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 .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim(s) 8-9 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morin (U.S. 9,434,778) in view of Vitti (U.S. 2016/0144025), supported by Aflibercept sequence.
Regarding claim 8, Morin teaches a kit (col. 164, l. 46) comprising:
a plurality of proteins (col. 164, l. 22: protein samples of interest), wherein the plurality of proteins comprises charge variant isoforms (col. 164, ll. 26-27: charge variant analysis by imaged capillary isoelectric focusing icIEF), and
one or more capillary tubes (col. 164, l. 52: a capillary) configured with a mixture of carrier ampholyte, methylcellulose, and a stabilizing additive (col. 164, ll. 53-55: a solution contains 0.35% methyl cellulose, 4% pH3-10 Pharmalytes, 4M urea; here, Pharmalytes is the carrier ampholyte and urea is the stabilizing additive).
Morin does not disclose the protein is vascular endothelial growth factor trap (VEGF-Trap) protein having SEQ ID NO:1.
However, Vitti teaches charge variant analysis was done using imaged capillary isoelectric focusing (iCIEF) for the formulated drug substance and drug product (¶203). The drug includes the co-formulated anti-Agn-2 antibody and VDGF antagonist (¶202). Specific exemplary VEGF antagonists include VEGF-inhibiting fusion proteins, also referred to herein as “VEGF-Traps” (¶85), e.g., a therapeutic composition of aflibercept ([Abstract]). As evidenced by Aflibercept sequence, the sequences of SEQ ID NO: 1 as filed on January 16, 2025 in the instant application and the sequences of aflibercept (as filed on December 20, 2023 in its parent application #17/837,550) are the same. Further, Vitti teaches that Aflibercept has three charge variants, i.e., acidic, main, and basic variants (p. 29: Table 25).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin for analyzing charge variants of a VEGF-Trap protein such as aflibercept (SEQ ID NO: 1) as suggested by Vitti because IEF is a suitable analysis tool for characterization of charge variants of proteins, e.g., VEGF-Trap protein samples. Here the substitution of the charge variants of a protein for charge variants of VEGF-Trap protein would yield nothing more than predictable results. MPEP 2141(III)(B). Also, use known technique to improve similar devices in the same way is prima facie obvious. MPEP 2141(III)(C).
Regarding claim 9, Morin teaches wherein the stabilizing additive is urea (col. 164, l. 55: 4M urea).
Regarding claim 12, Morin in view of Vitti teaches a method for analyzing charge variant isoforms of a vascular endothelial growth factor trap (VEGF-Trap) protein (Morin, col. 164, ll. 26-27: charge variant analysis by imaged capillary isoelectric focusing icIEF; Vitti, ¶¶202-203), the method comprising using the kit of claim 8 (as described in claim 8) in an image capillary isoelectric focusing (iCIEF) assay (Morin, col. 164, ll. 26-27).
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morin in view of Vitti, and further in view of Mack (S. Mack, A systematic study in CIEF: Defining and optimizing experimental parameters critical to method reproducibility and robustness, Electrophoresis, 2009(30), page 4049-58).
Regarding claim 10, Morin and Vitti disclose all limitations of claim 8, and Morin further teaches the amount of urea in the mixture is 4M urea (col. 164, l. 55). Morin and Vitti fail to teach wherein the amount of urea in the mixture comprises about 1 M to about 3 M.
However, Mack teaches the influence of urea on the shape of mAb isoform peaks, due to the protein aggregation and precipitation (p. 4054, col. 2, Section 3.3). The studied urea concentration of the isoform bands of IgG1k sample ranges from 0 to 6M (p. 4055, col. 1, ¶1), and Fig. 4 shows that peak resolution is much better with urea at a concentration of 3M (Fig. 4; p. 4055, col. 1, ¶1). Mack teaches the urea concentration needs to be optimized for different protein families (p. 4055, col. 1, ¶1), rendering it a result-effective variable to be optimized through routine experimentation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin and Vitti by adjusting the amount of urea within the claimed range because the urea concentration is a result-effective variable, i.e., a variable which achieves a recognized result of better peak resolution adapted for different proteins families (p. 4055, col. 1, ¶1), and thus can be optimized through routine experimentation. MPEP 2144.05 (II)(B).
Regarding claim 11, Morin and Vitti disclose all limitations of claim 8, and Morin further teaches wherein the mixture comprises about 0.35% methylcellulose, 4% carrier ampholyte having a pI of 3 to 10, 4M urea (col. 164, ll. 54-55). Morin and Vitti fail to teach the urea is 2M or the carrier ampholyte is 3%.
However, Mack teaches the influence of urea on the shape of mAb isoform peaks, due to the protein aggregation and precipitation (p. 4054, col. 2, Section 3.3, ll. 1-2). The studied urea concentration of the isoform bands of IgG1k sample ranges from 0 to 6M (p. 4055, col. 1, ¶1), and Fig. 4 shows that peak resolution is much better with urea at a concentration of 3M (Fig. 4; p. 4055, col. 1, ¶1). Mack teaches the urea concentration needs to be optimized for different protein families (p. 4055, col. 1, ¶1), rendering it a result-effective variable to be optimized through routine experimentation. Further, Mack teaches the amount of Pharmalyte pI 3-10 CAs is 1.8% w/v (p. 4053, col. 1, ¶2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin and Vitti by adjusting the amount of urea as claimed because the urea concentration is a result-effective variable, i.e., a variable which achieves a recognized result of better peak resolution adapted for different proteins families (p. 4055, col. 1, ¶1), and thus can be optimized through routine experimentation. MPEP 2144.05 (II)(B). Since Morin teaches an amount of carrier ampholyte at 4% and Mack teaches an amount of carrier ampholyte at 1.8%, it would also been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Mack by adjusting the amount of the carrier ampholyte as claimed through routine experimentation. MPEP 2144.05 (II)(B).
Claim(s) 13-14, 17-18, 20, 24-28, and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morin in view of Mack, and further in view Michels (D.A. Michels, Imaged Capillary Isoelectric Focusing for Charge-Variant Analysis of Biopharmaceuticals, Bioprocess Technical, 9(10), November 2011, page 48-54), supported by Salas-Solano (O. Salas-Solano, Robustness of iCIEF methodology for the analysis of monoclonal antibodies: An interlaboratory study, Journal of Separation Science, 2012 (35), page 3124-3129).
Regarding claim 13, Morin teaches a method for analyzing charge variants (col. 164, ll. 26-27: charge variant analysis by imaged capillary isoelectric focusing icIEF) of a protein (col. 164, l. 22: protein samples of interest), the method comprising:
loading a protein sample (col. 164, l. 19: modified FGF-21 polypeptides) onto a separation capillary tube (col. 164, ll. 47-50: deamidation was detected by charge variant analysis conducted by imaged capillary isoelectric focusing (icIEF); thus, the protein sample must be loaded into the separation capillary for icIEF) comprising a mixture of at least a carrier ampholyte, methyl cellulose, and urea (col. 164, ll. 53-55);
applying a first voltage for a first predetermined period of time (Col. 164, lines 57-58: applying 1.5 kV for 2 min) such that the carrier ampholyte forms a pH gradient within the separation capillary tube (this limitation is the intended result of the “applying” step and does not further limit the method as claimed because it does not require steps to be performed; in method claims, it is the overall method steps that are given patentable weight not the intended result thereof. MPEP 2111.04);
applying a second voltage for a second predetermined period of time (col. 164, l. 58: and then 3.0 kV for 11 min) to focus the migration of charge variants of the protein within the separation capillary tube (col. 164, l. 57: the focusing was achieved) such that the overall charge of the variants is neutral (this limitation is the intended result of the “applying” step and does not further limit the method as claimed because it does not require steps to be performed; in method claims, it is the overall method steps that are given patentable weight not the intended result thereof. MPEP 2111.04); and
detecting and quantifying charge variants of the protein (Col. 164, lines 58-61: quantification of (-) charge modified species relative to the parent species was performed by integration of the corresponding area under the curves).
Morin does not disclose the protein is vascular endothelial growth factor trap (VEGF-Trap) protein.
However, Vitti teaches charge variant analysis was done using imaged capillary isoelectric focusing (iCIEF) for the formulated drug substance and drug product (¶203). The drug includes the co-formulated anti-Agn-2 antibody and VDGF antagonist (¶202). Specific exemplary VEGF antagonists include VEGF-inhibiting fusion proteins, also referred to herein as “VEGF-Traps” (¶85), e.g., a therapeutic composition of aflibercept ([Abstract]). Further, Table 25 (p. 29) indicates that Aflibercept has three charge variants, i.e., acidic, main, and basic variants.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin for analyzing charge variants of a VEGF-Trap protein as suggested by Vitti because IEF is a suitable analysis tool for characterization of charge variants of proteins, e.g., VEGF-Trap protein samples. Here the substitution of the charge variants of a protein for charge variants of VEGF-Trap protein would yield nothing more than predictable results. MPEP 2141(III)(B). Also, use known technique to improve similar devices in the same way is prima facie obvious. MPEP 2141(III)(C).
Morin does not explicitly disclose the steps of detecting and quantifying charge variants comprising: (i) measuring an absorbance for a plurality of charge variant isoforms; (ii) segregating the plurality of charge variant isoforms into isolated regions comprising at least a first acid/acidic region (R1), a second neutral region (R2) comprising three principal peaks, and a third base/basic region (R3); and (iii) determining a percentage of charge variant isoforms falling within each of regions R1, R2 and R3.
However, Michels teaches analyzing charge variants of therapeutic proteins on imaged capillary isoelectric focusing iCIEF (p. 48, col. 1, ¶1). The resultant electropherogram shows various isoforms of an antibody-drug conjugates (ADCs) between the pI markers 7.6 and 9.7 (Fig. 1; p. 50, col. 2, ¶2). The main peak or 0-Lys form of the ADC has an apparent pI or 9.2 (Fig. 1; p. 50, col. 2, ¶2; here, the peak at pI is a neutral peak). The acidic variants are observed before the 0-Lys peak (Fig. 1; p. 50, col. 2,¶2), and the basic variants are observed after the 0-Lys peak (Fig. 1). For the QC applications, the relative percentage peak areas for acidic, main, and basic species were reproducible within 1.9, 0.9, and 16.6% RSD, respectively (p. 50, col. 1, ¶2). Thus, Michels teaches detecting and quantifying charge variants comprises:
(i) measuring an absorbance for a plurality of charge variant isoforms (Fig. 1: showing the electropherograms at UV absorbance at 280 nm);
(ii) segregating the plurality of charge variant isoforms into isolated regions (Fig. 1: showing the charge variant isoforms: 0-Lys, acidic variants, and basic variants) comprising at least a first acid/acidic region (R1) (Fig. 1: acidic variants), a second neutral region (R2) (Fig. 1: 0-Lys at the pI of 9.2), and a third base/basic region (R3) (Fig. 1: basic variants); and
(iii) determining a percentage of charge variant isoforms falling within each of regions R1, R2 and R3 (p. 50, col. 1, ¶2: the relative percentage peak areas for acidic, main, and basic species).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin by segregating the charge variants of protein isoforms on the resultant electropherogram and determining their peak area percentages as taught by Michels because characterization and peak identification of iCIEF profiles are important for understanding distribution of product charge isoforms and how they affect biological activity (Michels, p. 50, col. 2, ¶3, ll. 1-5). Use of known technique to improve similar method in the same way if prima facie obvious. MPEP 2141(III)(C). Further, the designation for R2 “comprising three principal peaks” is inherent to the VEGF-Trap protein because the obtained peaks from the iCEF electropherogram are characteristic to the specific protein to be analyzed. Here, this designation does not require steps to be performed and thus does not further limit the claim scope. In method claims, it is the overall method steps that are given patentable weight not the intended result thereof because the intended result does not materially alter the overall method. MPEP 2111.04(I).
Regarding claim 14, Morin teaches wherein detection of charge variants occurs at a wavelength of approximately 280 nm (col. 164, ll. 50-51: iCIEF was performed on a iCE280 instrument (ProteinSimple); as evidenced by Salas-Solano, the iCE280 Analyzer from ProteinSimple equipped with an UV detector at 280 nm (Salas-Solano, p. 3125, col. 2, Section 2.2, ¶1).
Regarding claim 17, Morin teaches wherein the mixture includes about 0.35% methylcellulose (col. 164, l. 54).
Regarding claim 18, Morin teaches wherein the first voltage comprises about 1500 V (col. 164, l. 57).
Regarding claim 20, Morin teaches wherein the second voltage comprises about 3000 V (col. 164, l. 58).
Regarding claim 24, Morin teaches wherein the mixture includes between 0.01% and 0.35% methylcellulose, or any intervening range (col. 164, l. 54).
Regarding claim 25, Morin teaches wherein the first voltage is between 1 V and 3000 V, or any intervening range (col. 164, l. 57).
Regarding claim 26, Morin teaches wherein the first predetermined time is between 1 second and 5 minutes, or any intervening range (col. 164, l. 58).
Regarding claim 27, Morin teaches wherein the second voltage is between 1 V and 6000 V, or any intervening range (col. 164, l. 57).
Regarding claim 28, Morin teaches wherein the second predetermined time is between 1 minute and 14 minutes, or any intervening range (col. 164, l. 58).
Regarding claim 30, Morin teaches wherein the capillary tube comprises a fluorocarbon coating (col. 164, l. 52).
Regarding claim 31, Morin in view of Vitti and Michels teaches wherein the VEGF-Trap protein (Vitti, [Abstract], ¶85) comprises the sequence of SEQ ID NO:1 (as evidenced by Aflibercept sequence, the sequences of SEQ ID NO: 1 as filed on January 16, 2025 in the instant application and the sequences of aflibercept (as filed on December 20, 2023 in its parent application #17/837,550) are the same.
Claim(s) 15, 19, and 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morin in view of Vitti and Michels, and further in view of Anderson (S. Anderson, Applications of imaged capillary isoelectric focusing technique in development of biopharmaceutical glycoprotein-based products, Electrophoresis, 2012(33), page 1538-44).
Regarding claims 15 and 22, Morin, Vitti, and Michels disclose all limitation of claim 13. Morin, Vitti, and Michels do not disclose wherein the concentration of protein loaded onto the separation capillary tube is 2.0 mg/ml (claim 15) or wherein the concentration of the protein loaded onto the separation capillary is between approximately 1.0 and 8.0 mg/ml, or any intervening range (claim 22).
However, Anderson teaches imaged capillary isoelectric focusing (icIEF) analyzing biopharmaceutical glycoprotein products such as mAbs, erthyropoietin (EPO), and recombinant Fc-fusion proteins (p. 1538, [Abstract]). The EPO sample is at a concentration of 2 mg/ml (p. 1540, col. 1, Section 2.3.3), which overlaps the claimed range in claim 22.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Michels by using a protein sample at concentration of 2.0 mg/ml as taught by Anderson because 2.0 mg/ml is a suitable concentration for a protein sample of icIEF analysis on iCE 280 Analyzer (p. 1539, col. 2, Section 2.3). In the case where the claimed ranges "overlap or lie inside ranges disclosed 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). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Regarding claims 19 and 21, Morin, Vitti, and Michels disclose all limitation of claim 13. Morin, Vitti, and Michels do not disclose wherein the first predetermined time is about 1 minute (claim 19) or wherein the second predetermined time is about 7 minute (claim 21).
However, Anderson teaches imaged capillary isoelectric focusing (icIEF) analyzing biopharmaceutical glycoprotein products such as mAbs, erthyropoietin (EPO), and recombinant Fc-fusion proteins (p. 1538, [Abstract]). All mAb samples were prefocused for 1-2 min using a voltage of 1500 V followed by a variable period of 4-20 min at 3000 V depending on the particular mAb samples (p. 1540, col. 1, Section 2.3.1), rendering the application times result-effective variables to be optimized through routine experimentation. For Fc-fusion sialidase A treated samples, they were prefocused from 1 min using a voltage of 1500 V followed by 7 min at 3000 V (p. 1540, col. 1, section 2.3.5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Michels by substituting the first predetermined time of application of the first voltage with 1 minute and the second predetermined time of application of the second voltage with 7 minutes because they are suitable application times of voltages for icIEF detection depending on the samples, i.e., result-effective variables, and can be optimized through routine experimentation. MPEP 2144.05 (II)(B). In the case where the claimed ranges "overlap or lie inside ranges disclosed 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). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Claim(s) 16, 23, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morin in view of Vitti and Michels, and further in view of Mack.
Regarding claims 16 and 23, Morin, Vitti, and Michels disclose all limitations of claim 13, and Morin further teaches wherein the mixture comprises 4M urea (col. 164, l. 55). Morin, Vitti, and Michels fail to wherein the amount of urea in the mixture comprises about 2M (claim 16) or wherein the amount of urea in the mixture is greater than 0M and less than 8M, or any intervening range (claim 23).
However, Mack teaches the influence of urea on the shape of mAb isoform peaks, due to the protein aggregation and precipitation (p. 4054, col. 2, Section 3.3). The studied urea concentration of the isoform bands of IgG1k sample ranges from 0 to 6M (p. 4055, col. 1, ¶1), and Fig. 4 shows that peak resolution is much better with urea at a concentration of 3M (Fig. 4; p. 4055, col. 1, ¶1). Mack teaches the urea concentration needs to be optimized for different protein families (p. 4055, col. 1, ¶1), rendering it a result-effective variable to be optimized through routine experimentation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Michels by adjusting the amount of urea as claimed because the urea concentration is a result-effective variable, i.e., a variable which achieves a recognized result of better peak resolution adapted for different proteins families (p. 4055, col. 1, ¶1), and thus can be optimized through routine experimentation. MPEP 2144.05 (II)(B). Further, in the case where the claimed ranges "overlap or lie inside ranges disclosed 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). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Regarding claim 29, Morin, Vitti, and Michels disclose all limitations of claim 13, and Morin further teaches wherein the mixture includes 0.35% methylcellulose, 4% pH3-10 Pharmalytes (i.e., carrier ampholyte having a pI of 3 to 10), and 4M urea (col. 164, ll. 54-55). Morin, Vitti, and Michels fail to teach the urea is about 2 M or the carrier ampholyte is about 3%.
However, Mack teaches the influence of urea on the shape of mAb isoform peaks, due to the protein aggregation and precipitation (p. 4054, col. 2, Section 3.3). The studied urea concentration of the isoform bands of IgG1k sample ranges from 0 to 6M (p. 4055, col. 1, ¶1), and Fig. 4 shows that peak resolution is much better with urea at a concentration of 3M (Fig. 4; p. 4055, col. 1, ¶1). Mack teaches the urea concentration needs to be optimized for different protein families (p. 4055, col. 1, ¶1), rendering it a result-effective variable to be optimized through routine experimentation. Further, Mack teaches the amount of Pharmalyte pI 3-10 CAs is 1.8% w/v (p. 4053, col. 1, ¶2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin and Vitti by adjusting the amount of urea as claimed because the urea concentration is a result-effective variable, i.e., a variable which achieves a recognized result of better peak resolution adapted for different proteins families (p. 4055, col. 1, ¶1), and thus can be optimized through routine experimentation. MPEP 2144.05 (II)(B). Since Morin teaches an amount of carrier ampholyte at 4% and Mack teaches an amount of carrier ampholyte at 1.8%, it would also been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Mack by adjusting the amount of the carrier ampholyte as claimed through routine experimentation. MPEP 2144.05 (II)(B).
Claim(s) 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Morin in view of Vitti and Michels, and further in view of Mack and Anderson.
Regarding claim 32, Morin, Vitti, and Michels disclose all limitations of claim 13, and further disclose wherein:
a) the mixture includes 0.35% methylcellulose, 4% pH3-10 Pharmalytes, i.e., ampholyte, and 4M urea (Morin, col. 164, ll. 54-55);
b) the first voltage comprises about 1500 V (col. 164, l. 57);
c) the second voltage comprises about 3000 V (col. 164, l. 58); and
d) the VEGF-Trap (Vitt, [Abstract], ¶85) comprises the sequence of SEQ ID NO: 1 (As evidenced by Aflibercept sequence, the sequences of SEQ ID NO: 1 as filed on January 16, 2025 in the instant application and the sequences of aflibercept (as filed on December 20, 2023 in its parent application #17/837,550) are the same).
Morin, Vitti, and Michels do not disclose the urea is 2M or the carrier ampholyte is 3%.
However, Mack teaches the influence of urea on the shape of mAb isoform peaks, due to the protein aggregation and precipitation (p. 4054, col. 2, Section 3.3). The studied urea concentration of the isoform bands of IgG1k sample ranges from 0 to 6M (p. 4055, col. 1, ¶1), and Fig. 4 shows that peak resolution is much better with urea at a concentration of 3M (Fig. 4; p. 4055, col. 1, ¶1). Mack teaches the urea concentration needs to be optimized for different protein families (p. 4055, col. 1, ¶1), rendering it a result-effective variable to be optimized through routine experimentation. Further, Mack teaches the amount of Pharmalyte pI 3-10 CAs is 1.8% w/v (p. 4053, col. 1, ¶2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin and Vitti by adjusting the amount of urea as claimed because the urea concentration is a result-effective variable, i.e., a variable which achieves a recognized result of better peak resolution adapted for different proteins families (p. 4055, col. 1, ¶1), and thus can be optimized through routine experimentation. MPEP 2144.05 (II)(B). Since Morin teaches an amount of carrier ampholyte at 4% and Mack teaches an amount of carrier ampholyte at 1.8%, it would also been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Mack by adjusting the amount of the carrier ampholyte as claimed through routine experimentation. MPEP 2144.05 (II)(B).
Morin, Vitti, and Michels do not disclose the first predetermined time is about 1 minute and the second predetermined time is about 7 minute.
However, Anderson teaches imaged capillary isoelectric focusing (icIEF) analyzing biopharmaceutical glycoprotein products such as mAbs, erthyropoietin (EPO), and recombinant Fc-fusion proteins (p. 1538, [Abstract]). All mAb samples were prefocused for 1-2 min using a voltage of 1500 V followed by a variable period of 4-20 min at 3000 V depending on the particular mAb samples (p. 1540, col. 1, Section 2.3.1), rendering the application times result-effective variables to be optimized through routine experimentation. For Fc-fusion sialidase A treated samples, they were prefocused from 1 min using a voltage of 1500 V followed by 7 min at 3000 V (p. 1540, col. 1, section 2.3.5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Morin, Vitti, and Michels by substituting the first predetermined time of application of the first voltage with 1 minute and the second predetermined time of application of the second voltage with 7 minutes because they are suitable application times of voltages for icIEF detection depending on the samples, i.e., result-effective variables, and can be optimized through routine experimentation. MPEP 2144.05 (II)(B). In the case where the claimed ranges "overlap or lie inside ranges disclosed 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). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Conclusion
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/C. SUN/Primary Examiner, Art Unit 1795
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