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 .
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 (i.e., changing from AIA to pre-AIA ) 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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/06/2026 has been entered.
Priority
The present application, filed 05/21/2020, claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/850,999, filed 05/21/2019.
Status of the Claims
Claims 1, 3-4, 6, 8-9, 11-19, 21-22, 24, 26-29 and 31-33 are pending; claims 2, 5, 7, 10, 20, 23, 25 and 30 are canceled; claims 1, 17 and 28 are amended. No claims are withdrawn. Claims 1, 3-4, 6, 8-9, 11-19, 21-22, 24, 26-29 and 31-33 are pending.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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.
Claim(s) 1, 3-4, 6, 8-9, 11-16 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Voss et al., US PG Pub No. 2009/0023156A1 (IDS entered 09/15/2020) in view of Bosteels et al., WO2018/065389A1, Rietveld, L., Polyclonal vs Monoclonal Explained. Stress Marq Biosciences Inc. (2015). https://www.stressmarq.com/blog/polyclonal-vs-monoclonal-antibodies/?srsltid=AfmBOopuJnojrsjzi2jd5Wt2bec5k2buTT_rkKSobzVVvrYjDZjgkEut. [Accessed 10/02/2025]., Burakov et al., WO2018039499A1, Yu et al., US PG Pub No. 2016/0319012A1, and Padhan, N, Highly Sensitive and Quantitative Detection of Proteins and Their Isoforms by Capillary Isoelectric Focusing Method, Journal of Visualized Experiments, 139, (2018), (6 pages).
Voss et al. teach a method of detection performed on a protein containing sample, specifically separating the components (protein components) of the sample by a physical parameter within a capillary (addressing one or more capillaries as claimed, see specifically addressing the elected species, namely resolving by isoelectric focusing, using an ampholyte reagent loaded in the fluid path for separation based on charge (paras [0061] and [0062]), contacting the separated components within the capillary with a primary antibody that binds protein of interest (para [0066], [0067]), and detecting the binding of the antibody (see abstract and paras [0023], [0024], [0042], [0046], [0061], [0062]). See further para [0071] the methods encompass using different detection agents, which bind and detect different types of analytes and standards for simultaneous detection. Voss also encompass embodiments separating by molecular weight (rather than charge), see for example para [0046], and more specifically, para [0060] (see for example separating in a gel (thereby addressing sieving matrix) by molecular weight).
See also para [0063] refers to resolving one or more (thereby addressing at least 2) analytes, detecting with one or more detection agent (paras [0063]-[0066]). Voss teaching resolving one or more analyte to separation the molecules, see para [0065] contacting detection agent with analyte or analytes of interest.
Voss et al. differs from the claimed invention in that Voss fails to teach specifically applying their method of detection in order to detect two or more variants (i.e., different forms) of a host cell protein contaminant of interest in a purified antibody preparation sample.
Further, although Voss teaching detecting one or more analytes by contact with a detection reagent, since Voss fails to teach detecting two or more variants of at least one host cell protein contaminant of interest, the reference also fails to specifically teach a primary antibody that specifically binds to the two or more variants of the host cell protein.
Bosteels et al. teach host cell proteins such as for example, putative phospholipase B-like 2 (PLBL2 or PLBD2) have been shown to have an increased propensity to co-purify with certain Ig variants (page 2, lines 7-22). PLBL2 is taught as an undesirable contaminant, having the potential to illicit immune response in patients and further has a potential causative agent for the degradation of formulation excipients necessary for stabilization of product protein in final formulation (thereby effecting shelf life and drug safety). Bosteels et al. teach use of anti-PLBL2 antibody for the detection of PLBL2 in an antibody preparation sample by western blot analysis (see for example, Example 2 at page 27).
Regarding a (singular) primary antibody that specifically binds to the two or more variants of PLBD2, see for example at Example 2 Bosteels et al. (at page 28, lines 5-21), teach an anti-PLBD2 polyclonal antibody as a commercially available antibody (Abcam, Ab138334).
Further, regarding polyclonal antibodies, see Rietveld, a reference comparing polyclonal and monoclonal antibodies, it is known in the art that polyclonal antibodies are a heterogeneous mixture of antibodies that recognize multiple epitopes, making them ideal for detection of modified proteins (see for example, first section “What are Polyclonal and Monoclonal Antibodies?”). See further in Rietveld, under “Polyclonal Antibodies in Multiplex Assays”, teaching polyclonal antibodies are known useful for detection protein isoforms and conformation variants, and further under “Best uses of polyclonal antibodies:”, the first bullet point, a best use is recognized in the art as to detect known or unknown isoforms of antigens with high antigen homology.
See also Burakov et al., Burakov is teaching invention based on a recombinant host cell and cell expression system thereof that decreases expression of two or more endogenous host cell fatty acid hydrolases; disrupting genes encoding at least two for optimized and efficient production and purification of biopharmaceutical produces expressed in these systems (see para [001117]). Burakov teach in addition to PLBD2, other fatty acid hydrolases in protein fractions of certain antibody -producing cells are considered contaminants, see for specifically Burakov teach an example of esterases, namely including PLDB2, lipoprotein lipase, and lysosomal acid lipase (para [00117], see also para [00127]).
Yu et al. teach for recombinant pharmaceutical proteins to be acceptable for administration to humans, it is important that residual impurities resulting from manufacture and purification processes are removed from the final product (para [0006]). Yu recognize that host cell impurities include process-specific host cell proteins (HCPs), which are process related impurities/contaminants, see Yu teaching a need to detect and quantitate HCPs. See further para [0017], consistent with Burakov, Yu teach PLBD2 as a species of CHOP (HCP) (see also para [0019]); at para [0017] Yu et al. teach it is known that PLBD2 exists as N and C terminal fragments (i.e., these variants are known to exist/be present, in addition to the intact form). Yu et al. also teach sample can be obtained from a step in the purification process or from the final purified product (purified sample).
Padhan teach cIEF as an automated, capillary-based immunoassay that is highly reproducible and capable of resolving proteins and their modified isoforms rapidly and quantitatively, Padhan teaching cIEF as an alternate to conventional methods such as western blotting (page 1 of 6, at the Introduction, paragraph 1). Padhan teach cIEF as a procedure that provides higher resolution and sensitivity.
It would have been prima facie obvious to one having ordinary skill in the art at the time the claimed invention was effectively filed to have applied the method of Voss for the detection of variants of PLBD2 (intact and variant forms of PLBD2, as taught by Yu et al.) in a purified antibody preparation sample as in Bosteel et al., Barkov et al. and Yu et al. (see specifically Yu, sample such as purified sample, namely to have modified Voss in order to perform the method on a purified sample for the detection of the targeted contaminants such as intact and variant forms of PLBD2). Specifically one motivated to use the technique on samples to detect PLBD2 (intact and truncated forms) because these endogenous host cell fatty acid hydrolases were recognized as undesirable contaminants that should be removed from final (i.e., purified) biological products (Yu et al.), for example see also Bosteel, teaching such contaminant as PLBD2 can potentially illicit immune response in patients and degrade excipients necessary for stabilization of antibody preparation products, reducing shelf-life and causing safety issues (Burakov and also Yu recognized PLBD2 as a contaminate that should be removed). Further the ordinarily skilled artisan would have been motivated to have used the technique of Voss (the cIEF) because cIEF is recognized as a suitable alternative to other detection techniques, for example western blot immunoassay (Bosteels using western blot), specifically because it is a rapid, quantitative alternative, which provides high resolution and sensitivity.
As a result, one having ordinary skill in the art would have a reasonable expectation of success, particularly since cIEF was recognized applicable for protein containing samples (Voss, Padhan), and see further one having a reasonable expectation of success given antibodies to these targets were known and available (see as cited above, Bosteel).
Regarding the limitation specific to a primary antibody that specifically binds to the two or more variants of the host cell protein, it would have been obvious to have used the specific polyclonal anti-PLDB2 antibody of Bosteel as the antibody to detect the PLDB2 variants because such an antibody would be expected to bind and detect the various forms in the sample because it is known that polyclonal antibodies are a heterogeneous mixture of antibody species capable of targeting various epitopes, usable for different protein isoform detection (see Rietveld). One having ordinary skill in the art would have a reasonable expectation because the polyclonal antibody of Bosteel was commercially available and known to those of ordinary skill in the art before the effective filing date of the claimed invention, and further would reasonably expect success because polyclonal antibodies were specifically recognized as useful for detection of different protein isoforms due to the heterogenous nature of the polyclonal antibodies (Rietveld).
Regarding claim 3-4 and 33, the combination of the cited art above addresses discriminating between proteins (and the variants of said proteins) of interest by a physical parameter, specifically by charge, using a separation matrix that is carrier ampholytes.
Regarding claims 6, see Voss also encompass embodiments separating by molecular weight (rather than charge), see for example para [0046], and more specifically, para [0060] (see for example separating in a gel (thereby addressing sieving matrix) by molecular weight).
Regarding claims 8 and 9, see the method of Voss involves contacting with a primary antibody, and a secondary labeled antibody for the primary antibody (e.g., para [0043]).
Regarding claim 11, see Voss above, the method is a quantitative detection method (detecting relative or absolute amounts).
Regarding claim 12, see Voss teach chemiluminescent or fluorescent label (e.g., para [0046] or [0066]).
Regarding claim 13, see Voss at paras [0035], [0036], particularly [0050], sample including internal standard.
Regarding claim 14, see Voss at paras [0061], [0094] (e.g., photoimmobilization).
Regarding claim 15, see for example Voss at para [0006], antibodies used in the methods can be polyclonal, see further the combination of the cited art teaching primary antibody that is a polyclonal antibody (antibodies which bind multiple epitopes, useable for detection of isoforms).
Regarding claim 16, see as cited in detail above, the combination of Voss and the cited art is addressing at least two variants of the species PLBD2 (Bosteels et al., cited above, see also Yu et al.).
Claim(s) 17-19, 21, 22, 24, 26-29, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Voss et al., US PG Pub No. 2009/0023156A1 (IDS entered 09/15/2020) in view of Bosteels et al., WO2018/065389A1, Rietveld, L., Polyclonal vs Monoclonal Explained. Stress Marq Biosciences Inc. (2015). https://www.stressmarq.com/blog/polyclonal-vs-monoclonal-antibodies/?srsltid=AfmBOopuJnojrsjzi2jd5Wt2bec5k2buTT_rkKSobzVVvrYjDZjgkEut. [Accessed 10/02/2025]., Burakov et al., WO2018039499A1, Yu et al., US PG Pub No. 2016/0319012A1, Padhan, N, Highly Sensitive and Quantitative Detection of Proteins and Their Isoforms by Capillary Isoelectric Focusing Method, Journal of Visualized Experiments, 139, (2018), (6 pages) and Bancel et a.., US 2013/0259924A1, as evidenced by Abcam. Anti-Lysosomal acid lipase/LAL antibody, ab89771. file:///C:/Users/emarcsisin/OneDrive%20-%20US%20Patent%20and%20Trademark%20Office/Documents/e-Red%20Folder/16880736/abcam%20ab89771.pdf . [Accessed: 10/02/2025]. (4 pages).
Voss et al. is as cited in detail previously above teaching a method of detection performed on a protein containing sample, specifically separating the components (protein components) of the sample by a physical parameter within a capillary (addressing one or more capillaries as claimed, see specifically addressing the elected species, namely resolving by isoelectric focusing, using an ampholyte reagent loaded in the fluid path for separation based on charge (paras [0061] and [0062]), contacting the separated components within the capillary with a primary antibody that binds protein of interest (para [0066], [0067]), and detecting the binding of the antibody (see abstract and paras [0023], [0024], [0042], [0046], [0061], [0062]). See further para [0071] the methods encompass using different detection agents, which bind and detect different types of analytes and standards for simultaneous detection. Voss also encompass embodiments separating by molecular weight (rather than charge), see for example para [0046], and more specifically, para [0060] (see for example separating in a gel (thereby addressing sieving matrix) by molecular weight).
As further cited above, Voss at paras [0043]-[0044] teaching a plurality of capillaries in order to analyze multiple samples simultaneously (i.e., detecting two or more proteins), splitting sample (capillaries loaded with the sample, singular, para [0043]). See also para [0063] refers to resolving one or more (thereby addressing at least 2) analytes (para [0063]).
Voss et al. differs from the claimed invention in that Voss fails to teach specifically applying their method of detection in order to detect two or more variants (i.e., different forms) of at least two or more host cell protein contaminants of interest in a purified antibody preparation sample (separate capillary for each host cell protein, detecting variants of one in one capillary, detected variants of the other in the other capillary), fails to teach first primary antibody specific for the two or more variants of the first host cell protein, second primary antibody specific for two or more variants of the second host cell protein.
Bosteels et al. is as cited previously above, teaching host cell proteins such as for example, putative phospholipase B-like 2 (PLBL2 or PLBD2) have been shown to have an increased propensity to co-purify with certain Ig variants (page 2, lines 7-22). PLBL2 is taught as an undesirable contaminant, having the potential to illicit immune response in patients and further has a potential causative agent for the degradation of formulation excipients necessary for stabilization of product protein in final formulation (thereby effecting shelf life and drug safety). Bosteels et al. teach use of anti-PLBL2 antibody for the detection of PLBL2 in an antibody preparation sample by western blot analysis (see for example, Example 2 at page 27).
Regarding a (singular) primary antibody that specifically binds to the two or more variants of PLBD2, see for example at Example 2 Bosteels et al. (at page 28, lines 5-21), teach an anti-PLBD2 polyclonal antibody as a commercially available antibody (Abcam, Ab138334).
Further, regarding polyclonal antibodies, see Rietveld, a reference comparing polyclonal and monoclonal antibodies, it is known in the art that polyclonal antibodies are a heterogeneous mixture of antibodies that recognize multiple epitopes, making them ideal for detection of modified proteins (see for example, first section “What are Polyclonal and Monoclonal Antibodies?”). See further in Rietveld, under “Polyclonal Antibodies in Multiplex Assays”, teaching polyclonal antibodies are known useful for detection protein isoforms and conformation variants, and further under “Best uses of polyclonal antibodies:”, the first bullet point, a best use is recognized in the art as to detect known or unknown isoforms of antigens with high antigen homology.
See also Burakov et al., Burakov is teaching invention based on a recombinant host cell and cell expression system thereof that decreases expression of two or more endogenous host cell fatty acid hydrolases; disrupting genes encoding at least two for optimized and efficient production and purification of biopharmaceutical produces expressed in these systems (see para [001117]).
Regarding claim 17, see further Burakov teach in addition to PLBD2, other fatty acid hydrolases in protein fractions of certain antibody -producing cells are considered contaminants, see for specifically Burakov teach an example of esterases, namely including PLDB2, lipoprotein lipase, and lysosomal acid lipase (LIPA/LAL) (para [00117], see also para [00127]). The reference further acknowledging variants of LIPA (see para [0049] and [0145]).
Yu et al. teach for recombinant pharmaceutical proteins to be acceptable for administration to humans, it is important that residual impurities resulting from manufacture and purification processes are removed from the final product (para [0006]). Yu recognize that host cell impurities include process-specific host cell proteins (HCPs), which are process related impurities/contaminants, see Yu teaching a need to detect and quantitate HCPs. See further para [0017], consistent with Burakov, Yu teach PLBD2 as a species of CHOP (HCP) (see also para [0019]); at para [0017] Yu et al. teach it is known that PLBD2 exists as N and C terminal fragments (i.e., these variants are known to exist/be present, in addition to the intact form). Yu et al. also teach sample can be obtained from a step in the purification process or from the final purified product (purified sample).
Padhan teach cIEF as an automated, capillary-based immunoassay that is highly reproducible and capable of resolving proteins and their modified isoforms rapidly and quantitatively, Padhan teaching cIEF as an alternate to conventional methods such as western blotting (page 1 of 6, at the Introduction, paragraph 1). Padhan teach cIEF as a procedure that provides higher resolution and sensitivity.
See also Bancel et al., teaching anti-lysosomal acid lipase antibody (Abcam, ab89771) is known and commercially available/obtainable to those of ordinary skill in the art (para [1958]). See the cited Abcam datasheet which is cited as evidentiary reference, Abcam shows that Abcam Antibody Ab897771 is a polyclonal antibody.
Regarding claim 17, as noted above, the claim recites detecting “two or more variants of two or more host cell protein contaminants of interest”, claim 32 further limiting “the host cell protein contaminants of interest” to those listed at the group recited at claim 32.
It would have been prima facie obvious to one having ordinary skill in the art at the time the claimed invention was effectively filed to have applied the method of Voss for the detection of variants of PLBD2 (intact and variant forms of PLBD2, as taught by Yu et al.) in a first capillary and for LIPA (intact and variant forms of LIPA, see Burakov et al.) in a second antibody, in a purified antibody preparation sample as in Bosteel et al., Barkov et al. and Yu et al. (see specifically Yu, sample such as purified sample, namely to have modified Voss in order to perform the method on a sample for the detection of the targeted contaminants such as intact and variant forms of PLBD2, and possible variants of HCP LAL).
Specifically one having ordinary skill would have been motivated to use the technique of Voss to detect HCP contaminants detect such as PLBD2 and LIPA/LAL, including variants (intact and truncated forms) of these HCPs because these endogenous host cell fatty acid hydrolases were recognized as undesirable contaminants that should be removed from final biological products (Burakov et al. and Yu et al.), for example see also Bosteel, teaching such contaminant can potentially illicit immune response in patients and degrade excipients necessary for stabilization of antibody preparation products, reducing shelf-life and causing safety issues (Burakov and also Yu recognized PLBD2 as a contaminate that should be removed). Further the ordinarily skilled artisan would have been motivated to have used the technique of Voss (the cIEF) because cIEF is recognized as a suitable alternative to other detection techniques, for example western blot immunoassay (Bosteels using western blot), specifically because it is a rapid, quantitative alternative, which provides high resolution and sensitivity.
As a result, one having ordinary skill in the art would have a reasonable expectation of success, particularly since cIEF was recognized applicable for protein containing samples (Voss, Padhan), and see further one having a reasonable expectation of success given antibodies to these targets were known and available (see as cited above, Bosteel and Bancel).
Regarding the limitation specific to a primary antibody that specifically binds to the two or more variants of each of the host cell proteins, it would have been prima facie obvious to have used the specific polyclonal anti-PLDB2 antibody of Bosteel as the antibody to detect the PLDB2 variants because such an antibody would be expected to bind and detect the various forms in the sample because it is known that polyclonal antibodies are a heterogeneous mixture of antibody species capable of targeting various epitopes, usable for different protein isoform detection (see Rietveld). One having ordinary skill in the art would have a reasonable expectation because the polyclonal antibody of Bosteel was commercially available and known to those of ordinary skill in the art before the effective filing date of the claimed invention, and further would reasonably expect success because polyclonal antibodies were specifically recognized as useful for detection of different protein isoforms due to the heterogenous nature of the polyclonal antibodies (Rietveld).
Similarly, it would have been prima facie obvious to have used the polyclonal antibody of Bancel (see as evidenced by Abcam) to detect LAL, for the same reasons, namely because such polyclonal antibodies were known as heterogenous antibody mixtures capable of detecting multiple different epitopes, capturing various isoforms. As indicated, one would have been motivated to target LAL, considering this recognized as a host cell species contaminant. One having ordinary skill in the art would have a reasonable expectation of success because polyclonal antibodies to LAL were also known and available to those hving ordinary skill in the art, and because Voss’s device and method are specifically taught as able to/for performing assay on multiple different capillaries for detecting different targeted proteins and host cell proteins are (as discussed in detail above) recognized as a type of protein that would benefit from this type of detection (e.g., Padhan).
Regarding claims 18 and 19, see Voss as cited previously above detecting with more than one (plurality of) antibodies, and see for example paras [0023], [0024], and further see as cited above, Voss teaching multiple capillary detection).
Regarding claims 21-22, the combination of the cited art above addresses discriminating between proteins (and their variants) of interest by a physical parameter, specifically by charge, using a separation matrix that is carrier ampholytes.
Regarding claim 24, Voss also encompass embodiments separating by molecular weight (rather than charge), see for example para [0046], and more specifically, para [0060] (see for example separating in a gel (thereby addressing sieving matrix) by molecular weight).
Regarding claims 26 and 27, see the method of Voss involves contacting with a primary antibody, and a secondary labeled antibody for the primary antibody (e.g., para [0043]).
Regarding claim 28, see Voss above, the method is a quantitative detection method (detecting relative or absolute amounts).
Regarding claim 29, see Voss teach chemiluminescent or fluorescent label (e.g., para [0046] or [0066]).
Regarding claim 31, see Voss at paras [0061], [0094] (e.g., photoimmobilization).
Regarding claim 32, see the combination taught by the cited art include host cell proteins that are PLBD2 and LAL.
Response to Arguments
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant disagrees with the reasons for rejection (remarks page 8-9), arguing that there is a lack of motivation to combine the referenced teachings. Applicant remarks (page 10) that Voss is not concerned with measuring or detecting impurities in a product, such as host cell proteins in a purified antibody preparation sample, much less variants of such.
However, this argument is not persuasive for the reasons discussed in the previous response to remarks, namely regarding the motivation (in part see from above), one having ordinary skill would have been motivated to use the technique (of Voss) on purified samples to detect HCPs, such as for example PLBD2 (intact and truncated forms), because these endogenous host cell fatty acid hydrolases were recognized as undesirable contaminants that should be removed from final biological products (Yu et al.), for example see also Bosteel, teaching such contaminant as PLBD2 can potentially illicit immune response in patients and degrade excipients necessary for stabilization of antibody preparation products, reducing shelf-life and causing safety issues (Burakov and also Yu recognized PLBD2 as a contaminate that should be removed).
Regarding the citation of Bosteels, Applicant argues Bosteels teach detecting and quantifying HCP contaminant PLBD2 in an antibody sample using ELISA (referring to Example 3), Applicant remarks that this ELISA is not capable of detecting variants of host cell proteins, and that there is no reason to deviate to use capillary electrophoresis as in Voss. However, Bosteels is not cited as primary reference, rather Voss et al. is teaching the base method using capillary electrophoresis for separation of targeted analytes. Specifically, regarding the analyses set forth in the rejection above, the reasoning applied is that it would have been obvious to have modified Voss in order to target variants of PLBD2. Nonetheless, see also regarding motivation to use cIEF as in Voss, the ordinarily skilled artisan would have been motivated to have used the technique of Voss (the cIEF) because cIEF is recognized as a suitable alternative to other detection techniques, for example western blot immunoassay (as in Bosteels western blot), specifically because it is a rapid, quantitative alternative, which provides high resolution and sensitivity. As such, there is specifically a motivation to use Voss’s technique in place of other assay techniques, such as those taught by Bosteels.
At remarks page 10-11 Applicant further argues that there is a lack of a reasonable expectation of success, Applicant argues as amended the claim recites that the protein contaminant is present in a “purified” antibody preparation. Applicant argues that one having ordinary skill would expect concentration of contaminants in already purified antibody sample would be substantially lower in than in the concentration of the antibody. Applicant argues that if one were to apply Voss’s method to detect variants of a host cell contaminant protein in purified sample, one would not have a reasonable expectation of success because the primary protein would overwhelm the detection signal arising from the contaminant protein.
However, this argument is not persuasive because cIEF is recognized as a suitable alternative to other detection techniques, for example western blot immunoassay (Bosteels using western blot), specifically because it is a rapid, quantitative alternative, which provides high resolution and sensitivity. Further, as earlier argued by Applicant, Bosteels et al. is teaching other assays techniques (such as ELISA, referring to Applicant’s earlier arguments) as suitable for detecting the claimed host cell contaminant proteins (see for example, as cited above Yu is teaching samples can involve samples taken from the purification process or after purification). Since the art recognized cIEF as a suitable alternative, and because cIEF is recognized as providing high resolution and sensitivity, one having ordinary skill in the art would have a reasonable expectation of success.
Applicant argues (remarks pages 11-12) unexpected results, asserting superior ability of the claimed method to detect contaminant proteins of variants at extremely low concentration levels in a purified antibody sample. Applicant refers to Figure 7 indicating HCP variants can be detected with acceptable resolution at a concentration of only 300 ng/ml (3ppm) as a lower limit by use of the claimed capillary method, compared to resolution achieved with ELISA. However, the argument that the capillary method achieves a greater resolution than ELISA is not persuasive that the claimed invention achieves an unexpected result over the cited prior art. In particular, the combination of the prior art is teaching assay that is similarly capillary method. There is motivation as set forth in detail above to combine the cited prior art. Further, in order to establish unexpected result, applicant must show evidenced that the results are in fact unexpected.
Whether evidence shows unexpected results is a question of fact and the party asserting unexpected results has the burden of proving that the results are unexpected. In re Geisler, 116 F.3d 1465, 1469-70, 43 USPQ2d 1362, 1364-5 (Fed. Cir. 1997). The evidence must be (1) commensurate in scope with the claimed subject matter, In re Clemens, 622 F.2d 1019, 1035, 206 USPQ 289, 296 (CCPA 1980), (2) show what was expected, to "properly evaluate whether a … property was unexpected", and (3) compare to the closest prior art. Pfizer v. Apotex, 480 F.3d 1348, 1370-71, 82 USPQ2d 1321, 1338 (Fed. Cir. 2007).
The burden of demonstrating unexpected results rests on the party asserting them, and “it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972). Moreover, it has been long held that “even though applicant’s modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art, unless the claimed ranges ‘produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art.” In re Huang, 100 F.3d 135, 139 (Fed. Cir. 1996) (quoting In re Aller, 220 F.2d 454, 456 (1955), and citing In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990)).
In this case, Applicant has not provided credible evidence or argument as to why these results may be characterized as unexpected or surprising.
For all of these reasons, Applicant’s arguments are not persuasive.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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