 99.5% pure FVIII. The newly submitted claim is an independent invention that recites exclusive characteristics such the amount of fibrinogen protein in the concentrate and the percent purity of the FVIII.
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 Accordingly, claim 40 is withdrawn from consideration as being directed to a non-elected invention.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.
Status of Claims
Claims 1-38 were originally filed on 12/20/2021.
The amendment received on 04/08/2024, cancelled claims 36-38; amended claims 1-2, 8, 11-12, 21-22, 26-29, 32-35; and added new claim 39.
The amendment received on 04/23/2025, amended claims 1, 12-14 and 39; and added new claims 40-41.
The amendments received on 10/02/2025, amended claims 1, and 39-40.
Claims 1-35 and 39-41 are currently pending and claims 1-35, 39 and 41 are under consideration.
Priority
The present application claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 63/111,191 filed November 9th 2020. Applicants’ claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C 120, 121, or 365 (c ) is acknowledged.
Response to Arguments
1. Applicants’ arguments, see Response, filed 10/02/2025, with respect to 35 U.S.C. 102(a)(1) as being anticipated by Kotitschke et al., US 4,272,523 Patent Date: Jun. 9, 1981 (herein after “Kotitschke”) (cited in the IDS received on 04/08/2024), as evidenced by Labcorp., Blood Specimens: Chemistry and Hematology, May 12, 2020, pp. 1-12, retrieved from https://www.labcorp.com/resource/blood-specimens-chemistry-and-hematology#:~:text=The%20primary%20purpose%20of%20the,which%20is%20removed%20from%20serum on 10/18/2024, (herein after “Labcorp”), Hulander et al., ACS Biomater. Sci. Eng. 2019, 5, pp. 4323-4330 (herein after “Hulander”), and Evonik Industries AG., Product Information - Aerosil®380, 2013, pp. 1-2 (herein after “Evonik”), have been fully considered and are persuasive. The 35 U.S.C. 102(a)(1) rejection to claims 1-3 and 35 has been withdrawn.
2. Applicants’ arguments, see Response, filed 10/02/2025, with respect to 35 U.S.C. 102(a)(1) as being anticipated by Schwarz et al., US 4,404,131 Patent Date: Sep. 13, 1983 (herein after “Schwarz”) (cited in the IDS received on 04/08/2024), have been fully considered and are persuasive. The 35 U.S.C. 102(a)(1) rejection to claim 41 has been withdrawn.
3. Applicants’ arguments, see Response, filed 10/02/2025, with respect to 35 U.S.C. 103 as being unpatentable over Baxter International Inc. (WO 2013/126904 A1) with International Publication Date of 29 August 2013 (Cited in the IDS received on 04/08/2024) (herein after “Baxter”), Hulander et al., ACS Biomater. Sci. Eng. 2019, 5, pp. 4323-4330 (herein after “Hulander”), as evidenced by Labcorp., Blood Specimens: Chemistry and Hematology, May 12, 2020, pp. 1-12, retrieved from https://www.labcorp.com/resource/blood-specimens-chemistry-and-hematology#:~:text=The%20primary%20purpose%20of%20the,which%20is%20removed%20from%20serum on 10/18/2024, (herein after “Labcorp”), Evonik Industries AG., Product Information - Aerosil®380, 2013, pp. 1-2 (herein after “Evonik”), and Yigzaw et al., Curr Pharm Biotechnol. 2009, 10(4): 421-426 (herein after “Yigzaw”), have been fully considered and are persuasive. The 35 U.S.C. § 103 rejection to claims 1-4, 12-15 and 33-35 has been withdrawn.
4. Applicants’ arguments, see Response, filed 10/02/2025, with respect to the 35 U.S.C 103 as being unpatentable over Baxter International Inc. (WO 2013/126904 A1) with International Publication Date of 29 August 2013 (Cited in the IDS received on 04/08/2024) (herein after “Baxter”) and Hulander et al., ACS Biomater. Sci. Eng. 2019, 5, pp. 4323-4330 (herein after “Hulander”), as applied to claim 1 above, and further in view of Shanbrom (US 4,188,318) Date of Patent: Feb. 12, 1980 (Cited in the IDS received on 04/08/2024)(herein after “Shanbrom”), Pikal et al., (WO 2010/054238 A1) with International Publication Date of 14 May 2010 (Cited in the IDS received on 04/08/2024) (herein after “Pikal”), Tisch Scientific., Nylon Mesh Filters, 2016, pp. 1-5, available online at https://scientificfilters.com/mesh-filters/nylon-mesh-filters-me17195, accessed on 10/09/2024 (herein after “Tisch Scientific”), and Lee et al., (US 5,605,884) Date of Patent: Feb. 25, 1997 (Cited in the IDS received on 04/08/2024) (herein after “Lee”), have been fully considered and are persuasive. The 35 U.S.C. § 103 rejection to claims 1, 5-11 and 16-32 has been withdrawn.
5. Applicants’ arguments, see Response, filed 10/02/2025, with respect to the 35 U.S.C 103 as being unpatentable over Schwarz et al., US 4,404,131 Patent Date: Sep. 13, 1983 (herein after “Schwarz”) (cited in the IDS received on 04/08/2024) in view of Baxter International Inc. (WO 2013/126904 A1) with International Publication Date of 29 August 2013 (Cited in the IDS received on 04/08/2024) (herein after “Baxter”); have been fully considered but are not persuasive. The 35 U.S.C. § 103 rejection to claim 39 has been maintained.
New Rejections in light of Amendment
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
1. Claims1, 4-8, 16, 23-25, 33-35 and 41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 4,478,825 Date of Patent: Oct 23, 1984 (herein after “Bloom”), as evidenced by Purdue Chemistry, “What is a solution?” first available online on 05/05/2001, retrieved from https://www.chem.purdue.edu/gchelp/solutions/whatis.html#:~:text=A%20solution%20is%20a%20homogeneous,solutes%20dissolved%20in%20a%20solvent.&text=Note%20that%20the%20solvent%20is,a%20liquid%20or%20a%20solid., on 12/12/2025 (herein after “Purdue Chemistry”), and Ratnoff, O.D., Ann Intern Med., 1978 Mar; 88(3):403-9. (herein after “Ratnoff”).
For claim 1, Bloom claims a method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen (see column 8, lines 1-5, claim 14); thereby corresponding to a method of separating a blood coagulation factor from fibrinogen in plasma cryoprecipitate, as recited in instant claim 1. Bloom’s method comprises: (a) suspending the cryoprecipitate in an ethanol-water solution (see column 8, claim 14, lines 5-6), (b) adjusting the pH of the solution and stirring to form a precipitate comprising fibrinogen and insoluble globulins (see column 8, claim 14, lines 11-14), thereby corresponding to plasma cryoprecipitate comprising the blood coagulation factor and fibrinogen, as recited in instant claim 1. Bloom’s method also comprises (c) adding a low concentration aluminum hydroxide solution to adsorb trace proteins, blood factors VII, IX and prothrombin (see column 8, lines 15-17, claim 14); thereby corresponding to contacting the plasma cryoprecipitate with solid SiO2 or Al(OH)3, thereby adsorbing the fibrinogen onto the solid SiO2 or Al(OH)3, as recited in instant claim 1(a). Bloom’s step (d) comprises removing the precipitate and adsorbed proteins formed in steps (b) and (c) and aluminum hydroxide by centrifugation to obtain an effluent (see column 8, lines 18-20); thereby corresponding to separating the fibrinogen adsorbed onto the solid SiO2 or Al(OH)3 from the blood factor, thereby forming the first fraction comprising the blood coagulation factor and the second fraction comprising the fibrinogen as recited in instant claim 1(b).
For claim 4, Bloom discloses (a) suspending the cryoprecipitate in a 0.5 to 10.0% v/v ethanol 99.5 to 90.0% v/v water solution (see column 8, claim 14, lines 5-6); thereby corresponding to further comprising (c), prior to (a), suspending the cryoprecipitate in water, forming a cryoprecipitate suspension, as recited in instant claim 4.
For claim 5-6, Bloom discloses that the suspension of the cryoprecipitate in an ethanol-water solution is at a temperature of 22° to 28°C (see column 8, claim 14, line 10); thereby corresponding to wherein the water is from about 15° to about 37° as recited in instant claim 5; and corresponding to wherein the water is from about 20 ° to about 32°C as recited in instant claim 6.
Additionally, MPEP 2131.03 (I) states that "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023). As such, the instantly claimed range of the water temperature as recited in claims 5 and 6 is anticipated by Bloom’s disclosure.
For claim 7, Bloom’s Example 1 discloses that 12kg of cryoprecipitate was dissolved in 34kg of the ethanol-water-heparin solution at a temperature of about 25°C (see column 5, lines 51-53); thereby corresponding to wherein the cryoprecipitate and water are in a ratio of from about 1:2 to about 1:7 in the cryoprecipitate suspension, as recited in instant claim 7.
For claim 8, Bloom’s Example 2 discloses that 6kg of cryoprecipitate was dissolved in 16kg of ethanol-water-heparin solution at a temperature of about 25°C (see column 6, lines 12-14); thereby corresponding to wherein the cryoprecipitate and eater are in a ratio of from about 1:3.5 to about 1:5 in the cryoprecipitate suspension, as recited in instant claim 8.
Pursuant to MPEP 2131.03(II), In ClearValue, the claim at issue was directed to a process of clarifying water with alkalinity below 50 ppm, whereas the prior art taught that the same process works for systems with alkalinity of 150 ppm or less. In holding the claim anticipated, the court observed that "there is no allegation of criticality or any evidence demonstrating any difference across the range." Id. at 1345, 101 USPQ2d at 1777. Additionally, Bloom discloses that various modifications of the invention will be apparent to those skilled in the art and may be made without departing from the spirit and scope thereof, and it is thereof to be understood that the invention is to be limited only by the scope of the appended claim (see column 6, lines 21-55). Since Bloom’s claims do not limit the scope of the invention to a specific/critical range and/or ratio of cryoprecipitate to water, then Bloom’s ratio of 6kg of cryoprecipitate dissolved in 16kg of the ethanol-water-heparin solution anticipates the instantly claimed 1:3.5 to about 1:5 ratio.
For claim 16, Bloom discloses suspending cryoprecipitate, obtained from human blood plasma, at room temperature in an ethanol-water solution containing up to 10% v/v ethanol to obtain a final solution of low ionic strength (see column 4, lines 4-7), thereby constituting wherein the cryoprecipitate suspension is mixed to homogeneity, as recited in instant claim 16. As evidenced by PurdueChemistry, a solution is a homogeneous mixture of one or more solutes dissolved in a solvent (see PurdueChemistry, pg. 1). As such, the claim limitations recited in claim 16 are anticipated by the disclosure of Bloom.
For claims 22-23, Bloom’s claim 14 discloses adding physiologically desired amounts of sodium citrate, glycine and sodium chloride to the clarified effluent (see column 8, lines 22-23); Bloom adds that the effluent was clarified by filtration and to 20 kg of solution was then added 33 g sodium chloride and that the resultant solution was diafiltered to removed ethanol and ultrafiltered to adjust the AHF potency (see column 6, lines 22-23 and 27-28).thereby corresponding to filtering the first filtrate, forming a first filtrate, as recited in instant claim 22; and corresponding to adding sodium chloride to the first filtrate, as recited in instant claim 23.
With respect to wherein sodium chloride is added to the filtrate to a final concentration of from about 100mM and about 200mM, as recited in instant claim 24; and of about 150mM, as recited in instant claim 25. The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not Applicants’ final concentration of sodium chloride is from about 100mM and about 200mM added to the first filtrate; and of about 150mM added to the first filtrate, and if so to what extent, from the physiologically desired amounts of sodium chloride (i.e., 72g sodium chloride in specific Example 1 and 33g sodium chloride in specific Example 2) disclosed in Bloom’s method. The prior art physiologically desired amounts of sodium chloride is similar to the claimed amounts because the physiological effect of sodium chloride on the filtrate comprising the target product depends on the ratio of water to cryoprecipitate in the cryoprecipitate suspension. The cited art taken as a whole demonstrates a reasonable probability that the physiologically desired amounts of sodium chloride (i.e., 72g sodium chloride in specific Example 1 and 33g sodium chloride in specific Example 2) of the prior art is either identical or sufficiently similar to the claimed final concentration of sodium chloride is from about 100mM and about 200mM added to the first filtrate; and of about 150mM added to the first filtrate and whatever differences exist are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants.
Merely because a characteristic of a known method for separating fibrinogen from AHF is not disclosed in a reference does not make the known separation method patentable. The instantly claimed method of separating a blood coagulation factor from fibrinogen in plasma cryoprecipitate possesses inherent characteristics which might not be displayed in Bloom’s Examples 1 and 2. Clear evidence that Bloom’s method does not possess a critical characteristic that is possessed by the instantly claimed method would advance prosecution and might permit allowance of claims to Applicants’ method of separating a blood coagulation factor from fibrinogen in plasma cryoprecipitate.
For claims 33 and 41, Bloom’s claim 14 is drawn to a method for producing a substantially fibrinogen-free antihemophilic factor product (see column 8, lines 1-2); thereby corresponding to wherein the blood coagulation factor is Factor VIII, as recited in instant claim 33.
As evidenced by Ratnoff, antihemophilic factor (Factor VIII) is an agent in normal plasma that corrects the coagulative defect of classic hemophillia (see Ratnoff, Abstract). As such, the disclosure of Bloom anticipates the claim limitations as recited in instant claim 33, where the blood coagulation factor is Factor VII and as recited in instant claim 41, wherein the blood coagulation factor is FVIII (anti-haemophilic factor or AHF), as recited in instant claim 41.
For claims 34-35, Bloom discloses that aluminum hydroxide solution is added per liter of solution followed by centrifugation or filtration to obtain a precipitate which is then discarded (see column 5, lines 11-15), thereby corresponding to wherein centrifugation is not used in separating the fibrinogen adsorbed on the solid SiO2 or Al(OH)3,as recited in instant claim 34. Bloom also discloses that centrifugation of the solution is accomplished at between 10,000 and 15,000 gravities for 10 to 30 minutes to effect sharp separation of the solid and liquid phases (see column 5, lines 15-18); thereby corresponding to wherein centrifugation is used in separating the fibrinogen adsorbed onto the solid SiO2 or Al(OH)3 , as recited in instant claim 35. Bloom adds that the solid phase now consists primarily fibrinogen and cold-insoluble globulin proteins (see column 5, lines 18-19) and that the liquid supernatant consists primarily of AHF and trace amounts of fibrinogen ( see column 5, lines 19-21); thereby constituting separating the fibrinogen from the blood coagulation factor, forming the first fraction and the second fraction, as recited in instant claims 34-35.
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 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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-3, 9-15, 17-22 and 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over US 4,478,825 Date of Patent: Oct 23, 1984 (herein after “Bloom”) in view of US 3,998,946 Date of Patent: Dec. 21, 1976 (herein after “Condie”) as evidenced by Taylor & Francis., Fumed Silica, 2019, available online at https://taylorandfrancis.com/knowledge/Engineering_and_technology/Chemical_engineering/Fumed_silica/, retrieved on 12/13/2025 (herein after “Taylor & Francis”); US 5,605,884 Date of Patent: Feb. 25, 1997 (herein after “Lee”); Baxter International Inc. (WO 2013/126904 A1) with International Publication Date of 29 August 2013 (Cited in the IDS received on 04/08/2024) (herein after “Baxter”) as evidenced by Yigzaw et al., Curr Pharm Biotechnol. 2009, 10(4): 421-426 (herein after “Yigzaw”); Filtrox, Celpure Technical Data Sheet, 05/19/2001, retrieved from https://protecnia.net/wp-content/uploads/2023/04/celpure-filtrox.pdf, on 12/13/2025 (herein after “Filtrox”).
Regarding claim 1, please see discussion of Bloom above.
Regarding claims 2-3, as previously mentioned Bloom teaches a method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen, where aluminum hydroxide solution is used to adsorb trace proteins (see column 8, claim 14). However, Bloom does not teach wherein the solid SiO2 is fumed SiO2, as recited in instant claim 2; nor wherein the fumed SiO2 is hydrophilic colloidal SiO2, as recited in instant claim 3.
However, Condie teaches a method of treating blood plasma or fractionated plasma products with fumed colloidal silica to remove fibrinogen without polymerization to fibrin, to remove the plasminogen-plasmin proteolytic enzyme system, to remove cholesterol and lipoproteins and reduce triglycerides, while maintaining plasma coagulation factor II at pretreatment levels and leaving immunoglobulins and other protein constituents unaffected, and the resulting product (see Condie, Abstract). As evidenced by Taylor & Francis, fumed silica is a synthetic, non-porous, amorphous material composed of silicon dioxide that is produced through hydrolysis at high temperatures and its surface is highly hydrophilic (see Taylor & Francis, pg. 1). As such the teachings of Condie, suggest the claim limitations recited in instant claims 2-3 wherein the SiO2 is fumed, colloidal and hydrophilic.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bloom’s method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen by substituting aluminum hydroxide with fumed colloidal silica, in order to arrive at the claimed invention. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because fumed colloidal leaves immunoglobulins and other protein constituents unaffected as taught by Condie; and also because fumed silica a is non-porous, amorphous material composed of silicon dioxide and its surface is highly hydrophilic as evidenced by Taylor & Francis.
One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated with reasonable expectation of success to make the substitutions given that fumed colloidal silica was known to be used in methods involving fractionated plasma products to remove fibrinogen without polymerization, cholesterol and lipoproteins and reduce triglycerides while maintaining the target product unaffected as taught by Condie. Therefore, substituting Bloom’s aluminum hydroxide with Condie’s fumed colloidal silica, in a method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen would support the instantly claimed method, by constituting a simple substation of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claims 9-11, 27 and 28, Bloom does not teach or suggest wherein the cryoprecipitate suspension further comprises CaCl2.
Lee is in the field of purified Factor VIII protein formulations (see Abstract). Lee’s invention relates to stable Factor VIII formulations, particularly, high purity Factor VIII protein is formulated in high ionic strength media for administration to patients suffering from hemophilia type A (see column 1, lines 15-18). Lee teaches encountering degradation problems with Factor VIII both during lyophilization and upon reconstitution with normal saline solution (see column 2, lines 4-7). Therefore, in order to provide effective Factor VIII formulations for injection, the degradation problems were extensively studied (see column 2, lines 8-10). It was found that highly purified Factor VIII can be formulated with physiologically acceptable compounds for stabilization against loss of activity during storage in a liquid state, lyophilization, storage in the lyophilized state and reconstitution preceding administration to patients (see column 2, lines 34-39).
Lee’s claim 1, is drawn to a stable Factor VIII formulation in an aqueous solution for the treatment of hemophilia type A consisting essentially of: a therapeutically effective amount of Factor VIII having an activity of at least 130 U/mg of protein; from about 0.40M to about 1.2M sodium chloride, potassium chloride, or mixtures thereof; from about 1.5 mM to about 40 mM calcium chloride; and from about 1 mM to about 50 mM histidine; said formulation having a pH of from about 6.0 to about 7.6 (see column 8, lines 8-19). Lee adds that the formulations comprise Factor VIII having activity in the range of about 130 to about 11,000 units/mg of protein or higher as the active ingredient for therapeutic use and a high ionic strength media (see column 2, lines 46-50).
Additionally, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. Therefore, the claimed CaCl2 range would have been obvious to one of ordinary skill in the art since the prior art range (i.e., 1.5 mM to about 40 mM calcium chloride) lies within the claimed range (i.e., from about 40µM to about 50mM for claim 10, and from about 100µM to about 60mM for claim 11).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bloom’s method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen by incorporating the teachings of Lee in order to arrive at the claimed invention. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because stable Factor VIII formulations in aqueous solution where known to comprise calcium chloride as taught by Lee. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated with reasonable expectation of success to incorporate calcium chloride as part of a method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen. Given that formulations comprising Factor VIII having activity in the range of about 130 to about 11,000 units/mg of protein or higher as the active ingredient for therapeutic use also comprise high ionic strength media (i.e., from about 1.5 mM to about 40 mM calcium chloride; and from about 1 mM to about 50 mM histidine); and given that highly purified Factor VIII can be formulated with physiologically acceptable compounds for stabilization against loss of activity during storage in a liquid state, lyophilization, storage in the lyophilized state and reconstitution preceding administration to patients, as taught by Lee. Therefore, incorporating calcium chloride as part of Bloom’s method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen would support the instantly claimed method, by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claims 12-13, Condie teaches adding sterile dry colloidal fumed silicon dioxide of the highest purity is then added to the plasma at room temperature with stirring to a final concentration of between about 10 to 50 and preferably about 25 to 40 gram of silica per liter of plasma (see column 4, lines 56-60). MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. Therefore, the claimed SiO2 per kilogram of the cryoprecipitate would have been obvious to one of ordinary skill in the art since the prior art range (i.e., 10 to 50 and preferably about 25 to 40 gram of silica per liter of plasma) lies within the claimed range (i.e., from about 5g to about 30g of SiO2 for claim 12, and from about 10g to about 20g of SiO2 for claim 13). Thereby the teachings of Condie suggest the claim limitations recited in instant claims 12 and 13.
Regarding claims 14-15, Bloom does not expressly teach wherein the cryoprecipitate suspension further comprises from about 2 g to about 10 g of filter aid per kilogram of cryoprecipitate suspension, as recited in instant claim 14; nor wherein the filter aid is present in the cryoprecipitate suspension in from about 4 g to about 8 g per kilogram of the cryoprecipitate suspension, as recited in instant claim 15.
Baxter teaches methods for the manufacture of blood protein compositions from pooled plasma (see Baxter, Abstract). Baxter’s methods include the co-isolation of other therapeutically important plasma-derived proteins, including alpha-1-antitrypsin (A1PI), Factor H, inter-alpha-inhibitor proteins (IaIp), Prothrombin complexes, Factor VII (FVII), Factor VIII (FVIII), antithrombin III (ATIII), fibrinogen, butyrylcholinesterase, and others (see Baxter, pg. 4, para[0014]). filter aid, for example Celpure C300 (Advanced Minerals) or Hyflo-Super-Cel (World Minerals), is added to the suspension after the silica dioxide treatment to facilitate depth filtration (see Baxter, pg. 58, para[00164]). Filter aid is added at a final concentration of from about 0.01 kg/kg (i.e., 10 g/kg) Fraction I-IV-I precipitate, or about 0.02 kg/kg (i.e., 20 g/kg) Fraction I-IV-I precipitate (see Baxter, pg. 58, para[00164]), thereby constituting where the cryoprecipitate suspension further comprises from about 2 g to about 10 g of filter aid per kilogram of cryoprecipitate suspension as recited in instant claim 14; and where the filter aid is present in the cryoprecipitate suspension in from about 4g to about 8g per kilogram of the cryoprecipitate suspension as recited in instant claim 15.
Filtrox teaches that celpure is the ideal filter aid if high purity standards are needed (see top of pg. 1). Celpure is the ideal choice when developing new high purity processes with diatomite filter aid (see pg. 1, left column, paragraph 1). Studies show that after replacing conventional diatomite filter aids with Celpure diatomite filter aids, extractable impurities are significantly reduced (see pg. 1, right column, paragraph 1). Celpure is used in many processes such as plasma fractionation as a filter aid for alluvial filtration (see pg. 1, left column, paragraph 1).
An ordinary skilled artisan would have been motivated with reasonable expectation of success before the effective filing date of the claimed invention to incorporate filter aid as taught by Baxter as part of Bloom’s method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen because filter aid (i.e., Celpure) was known to be an ideal choice when developing new high purity processes and because it was also known to be used in many processes such as plasma fractionation as taught by Filtrox. One of ordinary skilled in the art would have had a reasonable expectation of success given that Baxter’s methods for the manufacture of blood protein compositions incorporated filter aid; and given that Factor VIII (FVIII) was one of the co-isolated therapeutically important plasma-derived proteins in Baxter’s method. Therefore, incorporating filter aid as part of a method for producing a substantially fibrinogen-free antihemophilic factor product from a cryoprecipitate containing as its primary components antihemophilic factor and fibrinogen would support the instantly claimed method, by constituting a simple substation of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 17, Baxter teaches that inclusion of a SiO2 treatment step after extraction of the Fraction I-IV-I precipitate and prior to filtration of the Fraction I-IV-I suspension aids in the separation of AIPI, fibrinogen, Factor H, and IaIp into the insoluble filter cake formed during filtration of the Fraction I-IV-I suspension (see Baxter, pg. 57, para [00159]).
Regarding claims 18-19, Baxter teaches that in certain embodiments, the ultrafiltration is carried out in a cassette with an open channel screen (see Baxter, pg. 65, para[00185]); thereby constituting wherein the filtration device is a mesh screen as recited in instant claim 18, and wherein the porses are about 100µm to about 400µm, as recited in instant claim 19.
Regarding claim 20, Baxter adds that in order to minimize the loss of immunoglobulins during filtration, the filter cake formed should be washed with at least one dead volume, preferably at least two dead volumes, more preferably at least three dead volumes, of suspension buffer or a similar buffer thereto, which is not sufficient to solubilize non-immunoglobulin proteins present in the filter cake (see Baxter, pg. 59, para[00165]). Furthermore, Baxter teaches that the method comprising suspending a Fraction I-IV-1 precipitate in water or a low conductivity buffer (see Baxter, pg. 19, para[0094]); and that the first precipitate is suspended in Water for Injection (WFI) or a low ionic strength buffer (see Baxter, pg. 38, para[00120]). Therefore, the teachings of Baxter imply that the suspension buffer or a similar buffer thereto is an aqueous solution/buffer, thereby constituting washing the filter cake with an aqueous wash solution as recited in instant claim 20.
Regarding claim 21, Baxter teaches that the filter is washed with WFI or a suitable buffer after filtration to recover additional immunoglobulin and the post-wash added to the filtrate (see Baxter, pg. 50, para[00145]). The post-wash of the filter is performed using a sodium chloride solution with a conductivity of between about 2.5 and about 6.0 mS/cm (see Baxter, pg. 50, para[00145]), thereby implying that the aqueous wash solution is sodium chloride solution as recited in instant claim 21.
Regarding claim 22, Baxter teaches that the soluble portion of the suspension containing immunoglobulins, is separated from the insoluble portion and this is done by filtering the suspension with a depth filter having a nominal pore size of from 0.1µm and 0.4µm (see Baxter, pg. 50, para[00145]). In one embodiment, the nominal pore size of the depth filter is 0.2µm (e.g., Cuno VR06 filter or equivalent) (see Baxter, pg. 50, para[00145]), thereby constituting where filtering the first filtrate through a 0.2µm filter, forming a first filtrate as recited in instant claim 22.
Regarding claim 29, in one embodiment of the methods of Baxter, the method comprises a solvent/detergent (S/D) viral inactivation step (see Baxter, pg. 10, para[0051]). The first suspension or soluble fraction thereof, is treated with a detergent prior to performing the second precipitation step (see Baxter, pg. 43, para[00132]), thereby constituting the method according to claim 28, further comprising (h) contacting the first filtrate of (e) with a homogeneous solvent/detergent mixture, forming a first filtrate suspension as recited in instant claim 29.
Regarding claim 30, Baxter also teaches that solvent denotes an organic solvent (e.g., tri-N-butyl phosphate), which is part of the solvent detergent mixture used to inactivate lipid-enveloped viruses in solution (see Baxter, pg. 16, para[0082]). Baxter also teaches the term “detergent” which is used interchangeably with the term “surfactant” or “surface acting agent,” some examples of common surfactants include triton detergents (see Baxter, pg. 17, para[0084]). Additionally, Baxter’s Table 38 displays SD reagents which include Octoxynol 9 (Triton X100) and Tri(n-butyl)phosphate (see Baxter, Table 38, pg. 121), thereby constituting wherein the homogeneous solvent/detergent mixture is octoxynol and tri(n-butyl)phosphate as recited in instant claim 30.
Regarding claim 31, Baxter teachings also include adding triton X-100, Tween-20, and tri(n-butyl)phosphate (TNBP) to the clarified PptG filtrate at final concentrations of about 1.0%, 0.3%, and 0.3%, respectively, the mixture is then stirred at a temperature between 18°C and 25° for at least an hour (see Baxter, pg. 63, para[00177]), thereby constituting wherein the homogeneous solvent/detergent mixture is 1.0% ± 0.1% (v/v) octoxynol and 0.3% ± 0.03% (v/v) tri(n-butyl)phosphate as recited in instant claim 31.
Regarding claim 32, Baxter’s method also include an anion exchange chromatography enrichment step (see Baxter, pg. 10, para[0048]). Immunoglobulin fractions obtained after fractionation using an initial precipitation step that precipitates immunoglobulins and alpha-1-antitrypsin (Al PI), but not albumin, can be further enriched according to well-known methods in the art, including without limitation: chromatography (e.g., anion exchange chromatography, cation exchange chromatography, hydrophobic interaction chromatography (HIC), hydroxyapatite chromatography (HAP), Protein A affinity chromatography, immuno-affinity chromatography, size exclusion chromatography, etc.) (see Baxter, pg. 51, para[00146]).
As evidenced by Yigzaw, cation exchange is one of the most widely used polishing steps effective in removing not only aggregates but also other impurities such as product isoforms, host cell proteins (HCP), leached Protein A and DNA (see Yigzaw, pg. 421, right column, first paragraph). As for anion exchange chromatography, Yigzaw teaches that resin type, load buffer composition, protein load factor, elution pool collection criteria are some of parameters that determine the level of aggregate removal with AEX chromatography in flow-through operation (see Yigzaw, pg. 423, right column, third paragraph). As such, the teachings of Baxter suggest the claim limitations as recited in instant claim 32, where the first filtrate suspension is filtered through an aggregation removal filter, forming a second filtrate.
Maintained/Modified Rejections
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Schwarz et al., US 4,404,131 Patent Date: Sep. 13, 1983 (herein after “Schwarz”) (cited in the IDS received on 04/08/2024) in view of Baxter International Inc. (WO 2013/126904 A1) with International Publication Date of 29 August 2013 (Cited in the IDS received on 04/08/2024) (herein after “Baxter”).
Regarding claim 39, Schwarz teaches a method of producing a factor-VIII (AHF)-high concentrate having a specific activity of at least 2.5 units AHF and a fibrinogen content of less than 0.25 mg/mg protein from human or animal plasma, the plasma is subjected to a multi-step fractionation (see Schwarz, Abstract and column 4, claim 1). The fraction purified by these fractionation measures and enriched in factor VIII (AHF) is subjected to a cryoalcohol precipitation and the resulting precipitate is processed into a stable form (see Schwarz, Abstract). Thus, the method of producing a FVIII (AHF)-high concentrate having a specific activity of at least 2.5 units AHF and a fibrinogen content of less than 0.25mg/mg of protein taught by Schwarz constitute the claim limitations as recited in instant claim 39. However Schwarz does not expressly teach wherein the concentrate comprises less than about 5% of the fibrinogen present in the plasma or cryoprecipitate starting material. However, Schwarz does not expressly teach a FVIII high-concentrate wherein the concentrate comprises less than about 5% of the fibrinogen present in the plasma or cryoprecipitate starting material, as recited in instant claim 39.
Baxter teaches methods for the manufacture of blood protein compositions from pooled plasma (see Baxter, Abstract). Baxter’s methods include the co-isolation of other therapeutically important plasma-derived proteins, including alpha-1-antitrypsin (A1PI), Factor H, inter-alpha-inhibitor proteins (IaIp), Prothrombin complexes, Factor VII (FVII), Factor VIII (FVIII), antithrombin III (ATIII), fibrinogen, butyrylcholinesterase, and others (see Baxter, pg. 4, para[0014]).
Baxter also teaches that the first precipitation step, referred to as Fraction I precipitation, is performed at high pH (7.2) and low ethanol concentration (8-10% v/v) to precipitate protein such as fibrinogen and Factor XIII away from IgG and Al PI, which remain in the supernatant (see Baxter, pg. 5, para[0015]). Baxter’s Table 14 depicts the fibrinogen content, express as g/L starting plasma, of the various fractions formed during fractionation of plasma (see Baxter, pg. 101, Table 14); where it can be noted that the amount of fibrinogen in plasma is 1.45g/L (i.e., starting material). Additionally, Baxter’s Table 9 displays the yield of proteins in precipitation supernatant, expressed as a percent of the protein content of the starting material (Fraction I supernatant) (see Baxter, pg. 98, Table 9); where it can be appreciated that the percent of fibrinogen is below 5%. Therefore, the teachings of Baxter demonstrate a fibrinogen content of less 5% in the concentrate (i.e., Fraction I supernatant). As such the teachings of Schwarz, when combined with the teachings of Baxter suggest the claim limitations as recited in instant claim 39.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Schwarz and precipitate fibrinogen at high pH (7.2) and low ethanol concentration (8-10%). One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because the method for the manufacture of blood protein compositions from pooled plasma include the co-isolation of Factor VIII (FVIII) as taught by Baxter. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that a FVIII (AHF)-high concentrate having a specific activity of at least 2.5 units AHF and a fibrinogen content of less than 0.25mg/mg of protein, and given that the FVIII (AHF) is subjected to a cryoalcohol precipitation as taught by Schwarz. Therefore, modifying the method of Schwarz by incorporating the teachings of Baxter would support a FVIII (anti-haemophilic factor or AHF)-high-concentrate wherein the concentrate comprises less than about 5% of the fibrinogen present in the plasma or cryoprecipitate starting material by constituting some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 U.S.C §103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicants’ arguments filed 10/02/2025, with respect to the 35 U.S. C 103 rejection have been fully considered but are not persuasive for the following reasons:
Applicants argue that Baxter is not analogous art, as it is neither from the same field of endeavor as the claimed invention nor reasonably pertinent to the problem solved. Rather than describing purification of blood coagulation factors such as FVIII, Baxter is directed to immunoglobulin purification. Even assuming arguendo that Baxter is prior art, the combination of Baxter in view of Hulander, Labcorp, Evonik, and Yigzaw, or alternatively in view of Shanbrom, Pikal, and Tisch Scientific, fails to teach all of the elements of the claimed invention, including each step of the claimed method. Moreover, a person of ordinary skill would not have had a reasonable expectation of success in achieving the presently claimed invention in light of these references. To the contrary, Baxter affirmatively teaches away from the claimed approach (see Remarks, filed, 10/02/2025, pg. 21, summary).
Pursuant to MPEP 2141.01 (a)(I), [i]n order for a reference to be proper for use in an obviousness rejection under 35 U.S.C. 103 , the reference must be analogous art to the claimed invention. In re Bigio, 381 F.3d 1320, 1325, 72 USPQ2d 1209, 1212 (Fed. Cir. 2004). A reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). Note that "same field of endeavor" and "reasonably pertinent" are two separate tests for establishing analogous art; it is not necessary for a reference to fulfill both tests in order to qualify as analogous art. See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212. Baxter is analogous art to the claimed invention because: (1) it teaches an alcohol fractionation scheme that allows for significant increases in the yield of blood proteins purified from the starting plasma sample (see Baxter, Abstract); even if it addresses a different problem (i.e., manufacturing enriched immunoglobulin compositions from a Chron pool).
With respect to Applicants’ assertion that B) Assuming arguendo Baxter is prior art, the pending claims are patentable over Baxter in view of Hulander as evidenced by Labcorp, Evonik and Yigzaw (see Remarks, filed 04/23/2025; pg. 14), a. the proposed combination of references is missing elements of the claimed invention (see remarks, filed 10/02/2025), are found unpersuasive.
The Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Additionally, Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where; to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. In the instant case, as discussed above in the 103 rejection, the teachings of Baxter as evidenced Yigzaw, are suggestive of the claim limitations as recited in the instant claims.
With respect to Applicants’ assertion that assuming arguendo Baxter is prior art, the pending claims are patentable over Baxter and that there is no reasonable expectation of success (see Remarks, filed 10/02/2025), are found unpersuasive.
Pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976).
Accordingly, the 35 U.S.C. §103 rejections are maintained as Applicants’ arguments are found unpersuasive.
Conclusion
No claims are allowed.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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