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 .
Applicants are advised that the Examiner of Record has changed.
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 Accordingly, claim 40 is withdrawn from consideration as being directed to a non-elected invention.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.
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 04/23/2025, with respect to the claim objections, have been fully considered and are persuasive. The objection to claim 39 has been withdrawn.
2. Applicants’ arguments, see Response, filed 04/23/2025, 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 but are not persuasive. The 35 U.S.C. 102(a)(1) rejection to claims 1-3 and 35 has been maintained.
3. Applicants’ arguments, see Response, filed 04/23/2025, 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 39 has been withdrawn.
4. Applicants’ arguments, see Response, filed 04/23/2025, 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 not persuasive. The 35 U.S.C. § 103 rejection to claims 1-4, 12-15 and 33-35 has been maintained.
5. Applicants’ arguments, see Response, filed 04/23/2025, with respect to 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 not persuasive. The 35 U.S.C. § 103 rejection to claims 1, 5-11 and 16-32 has been maintained.
Maintained/Modified Rejections Necessitated by 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. Claims 1-3 and 35 are rejected under 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”).
For claims 1-3 and 35, with respect to a method of separating plasma cryoprecipitate comprising a blood coagulation factor and fibrinogen into a first fraction comprising a blood coagulation factor isolate and a second fraction containing the fibrinogen, the method comprising:(a) contacting the plasma cryoprecipitate with solid SiO2 or Al(OH)3, thereby adsorbing the fibrinogen onto the solid SiO2 or Al(OH)3; and(b) separating the fibrinogen adsorbed onto the solid SiO2 or Al(OH)3 from the blood factor, thereby forming the first fraction and the second fraction, as recited in instant claim 1; wherein the solid SiO2 is fumed SiO2, as recited in instant claim 2; wherein the fumed SiO2 is hydrophilic colloidal SiO2, as recited in instant claim 3; and where centrifugation is used in separating the fibrinogen adsorbed onto the solid SiO2 from the blood coagulation factor, forming the first fraction and the second fraction, as recited in instant claim 35:
Kotitschke discloses a specific embodiment of a method for making fibrinogen, a prothrombin complex containing coagulation factors II, VII, IX and X that contains antithrombin III, antithrombin III and a solution of stable serum proteins from a blood plasma (see Kotitschke, Abstract). In particular Kotitschke’s Example 1 (A), discloses the preparation of antihemophilic globulin A-containing concentrate where frozen plasma was frozen within 48 hours at -40°C (see Kotitschke, column 7, lines 20-39). The frozen plasma was thawed at a temperature of +2° to +4°C; the centrifuging was effected through single vessel centrifuging and from the so obtained cold precipitation (cryoprecipitate) a concentrate was produced in known manner which contained the antihemophilic globulin A (see Kotitschke, column 7, lines 33-36).
As evidenced by Labcorp, either plasma or serum are separated from blood cells by centrifugation; the essential difference between plasma and serum is that plasma retains fibrinogen (the clotting component) (See Labcorp, pg. 1, paragraph 7). Plasma is obtained from blood that has been mixed with an anticoagulant, this mixed blood is then centrifuged, yielding plasma, which contains albumin, globulin, and fibrinogen (see Labcorp, pg. 1, paragraph 9). As such, the disclosure of Kotitschke as evidenced by Labcorp corresponds to a method of separating a plasma cryoprecipitate comprising fibrinogen and a blood coagulation factor (i.e., prothrombin complex containing factors II, VII, IX and X) as recited in instant claim 1.
Step (B) in Kotitschke’s Example 1, discloses that the cryoprecipitate-free citrate plasma pool obtained in step A was stirred for one hour at room temperature and during this time the pH value maintained at 7.2 (see Kotitschke, column 7, lines 39-44). The beta-propiolactone-treated and UV-irradiated plasma was mixed with “Aerosil 380” to a concentration of 1.5 g colloidal silica/100 ml plasma or 250 mg per g protein (see Kotitschke, column 7, lines 50-54), thereby corresponding to contacting the plasma cryoprecipitate with solid SiO2 as recited in instant claim 1, step (a). Kotitschke continues to disclose that the mixture was then centrifuged and the precipitate processed further to obtain fibrinogen, while the supernatant was used as a starting material for the preparation of PPSB/AT III and a solution of stable serum proteins (see Kotitschke, column 7, lines 54-58), thereby corresponding to a separated fibrinogen fraction and constituting a method of separating plasma cryoprecipitate comprising a blood coagulation factor and fibrinogen as recited in instant claim 1. As evidenced by Hulander, fibrinogen (100 μg/mL) was found to be adsorb to a higher degree on silicon dioxide quartz crystal microbalance (QCM) sensors functionalized with SiO2 nanoparticles than smooth silicon dioxide sensors (see Hulander, pg. 4327, left column, second paragraph); and on average, the adsorbed amount increased with 16% on the nanostructured surfaces (see Hulander, pg. 4327, left column, second paragraph). As such, although Kotitschke does not expressly disclose that contacting the cryoprecipitate with solid SiO2 results in the absorption of fibrinogen to the solid SiO2, it would necessarily follow that fibrinogen absorbs onto the solid SiO2 since Kotitschke separates a fibrinogen fraction from the cryoprecipitate via contact with solid SiO2 and forming a fibrinogen fraction via centrifugation. Thus, the disclosure of Kotitschke satisfies the claim limitation with respect to contacting the plasma cryoprecipitate with solid SiO2, thereby adsorbing the fibrinogen onto the solid SiO2 as recited in instant claim 1, step (a). Furthermore, since fibrinogen is separated from the cryoprecipitate where such separation results in a fibrinogen fraction, it must then follow that the fibrinogen-free cryoprecipitate is a second fraction containing the prothrombin complex and coagulation factors; thereby corresponding to separating the fibrinogen adsorbed onto the solid SiO2, from the blood factor, thereby forming the first fraction and the second fraction as recited in instant claim 1, step (b).
Moreover, since Kotitschke utilizes centrifugation to separate the absorbed fibrinogen, such step corresponds to wherein centrifugation is used in separating the fibrinogen adsorbed onto the solid SiO2 from the blood coagulation factor, forming the first fraction and the second fraction as recited in instant claim 35. Thus, Kotitschke’s method of making fibrinogen, a prothrombin complex containing coagulation factors II, VII, IX and X that can contain antithrombin III, antithrombin III and a solution of stable serum proteins from a blood plasma constitutes a method of separating plasma cryoprecipitate into two fractions; namely, one fraction containing blood coagulation factors and a second fraction containing fibrinogen as recited in instant claim 1.
Similarly, as evidenced by Evonik Industries AG, Aerosil® 380 is a hydrophilic fumed silica with a specific surface area of 380 m2/g (see Evonik, pg. 1, right column, first sentence). As such, the disclosure of Kotitschke as evidenced by the disclosure of Evonik anticipate the claim limitations as recited in instant claims 2-3, wherein the solid SiO2 is fumed SiO2 as recited in instant claim 2; and wherein the fumed SiO2 is hydrophilic colloidal SiO2 as recited in instant claim 3.
Additionally, Kotitschke discloses that the coagulation factors II, VII, IX and X are also called PPSB in which P = prothrombin (factor II), P = proconvertin (factor VII), S = Stuart-Prower factor (factor X), B = antihemophilic globulin B (factor IX) (see Kotitschke, column 1, lines 43-48). Therefore the disclosure of Kotitschke anticipates the claim limitations as recited in instant claim 1, and in step (b), where the fibrinogen adsorbed onto the solid SiO2 is separated from the blood factor.
Accordingly, the disclosure of Kotitschke anticipates the claim limitations as recited in instant claims 1-3 and 35.
2. Claim 41 is rejected under 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). Please note that the rejection has been updated is in light of Applicants amendments: namely amendment to claim 39 and addition of new claim 41.
Schwarz discloses 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 disclosed by Schwarz anticipates the claim limitations as recited in instant claim 41.
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).
3. Claims 1-4, 12-15 and 33-35 are rejected under 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”).
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Regarding claims 1-4, 12-15 and 33-35, a method of separating plasma cryoprecipitate comprising a blood coagulation factor and fibrinogen into a first fraction comprising a blood coagulation factor isolate and a second fraction containing the fibrinogen, the method comprising: (a) contacting the plasma cryoprecipitate with solid SiO2 or Al(OH)3, thereby adsorbing the fibrinogen onto the solid SiO2 or Al(OH)3; and(b) separating the fibrinogen adsorbed onto the solid SiO2 or Al(OH)3 from the blood factor, thereby forming the first fraction and the second fraction, as recited in instant claim 1; wherein the solid SiO2 is fumed SiO2, as recited in instant claim 2; wherein the fumed SiO2 is hydrophilic colloidal SiO2, as recited in instant claim 3; further comprising (c), prior to (a), suspending the cryoprecipitate in water, forming a cryoprecipitate suspension, as recited in instant claim 4; wherein the solid SiO2 is present in the suspension in from about 5 g to about 30 g of SiO2 per kilogram of the suspension, as recited in instant claim 12; wherein the SiO2 is present in the suspension in from about 10 g to about 20 g of SiO2 per kilogram of the suspension, as recited in instant claim 13; 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; 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; wherein the blood coagulation factor is Factor VIII, as recited in instant claim 33; where centrifugation is not used in separating the fibrinogen adsorbed onto the solid SiO2 from the blood coagulation factor, forming the first fraction and the second fraction, as recited in instant claim 34; and where centrifugation is used in separating the fibrinogen adsorbed onto the solid SiO2 from the blood coagulation factor, forming the first fraction and the second fraction, as recited in instant claim 35:
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]), thereby constituting a method of separating a plasma sample comprising a blood coagulation factor and fibrinogen as recited in instant claim 1, and where in the blood coagulation factor is Factor VIII as recited in instant claim 33. Baxter’s purification process typically starts with thawing previously frozen pooled plasma, which has already been assayed for safety and quality considerations (see Baxter, pg. 21, para[0098]). Thawing is typically carried out at a temperature no higher than 6°C (see Baxter, pg. 21, para[0098]). After complete thawing of the frozen plasma at low temperature, centrifugation is performed in the cold ( e.g., ≤6°C) to separate solid cryo-precipitates from the liquid supernatant (see Baxter, pg. 21, para[0098]). Alternatively, the separation step can be performed by filtration rather than centrifugation (see Baxter, pg. 21, para[0098]). The liquid supernatant (also referred to as "cryo-poor plasma," after cold-insoluble proteins removed by centrifugation from fresh thawed plasma) is then processed in the next step (see Baxter, pg. 21, para[0098]). Various additional steps can be taken at this juncture for the isolation of factor eight inhibitor bypass activity (FEIBA), Factor IX-complex, Factor VII, antithrombin III, Prothrombin complexes, etc. (see Baxter, pg. 21, para[0098]); thereby constituting a method of separating plasma cryoprecipitate as recited in instant claim 1.
Baxter’s methods rely on a single initial step that captures all of the proteins normally precipitated in the Fraction I, Fraction II+III, and Fraction IV-1 precipitates combined; this single precipitation step is referred to as “Fraction I+II+III+IV-1 precipitation,” or a “Fraction I-IV-1 precipitation” (see Baxter, pg. 5, para[0017]). Accordingly, among other aspects, the present invention provides a new plasma fractionation process which separates plasma or cryo-poor plasma (i.e., a cryoprecipitate) in an initial step into a Fraction I-IV-1 precipitate and a Fraction I-IV-1 supernatant (see Baxter, pg. 6, para[0019]). The Fraction I-IV-1 precipitate contains nearly all immunoglobulins (e.g., IgG, IgA, and IgM) and alpha 1 elastase inhibitor (A1 PI), while the supernatant contains mainly albumin (see Baxter, pg. 6, para[0019]).
As evidenced by Labcorp, either plasma or serum are separated from blood cells by centrifugation; the essential difference between plasma and serum is that plasma retains fibrinogen (the clotting component) (See Labcorp, pg. 1, paragraph 7). Plasma is obtained from blood that has been mixed with an anticoagulant, this mixed blood is then centrifuged, yielding plasma, which contains albumin, globulin, and fibrinogen (see Labcorp, pg. 1, paragraph 9). As such, the teachings of Baxter as evidenced by Labcorp suggest that fibrinogen is found in plasma cryoprecipitate.
The step of separating the soluble portion of the first suspension from the insoluble portion of the first suspension comprises: (i) mixing finely divided silicon dioxide (SiO2) with the first suspension; and (ii) separating the SiO2 from the suspension (see Baxter, pg. 8, para[0034]), thereby constituting contacting the plasma cryoprecipitate with solid SiO2 as recited in instant claim 1, step (a). Baxter teaches that the starting material used for the fractionation of a plasma sample or pool of plasma samples is a “Cohn pool” (see Baxter, pg. 15, para[0078]). Cohn pools may include one or more of whole plasma, cryo-poor plasma, and cryo-poor plasma that has been subjected to a pre-processing step (see Baxter, pg. 15, para[0078]). A Cohn pool is a cryo-poor plasma sample from which one or more blood factors have been removed in a pre-processing step, for example, by adsorption onto a solid phase (e.g., aluminum hydroxide, finely divided silicon dioxide, etc.) (see Baxter, pg. 15, para[0078]), thereby constituting adsorbing the fibrinogen onto the solid SiO2, as recited in instant claim 1, step (a). Baxter also teaches that the step of separating the soluble portion of the first suspension comprises: (i) mixing finely divided silicon dioxide (SiO---2) with the first suspension; and (ii) separating the SiO2 from the suspension (see Baxter, pg. 8, para[0034]), thereby constituting separating the fibrinogen adsorbed onto the solid SiO2 from the blood factor, thereby forming the first fraction and the second fraction as recited in instant claim 1, step (b).
Regarding absorbing the fibrinogen onto the solid SiO2, Hulander teaches using quartz crystal microbalance (QCM) to assess the absorbed amount of fibrinogen to smooth and nanostructured SiO2 surfaces (see Hulander, pg. 4325, right column, third paragraph). Standard SiO2 QCM sensors were cleaned in 99.5% ethanol for 30 min on an ultrasonic bath, followed by rinsing in MQ water, and blow drying with gaseous nitrogen (see Hulander, pg. 4325, right column, third paragraph). Sensors were then left for 1 h in an UV/O3 cleaning chamber and then amine-functionalized with APTES, using the same protocol as described for the gradient surfaces (see Hulander, pg. 4325, right column, third paragraph). On half of the sensors SiO2 nanoparticles (40 nm) was immobilized by immersing the sensors in a solution of 5 mM sodium citrate buffer at pH 4 containing ∼6 × 10−9 M of nanoparticles for 15 min and then washed with Milli-Q-water and blow dried with nitrogen (g) (see Hulander, pg. 4325, right column, third paragraph). Prior to the protein adsorption experiments, all sensors were heat-treated at 400 °C in ambient air for 1 h to remove any APTES residues (see Hulander, pg. 4325, right column, third paragraph). A 100 μg/mL solution of fibrinogen dissolved in phosphate buffer (10 mM) was injected at a flow rate of 25 μL/min (see Hulander, pg. 4325, right column, fourth paragraph). After 60 min of adsorption, a 10 min rinse with phosphate buffer was again performed (see Hulander, pg. 4325, right column, fourth paragraph). Measurements were performed at room temperature (22 °C) and were repeated three times on two different occasions (see Hulander, pg. 4325, right column, fourth paragraph). Hulander reports that fibrinogen (100 μg/mL) was found to be adsorb to a higher degree on silicon dioxide QCM sensors functionalized with SiO2 nanoparticles than smooth silicon dioxide sensors (see Hulander, pg. 4327, left column, second paragraph). After 60 min of adsorption, 395 ng/cm2 was adsorbed to the smooth SiO2 sensors and 457 ng/cm2 on the nanostructured (see Hulander, pg. 4327, left column, second paragraph). On average, the adsorbed amount increased with 16% on the nanostructured surfaces (see Hulander, pg. 4327, left column, second paragraph). Therefore, a person of ordinary skill in the art would have been motivated with reasonable expectation of success to use SiO2 to absorb fibrinogen from the plasma cryoprecipitate.
Baxter also teaches that fumed silica (e.g., Aerosil 380 or equivalent) is added to the Fraction I-IV-I suspension to a final concentration of 40±20 g/kg Fraction I-IV-I precipitate (see Baxter, pg. 39, para[00124]), thereby constituting where the solid SiO2 is fumed SiO2 as recited in instant claim 2. The final concentration of the fumed silica may be added at a concentration of about 20 g/kg Fraction I-IV-1 precipitate, or about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 g/kg Fraction I-IV-1 precipitate (see Baxter, pg. 39, para[00124]), thereby constituting where the solid SiO2 is present in the suspension to about 30g of SiO2 per kilogram of the suspension as recited in instant claim 12; and wherein the SiO2 is present in the suspension in to about 20g of SiO2 per kilogram of the suspension as recited in instant claim 13.
Regarding the amount of solid SiO2 present in the suspension, the 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. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed solid SiO2 present in the suspension in from about 5g to about 30 g per kilogram of the suspension as recited in instant claim 12, and from about 10g to about 20 g per kilogram of the suspension as recited in instant claim 13 would have been suggested to one skilled in the art given that Baxter teaches utilizing about 20 g/kg solid SiO2, which lies within the claimed ranges.
Additionally, as evidenced by Evonik Industries AG, Aerosil® 380 is a hydrophilic fumed silica with a specific surface area of 380 m2/g (see Evonik, pg. 1, right column, first sentence). As such, the teachings of Baxter as evidenced by the teachings of Evonik satisfy the claim limitations as recited in instant claim 3.
Baxter adds that in certain embodiments, 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.
Baxter teaches that the first precipitate is suspended in water for injection (WFI) or a low ionic strength buffer suitable to extract immunoglobulins from the precipitate (see Baxter, pg. 38, para[00120]), thereby constituting where further comprising (c), prior to (a), suspending the cryoprecipitate in water, forming a cryoprecipitate suspension as recited in instant claim 4.
Regarding where centrifugation is not used or where centrifugation is used in separating the fibrinogen adsorbed onto the solid SiO2, as discussed above, Baxter teaches that the step of separating the soluble portion of the first suspension from the insoluble portion of the first suspension comprises: (i) mixing finely divided silicon dioxide (SiO2) with the first suspension; and (ii) separating the SiO2 from the suspension (see Baxter, pg. 8, para[0034]) and that the soluble portion of the first suspension is separated from the insoluble portion of the first suspension by centrifugation or filtration (see Baxter, pg. 8, para[0033]); thereby constituting where centrifugation is not used in separating the fibrinogen adsorbed onto the solid SiO2 from the blood coagulation factor, forming the first fraction and the second fraction as recited in instant claim 34; and constituting where centrifugation is used in separating the fibrinogen adsorbed onto the solid SiO2 from the blood coagulation factor, forming the first fraction and the second fraction as recited in instant claim 35.
Ascertaining the Differences between the Prior Art and the Claims at Issue (MPEP §2141.02)
Baxter does not expressly teach a method of separating plasma cryoprecipitate comprising a blood coagulation factor and fibrinogen into a first fraction comprising a blood coagulation factor isolate and a second fraction containing the fibrinogen, the method comprising: (a) contacting the plasma cryoprecipitate with solid SiO2 or Al(OH)3, thereby adsorbing the fibrinogen onto the solid SiO2 or Al(OH)3; and (b) separating the fibrinogen adsorbed onto the solid SiO2 or Al(OH)3 from the blood factor, thereby forming the first fraction and the second fraction as recited in instant claim 1. However, the teachings of Baxter and Hulander cure these deficiencies 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.
Finding the Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
With respect to a method of separating plasma cryoprecipitate comprising a blood coagulation factor and fibrinogen into a first fraction comprising a blood coagulation factor isolate and a second fraction containing the fibrinogen, the method comprising:(a) contacting the plasma cryoprecipitate with solid SiO2 or Al(OH)3, thereby adsorbing the fibrinogen onto the solid SiO2 or Al(OH)3; and(b) separating the fibrinogen adsorbed onto the solid SiO2 or Al(OH)3 from the blood factor, thereby forming the first fraction and the second fraction as recited in instant claim 1, 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 Baxter and co-isolate therapeutically important plasma-derived proteins including Factor VIII and fibrinogen by mixing finely divided SiO2 as a solid SiO2 with a first suspension containing a plasma cryoprecipitate comprising FVIII and fibrinogen and separating the SiO2 from the suspension where the separation of the SiO2 from the suspension results in the separation of the fibrinogen from the remaining plasma derived proteins including FVIII, given that fibrinogen absorbs onto solid SiO2. One of ordinary skill in the art would have been motivated to do so because SiO2 was known to absorb fibrinogen as taught by Hulander. 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 the method of Baxter co-isolates therapeutically important plasma-derived proteins including Factor VIII and fibrinogen in a plasma cryoprecipitate that is added to a suspension and finely divided SiO2 are added to the suspension as a pre-processing step to remove one or more blood factors from plasma cryoprecipitate. Therefore, mixing finely divided SiO2 as a solid SiO2 with the first suspension and separating the SiO2 from the suspension would support the co-isolation of therapeutically important plasma-derived proteins including Factor VIII and fibrinogen given that fibrinogen (100 μg/mL) was found to be adsorbed to a higher degree with SiO2 nanoparticles 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.
4. Claims 1, 5-11 and 16-32 are rejected under 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”), and 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”), as applied to claims 5-11 and 16-32 herewith.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Regarding claim 1, please see discussion of Baxter and Hulander above.
Regarding claims 5-11 and 16-32, wherein the water is from about 15° C to about 37° C as recited in instant claim 5; wherein the water is from about 20° C to about 32° C as recited in instant claim 6; 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; wherein the cryoprecipitate and water are in a ratio of from about 1:3.5 to about 1:5 in the cryoprecipitate suspension as recited in instant claim 8; wherein the cryoprecipitate suspension further comprises CaCl2 as recited in instant claim 9; wherein the CaCl2 is present in from about 40 µM to about 50mM in the cryoprecipitate suspension as recited in instant claim 10; wherein the CaCl2 is present in from about 100 µM to about 60 mM in the cryoprecipitate suspension as recited in instant claim 11; wherein the cryoprecipitate suspension is mixed to homogeneity as recited in instant claim 16; the method according to claim 16, further comprising (d) passing the cryoprecipitate suspension through a filtration device, thereby forming a filter cake and a first filtrate as recited in instant claim 17; wherein the filtration device is a mesh screen as recited in instant claim 18; wherein the mesh screen has pores of from about 100 µm to about 400 µm in diameter as recited in instant claim 19; the method according to claim 17, further comprising (e) following (d), washing the filter cake with an aqueous wash solution as recited in instant claim 20; wherein the aqueous wash solution is sodium chloride solution as recited in instant claim 21; further comprising (e) filtering the first filtrate through a 0.2 µm filter, forming a first filtrate as recited in instant claim 22; further comprising (f), prior to (e), adding sodium chloride to the first filtrate as recited in instant claim 23; the method according to claim 23, wherein the sodium chloride is added to the first filtrate to a final concentration of from about 100mM and about 200mM as recited in instant claim 24; wherein the sodium chloride is added to the first filtrate to a final concentration of about 150mM as recited in instant claim 25; further comprising (g), prior to (e),adding calcium chloride to the first filtrate as recited in instant claim 26; further comprising (g), prior to (e), adding calcium chloride to the first filtrate to a final concentration of from about 0.045M to about 0.055M as recited in instant claim 27; wherein the calcium chloride is added to the first filtrate to a final concentration of about 0.050M as recited in instant claim 28; the method of 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; wherein the homogeneous solvent/detergent mixture is octoxynol and tri(n-butyl)phosphate as recited in instant claim 30; 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; and the method of claim 29, further comprising (i), filtering the first filtrate suspension through an aggregation removal filter, forming a second filtrate as recited in instant claim 32:
The methods for the manufacture of blood protein compositions of Baxter include a SiO2 treatment step after extraction of the Fraction I-IV-1 precipitate and prior to filtration of the Fraction I-IV-1 suspension aids in the separation of A1PI, fibrinogen, Factor H, and IaIp into the insoluble filter cake formed during filtration of the Fraction I-IV-1 suspension (see Baxter, pg. 57, para[00159]). Additionally, as previously discussed above, fibrinogen is a plasma component (see discussion of Labcorp), that gets absorbed by SiO2 (please refer to discussion of Hulander). As such, the teachings of Baxter constitute where fibrinogen is separated from a cryoprecipitate by passing the cryoprecipitate through a filtration device, thereby forming a filter cake and a first filtrate as recited in instant claim 17, step (d).
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. Baxter also teaches that immunoglobulins are recovered from the second precipitate by suspending the precipitate with a cold extraction buffer (see Baxter, pg. 50, para[00143]). For example, the second precipitate is suspended at a ratio of 1 part precipitate to 2-15 parts of water for injection or low conductivity buffer (see Baxter, pg. 50, para[00143]). The conductivity of the suspension is increased to between 2.3 and 6.0 mS/cm to increase solubility of immunoglobulins (see Baxter, pg. 50, para[00143]). In on one embodiment, the conductivity is increased by the addition of sodium chloride (see Baxter, pg. 50, para[00143]), thereby constituting prior to (e), adding sodium chloride to the first filtrate as recited in instant claim 23. Example 6 of Baxter’s invention teaches that after incubation, 10mmol Tris and 150mmol sodium chloride per kg suspension were added to the samples (i.e., 150mmol is equivalent to 324 mmol/L when the density of NaCl is 2.16kg/L), and that the suspensions were then filtered to remove the insoluble material (see Baxter, pg. 111, para[00291]). Baxter adds that sodium chloride is added to the suspension to increase the conductivity to between 2.5 and 6.0 mS/cm, to increase the solubility of the immunoglobulins (see Baxter, pg. 50, para[00143]), thereby constituting adding sodium chloride to the first filtrate (i.e., step f), prior to filtering the first filtrate (i.e., step e) as recited in instant claim 23.
With respect to the sodium chloride added to the first filtrate in a final concentration of from about 100mM and about 200mM, and of about 150mM, it is noted that Baxter teaches adding 150mmol sodium chloride per kg suspension. The final concentration of sodium chloride is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal final concentration of sodium chloride suspension needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the concentration of sodium chloride as taught by Baxter for increasing the conductivity of the suspension to between 2.5 and 6.0 mS/cm, thereby resulting in an increase in solubility of the immunoglobulins, because an ordinary skilled artisan would have been able to utilize the teachings of Baxter to obtain various concentration parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the final concentration of sodium chloride in the suspension would have been obvious at the time of applicant's invention. Therefore, the claimed 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, because the combined teachings of the prior art are fairly suggestive of the claimed invention. As such, the teachings of Baxter are suggestive of where the sodium chloride is added to the first filtrate to a final concentration of from about 100mM and about 200mM as recited in instant claim 24, and wherein the sodium chloride is added to the first filtrate to a final concentration of about 150mM as recited in instant claim 25.
Additionally, 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. 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.
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. 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. 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,