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.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2015/063781, filed 06/18/2015. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 14177005.7, filed on 07/15/2014 with the European Patent Office.
Status of the Claims
Claims 1-3, 6, 15-19, 21-25, 27 and 31-39 are pending; claims 18-19, 21-25, 27 and 31 are withdrawn; claims 4, 5, 7-14, 20, 26 and 28-30 are canceled; claims 2-3, 6, 15-17, 32-36, 38 and 39 are amended. Claims 1-3, 6, 15-17 and 32-39 are examined below.
Withdrawn Objections/Rejections
The previous objections to the claims are withdrawn in response to Applicant’s amendments to the claims.
Maintained Grounds of Rejection
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.
Claims 1, 6, 15, 16 and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Sayoko et al. JP2005337805 in view of Fowler et al., Self-Assembled Layer of Thiolated Protein G as an Immunosensor Scaffold, Anal. Chem., 79, (2007), p. 350-354 and Prober et al., US PG Pub No. 2005/0019842A1.
Sayoko is not an English language document; however, English language translations are available (see machine translation obtained via Dialog attached to the Office action mailed 7/17/2019; and English language translation of the patent provided by Google Patents, 5 pages, attached 01/30/2020). The citations of Sayoko below refer to the text of the Google Patents translation.
Sayoko teach methods for measuring the concentration of an antibody or antigen in a liquid sample, the methods of Sayoko comprising the steps of incubating sample in a well with labeled antibody-binding probe, such as Rhodamine Green or ALEXA® fluorescent dye labeled protein A (a generic antibody binding protein conjugated dye). See especially the abstract and page 2 of the attached translation. More particularly, Sayoko et al. teach using (i.e., selecting) a protein that binds with the antibody to be detected, at the end or terminal of the antibody, such as protein A or protein G (page 2), thereby selecting a generic antibody binding protein. Sayoko et al. further teach performing a fluorescence polarization assay on the mixture to detect change in polarization between excitation and emission light) (see for example page 3 of the translation, the three paragraphs following the paragraph describing Figure 1-2 (second half of page), exemplifying using Alexa647-labeled protein A to bind and detect antibodies, see page 3 “Flow 3” procedure; see also page 4, referring to Figures 3 and 4).
With respect to the recitation that the dye is a long-life fluorescent dye, Sayoko does teach Rhodamine Green as an example of the fluorescent dye that can be used (page 2), which is a long lifetime dye (for example Rhodamine with green emission having a long lifetime of about 4 ns, see for example Applicant’s own originally filed disclosure page 12, Rhodamine 101, i.e. Rhodamine with green fluorescence).
However, Sayoko does not specifically teach that the antibody binding protein is truncated (claim 1), specifically Sayoko differs from the claimed invention in that it fails to teach truncated protein G having at least one less antibody binding site than a full length protein G (claim 1); further fails to teach the truncated protein G having a molecular weight of less than 20kD (claim 6).
Fowler teach recombinant protein G, which binds antibody (IgG) through its constant Fc region. More particularly, Fowler teach a truncated protein G having a molecular weight of 17kDa (see page 354, col. 1, para 1; see page 351, first paragraph regarding binding of protein A or G to IgG, both were known to bind IgG). See also page 351, col. 1, Materials and Instrumentation section, Fowler purchased commercially available recombinant protein G (MW 17000), which therefore reads on truncated as per the specification at [0050]. Fowler teach protein G will only bind antibody through its Fc region (see page 354, col. 1, para 2), protein G has three Fc binding domains (page 351, col. 1, para 2).
Further, see for example Prober et al. at para [0365] describes truncated protein G. Prober et al. teach Protein G is a bacterial membrane protein separates from a group G streptococcal strain that can specifically bind the constant (Fc) region of mammalian IgG molecules. Prober teach an example of truncated protein G, which lacks the albumin, Fab, and membrane binding sites while retaining the Fc binding site is more specific for IgG than the native form of the protein.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Sayoko et al., in order to have selected and used the truncated recombinant protein G of Fowler (the recombinant protein G having a molecular weight of only 17000 (17kDa), thereby also addressing claim 6) as the antibody terminal binding protein G, when performing the methods of Sayoko, as an obvious matter of a simple substitution of one known generic antibody binding protein for another. Specifically, each of the generic binding proteins (namely, truncated protein G of Fowler, and protein G (not truncated) of Sayoko) were known (and known for their use) in the art for binding IgG, Sayoko differing from that which is claimed in that Sayoko does not teach a truncated version of the protein (Sayoko does teach both protein A and G as generic antibody binding proteins).
One of ordinary skill in the art would have found it prima facie obvious to have substituted the truncated protein G for the protein G of Sayoko and reasonably expected success (namely no change in the binding in terms of the ability to bind/detect IgG as targeted by Sayoko, as in the truncated protein would still be expected to bind and detect) since both were art recognized proteins that were known in the art to bind IgG (both were known for the same purpose, and as such, one would expect success using the truncated version of the protein, see Fowler).
Even further, one having ordinary skill in the art would have been motivated to rely on truncated forms of protein G for antibody binding (truncated to, for example omit the Fab binding site, as in Prober) rather than the full length protein G because Prober teach truncated forms are more specific (the art suggesting that the omission of non-Fc binding sites, such as Fab binding site and albumin binding site, improves antibody binding specificity).
Similarly, regarding the amended language “wherein employing the selected truncated Protein G having the at least one less antibody-binding site increase the sensitivity relative to employing the full length protein G” (and see at the preamble, the preamble previously amended in order to recite “method for increasing sensitivity), as noted previously above, the combination of the cited art addresses a method comprising the same steps, elements/reagents as claimed. As a result, it is expected that the method as taught by the cited art achieve/result in the same sensitivity as claimed, namely sensitivity that is increased relative to the method with a higher molecular weight protein G, since this appears to be natural consequence of the use of the truncated form, and the prior art does provide direct motivation (Prober for example) to rely specifically on truncated protein G for detection/binding antibody target (more specific for antibody binding). See for example, MPEP 2144, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. Therefore, while Applicant’s claim recites and asserts “increase in the sensitivity”, the prior art does provide a motivation to rely on truncated forms of the protein (more specific antibody binding), it would be expected that since the combination of the prior art is using the same truncated protein as claimed, the method would similarly result in increase in the sensitivity relative to methods performed with full length protein G.
Regarding the limitation “truncated protein G having at least one less antibody-binding site than a full-length Protein G”, see Applicant’s originally filed specification at page 9, Applicant discloses “probes, which have a molecular weight of approximately 20 kD are modified to have at least one IgG binding domain removed”. As cited previously and above, Fowler’s truncated protein G is reported as having a molecular weight of 17 kDa. Absent evidence to the contrary, the truncated form of the protein is structurally indistinct from those presently claimed, particularly since those probes reported to be below 20 kDa are indicated by Applicant’s originally filed specification to be missing at least one IgG binding domain.
Regarding claim 15, see Sayoko teach performing the assay in the wells of a multiwell plate (see cited above, page 5 of the translation, paragraph 6).
Regarding claim 16, Sayoko does teach sample that is a cell culture fluid (see page 1 of the translation, paragraph 3, and page 3, paragraph 2).
Regarding claim 37, see the analysis above (regarding claim 1), as the same reasoning also applies presently.
Regarding claims 38 and 39, (limitations previously recited at the independent claims), the newly recited claims recite “wherein the determining of concentration of the antibody in the liquid sample down to a level of 0.001 mg/ml”, the limitation appears to be indicating the method is capable of detecting down to a level of 0.001 mg/ml (as previously recited at claim 1). However, as indicated previously (see also previous response to remarks), the combination of the cited art addresses the method steps and elements as presently recited (comprising fluorescent polarization assay measurement, capturing target analyte using truncated protein G), as such, it would be expected that the combination of the cited art would therefore similarly be capable of/achieve the same the same sensitivity, namely sensitivity to detect antibody concentration down to a level of 0.001mg/ml).
Claims 1, 3, 6, 15, 16 and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Sayoko et al. JP2005337805 in view of Fowler et al., Prober et al., Montero-Julian et al., US PG Pub No. 2005/0095655A1 and Chiapetta et al., U.S. Patent No. 4,751,190.
Regarding claim 3, Sayoko et al. and the cited prior art (cited previously above, including Fowler and Prober) teach a method substantially as claimed, the method comprising fluorescence polarization assay to measure the concentration of antibody in a sample using a fluorescent dye having a lifetime of at least 4 ns (see as detailed previously above, as the analyses applied above, Sayoko modified by Fowler at claim 1, also applies presently).
However, Sayoko et al. teaches Rhodamine Green as an example of the fluorescent dye that can be used, and as such fails to teach FITC (an alternative recited at claim 3).
Montero-Julian et al. teach, regarding bound detectable label, FITC molecule as a label preferred over other labels because of its small size (MW 389 Daltons) and because it can be coupled easily to peptides, see also the reference teaching most importantly the FITC molecule has very high yield compared to other fluorochromes, such as Alexa® dyes or others (para [0127]). As such, Montero-Julian et al. teach FITC as a desirable label compared to Alexa dyes.
Chiapetta et al. also teach that fluorescein and derivatives, such as FITC, have properties that are useful as tracer compounds in fluorescence polarization immunoassays. These compounds provide the fluorescent response when excited by polarized light of an appropriate wavelength, thereby to enable the fluorescence polarization measurement to be made. As examples, Chiapetta et al. name FITC and DTAF. See column 4, line 55 to column 5, line 10.
As such, it would have been additionally prima facie obvious to one having ordinary skill before the effective filing date of the claimed invention to have modified the method of Sayoko, Fowler and Prober (see previously above) in order to have provided FITC as the label (FITC-truncated protein G as the antibody binding protein conjugate), one having ordinary skill in the art would have been motivated to use the label FITC because it was known in the art that FITC is a suitable label for use in fluorescence polarization assays and in fact is a superior, more desirable label compared to labels such as the Alexa® dye (another alternative, as used in Sayoko, see as is taught by Montero-Julian et al., teaching FITC has higher yield compared to other fluorochromes such as Alexa dyes). One having ordinary skill in the art would have had a reasonable expectation of success in using FITC because the art specifically disclosed FITC as a suitable label for polarization assay (see as in Chiapetta, teaching this as a suitable label for fluorescence polarization assays, Sayoko teaching fluorescent polarization assay). One would expect success using a known reagent for its art recognized purpose.
Regarding claim 3, see as cited previously above, the combination of the cited art teaches the long lifetime fluorescent dye, FITC.
Regarding claim 15, see Sayoko teaching performing the assay in the wells of a multiwell plate (see cited above, page 5 of the translation, paragraph 6).
Regarding claim 16, Sayoko does teach sample that is a cell culture fluid (see page 1 of the translation, paragraph 3, and page 3, paragraph 2).
Regarding claim 37, see the analysis above (regarding claim 1), as the same reasoning also applies presently.
Regarding claims 38 and 39, (limitations previously recited at the independent claims), the newly recited claims recite “wherein the determining of concentration of the antibody in the liquid sample down to a level of 0.001 mg/ml”. However, as indicated previously (see also previous response to remarks), the combination of the cited art addresses the method steps and elements as presently recited (comprising fluorescent polarization assay measurement, capturing target analyte using truncated protein G), as such, it would be expected that the combination of the cited art would therefore similarly achieve the same ability, namely achieve/be capable of the same sensitivity with the ability to detect antibody concentration down to a level of 0.001mg/ml).
Claims 1, 6, 15, 16, 32 and 33-39 are rejected under 35 U.S.C. 103 as being unpatentable over Sayoko et al. JP2005337805 in view of Allemann et al., US PG Pub No. 2010/0086490A1, Prober et al., US PG Pub No. 2005/0019842A1 and as evidenced by Selenko et al., Quantitative NMR analysis of the protein G B1 domain in Xenopus laevis egg extracts and intact oocytes, PNAS, 103(32), (2006) p.11904-11909.
Sayoko is as cited previously and above. Sayoko teach methods for measuring the concentration of an antibody or antigen in a liquid sample, the methods of Sayoko comprising the steps of incubating sample in a well with labeled antibody-binding probe, such as Rhodamine Green or ALEXA® fluorescent dye labeled protein A (a generic antibody binding protein conjugated dye). See especially the abstract and page 2 of the attached translation. More particularly, Sayoko et al. teach using a protein that binds with the antibody to be detected, at the end or terminal of the antibody, such as protein A or protein G (page 2), (a generic antibody binding protein). Sayoko et al. further teach performing a fluorescence polarization assay on the mixture to detect change in polarization between excitation and emission light) (see for example page 3 of the translation, the three paragraphs following the paragraph describing Figure 1-2 (second half of page), exemplifying using Alexa647-labeled protein A to bind and detect antibodies, see page 3 “Flow 3” procedure; see also page 4, referring to Figures 3 and 4).
With respect to the recitation that the dye is a long-life fluorescent dye, Sayoko does teach Rhodamine Green as an example of the fluorescent dye that can be used (page 2), which is considered to be a long lifetime dye (for example Rhodamine with green emission having a long lifetime of about 4 ns, see for example Applicant’s own originally filed disclosure page 12, Rhodamine 101, i.e. Rhodamine with green fluorescence).
Sayoko does not teach that the antibody binding protein is truncated protein G having at least one less antibody-binding site than a full length protein G (claim 1), namely truncated protein G having a molecular weight of less than 20 kD (claim 6); having a molecular weight of less than 15 kD (claim 32), or less than 10 kD (claim 33).
As indicated previously above (Sayoko), it was well known in the art that Protein G and protein A are antibody binding components/molecules. In particular, the prior art recognized these molecules as Fc binding components, see in addition to Sayoko et al., Allemann et al. at para [0069]-[0073] (examples of suitable Fc-binding components include proteins having binding affinity for the Fc-region of antibodies, such as natural or recombinant protein G or A or recombinant fusion protein A/G). At para [0074] Allemann et al. teach additional Fc-binding components include fragments of these proteins, such as a fragment of the B1 domain of protein G, see Allemann teaching this as a commercially available protein.
Further, see for example Prober et al. at para [0365] describing truncated protein G. Prober et al. teach Protein G is a bacterial membrane protein separates from a group G streptococcal strain that can specifically bind the constant (Fc) region of mammalian IgG molecules. Prober teach an example of truncated protein G, which lacks the albumin, Fab, and membrane binding sites while retaining the Fc binding site is more specific for IgG than the native form of the protein.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have selected and used the Protein G binding fragment (B1 domain, i.e. truncated protein G, as in Allemann) as the antibody binding protein G, as taught by Sayoko et al., when performing the methods of Sayoko, as an obvious matter of a simple substitution of one known generic antibody binding protein for another. Specifically, each of the generic binding proteins (the truncated protein G, such as the protein G B1 domain fragment of Allemann et al. and protein G generally as in Sayoko) were art recognized binding proteins known for the same purpose, namely for binding IgG, each were recognized in the art as suitable alternatives (see as in Allemann, the truncated form of protein G recognized also as binding). Further protein G, as well as the truncated version (truncated protein G), were both known to those of ordinary skill to be readily, commercially available (Allemann). One of ordinary skill would have substituted one for the other and had a reasonable expectation of success (namely no change in the binding, as in the truncated protein would still be expected to bind and detect) since both were art recognized proteins that bind IgG (a simple substitution of the truncated version for protein).
Even further, one having ordinary skill in the art would have been motivated to rely on truncated forms of protein G for antibody binding rather than the full length protein G because Prober teach truncated forms are more specific (the art suggesting that the omission of non-Fc binding sites improves antibody binding in terms of being more specific for IgG).
Similarly, regarding the amended language “wherein employing the selected truncated Protein G having the at least one less antibody-binding site increase the sensitivity relative to employing the full length protein G” (and see at the preamble, the preamble previously amended in order to recite “method for increasing sensitivity), as noted previously above, the combination of the cited art addresses a method comprising the same steps, elements/reagents as claimed. As a result, it is expected that the method as taught by the cited art achieve the same sensitivity as claimed, namely sensitivity that is increased relative to the method with a higher molecular weight protein G, since this appears to be natural consequence of the use of the truncated form, and the prior art does provide direct motivation (Prober for example) to rely specifically on truncated protein G for detection/binding antibody target (more specific for antibody binding).
See for example, MPEP 2144, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. Therefore, while Applicant’s claim recites and asserts “increase in the sensitivity”, the prior art does provide a motivation to rely on truncated forms of the protein (more specific antibody binding), it would be expected that since the combination of the prior art is using the same truncated protein as claimed, the method would similarly result in increase in the sensitivity relative to methods performed with full length protein G.
Regarding the limitation “truncated”, namely that the “generic antibody-binding protein is truncated Protein G”, the B1 domain fragment of Protein G, as taught by Allemann et al. is consistent with Applicant’s originally filed specification (see at page 9, Applicant indicates the term “truncated generic antibody binding protein” is understood to mean generic antibody binding protein that is modified to remove part of the protein, thereby reducing its molecular weight, see further the term includes fragments of generic antibody binding proteins, including for example peptide gb1, a fragment of protein G). Further, the fragment of protein G as taught by Allemann (the B1 domain) addresses claims 6, 32 and 33 because the truncated protein G of Allemann is less than 10 kD (and as such, is necessarily also less than 15kD and 20kD). Specifically, a chemical composition and its properties are inseparable (MPEP 2112.01), therefore if the prior art teaches an identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In the present case, Applicant’s disclosure (specification, page 9) indicates the B1 domain of protein G as an example of binding protein of less than 10kD, as presently claimed.
As indicated in detail above, Allemann is teaching the same binding protein (B1 domain of protein G).
As a result, it would further be expected (for the same reasons, namely since a chemical composition and its properties are inseparable) that the method as taught by the combination of the cited art, comprising the truncated form of protein G (B1 domain), achieve a higher sensitivity as compared to methods comprising higher molecular weight protein. Put another way, because the combination of the cited art is relying on the same truncated protein as claimed, it would necessarily be expected to achieve or result in the same binding as claimed in terms of sensitivity (i.e., have lower binding affinity than higher molecular weight fragment as claimed, considering the truncated protein taught by the art is structurally indistinguishable/the same truncated protein as disclosed by Applicant as having these claimed characteristics).
One of ordinary skill would have a reasonable expectation of success using the truncated form of the protein because it was recognized in the art to achieve binding (is taught as a suitable binding protein in place of the whole protein, namely it would still be expected to bind antibody, e.g., Allemann), and because truncated forms of the protein were indicated to achieve more specific binding (Prober et al.).
Regarding claims 38 and 39, (limitations previously recited at the independent claims), the newly recited claims recite “wherein the determining of concentration of the antibody in the liquid sample down to a level of 0.001 mg/ml”. However, as indicated previously (see also previous response to remarks), the combination of the cited art addresses the method steps and elements as presently recited (comprising fluorescent polarization assay measurement, capturing target analyte using truncated protein G), as such, it would be expected that the combination of the cited art would therefore similarly achieve the same ability, namely achieve the same sensitivity with the ability to detect antibody concentration down to a level of 0.001mg/ml).
Regarding claim 15, see Sayoko teaching performing the assay in the wells of a multiwell plate (see cited above, page 5 of the translation, paragraph 6).
Regarding claim 16, Sayoko does teach sample that is a cell culture fluid (see page 1 of the translation, paragraph 3, and page 3, paragraph 2).
Regarding claims 34 and 35, see as discussed in detail above the fragment of protein G as taught by Allemann (the B1 domain) is truncated protein G that is less than 10 kD (and as such, is necessarily also less than 15kD and 20kD), Allemann’s truncated protein G therefore addressing truncated protein having no more than one IgG binding site. As further evidence, see Selenko at page 11904, col. 2, para 3, which indicates the protein G B1 domain is 56 residues and has a molecular weight of 7kDa.
Regarding claim 36, see the evidence (Selenko) as cited above, the G B1 domain taught by Allemann is 7kDa. See also paras [0071]-[0073], Selenko does describe protein G tagged with a His-Tag (his-tagged IgG binding receptor). Although at para [0074] Allemann fails to teach the B1 domain as His-tagged protein G, given that it was known to provide protein G and protein G fragments tagged with a His-tag, it would have been an obvious matter to try. Namely, it would have been obvious to provide the B1 domain as a His-Tagged fragment as this was an art recognized, prior art known manner of providing such binding proteins. One having ordinary skill in the art would have a reasonable expectation of success considering it was known in the art (before the effective filing date) to provide such binding fragment as His-tagged proteins.
Regarding claim 37, see the analysis above (regarding claim 1), as the same reasoning also applies presently.
Claims 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Sayoko et al. in view of Fowler et al. and Prober et al., as applied to claim 1 above, and further in view of Berlin et al., US PG Pub No. 2004/0121359; or alternatively, Sayoko et al. in view of Fowler et al., Prober et al., Montero-Julian et al. and Chiapetta et al., as applied to claim 1 above, and further in view of Berlin et al; and alternatively, Sayoko et al. in view of Allemann et al. and Prober et al., and as evidenced by Selenko et al., as applied to claim 1 above, and further in view of Berlin.
Sayoko et al. and the cited prior art teach a method substantially as claimed, the method comprising fluorescence polarization assay to measure the concentration of antibody in a sample using a fluorescent dye having a lifetime of at least 4 ns (see as detailed previously above).
However, Sayoko and the cited art each fails to teach fluorescent dye having a lifetime of at least 5 ns (claim 2); fails to teach long lifetime dye is FITC (claim 3) (see the alternative grounds of rejection above, each teaching labels with lifetimes of 4ns).
Berlin et al. also teach that there are wide variety of fluorophores suitable for use in fluorescence polarization techniques (see para [0090]), Berlin teaching selection of appropriate fluorophores is within the skill level of the ordinary artisan (see at para [0090] Berlin teach a finite list of exemplary fluorophores, including fluorophores with at least 5 ns, such as BODIPY).
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Sayoko et al. and the cited prior art in order to rely on a fluorescent dye with a lifetime of 5 ns, such as BODIPY of Berlin, in place of the 4ns fluorescent dyes (such as those in Sayoko for example) as an obvious matter of a simple substitution of one known long lifetime dye for another, both usable for the same purpose (for the same type of assay, fluorescence polarization).
Additionally, it also would have been obvious to have arrived at a dye having a lifetime of at least 5 ns out of routine optimization of experimental parameters, specifically because it was known in the art before the effective filing date that selection of a dye is within the skill level of the ordinary artisan (see as taught by Berlin). It would have been obvious to have arrived at a dye such as BODIPY-Texas red as in Berlin as an obvious matter to try, selecting from alternatives disclosed in the finite list of suitable alternatives as disclosed by Berlin. The ordinarily skilled artisan would have a reasonable expectation of success because Berlin teach these dyes used for fluorescence polarization assays.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Sayoko et al. in view of Fowler et al. and Prober et al., as applied to claim 1 above, and further in view of Li et al., Cell culture processes for monoclonal antibody production, Landes Bioscience, 2(5), (2010), p. 466-477; or alternatively, claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Sayoko et al. in view of Fowler et al., Prober et al., Montero-Julian et al. and Chiapetta et al., as applied to claim 1 above, and further in view of Li et al.; and alternatively, Sayoko et al. in view of Allemann et al. and Prober et al., and as evidenced by Selenko et al., as applied to claim 1 above, and further in view of Li et al.
Sayoko et al. in view of the cited prior art teach a method substantially as claimed (see as set forth in detail previously above).
However, the previously discussed references fail to specifically teach that the cell culture sample is a cell culture fluid from a biopharmaceutical producer cell culture.
Li teach animal culture technology has advanced significantly and is not generally considered a reliable, robust and relatively mature technology, that a range of bio therapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities (abstract, see page 466, col. 1, para 1, teaching protein therapeutics, especially monoclonal antibodies). See at page 467, col. 1-2, Li discuss mammalian expression systems, Li teach therapeutic antibodies are mainly produced in mammalian host cell lines (para 1), and teach that CHO cells are the predominant host use to produce therapeutic proteins (col. 2, para 2).
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have employed the methods of detecting antibodies of Sayoko and the combined cited prior art, in order to detect antibodies in an antibody expression system that is a cell culture fluid from a biopharmaceutical producer cell culture (such as a CHO expression system), the motivation to do so being to detect desirable therapeutic mAbs (one would be motivated because said expression system is an art recognized, desirable system for producing therapeutic mAbs). Such a modification would merely be a simple substitution of one known antibody producing culture system for another (modifying the A549 system for a therapeutic producing system, such as the well-known CHO expression culture system), both systems known in the art, further it known that both systems produce antibodies detectable by generic antibody binding protein. Furthermore, as Sayoko pertains to detection of antibodies in general, it would have been obvious to adapt such methods in order to detect therapeutic antibodies in production, e.g. in order to verify and/or quantify yield.
One of ordinary skill would have a reasonable expectation of success since the method as taught by the combination of the art relies on a protein with affinity generic to the produced antibodies.
Response to Arguments
Applicant's arguments filed 09/08/2025 have been fully considered but they are not persuasive for the following reasons.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant argues that although the prior art describes the use of protein G and truncated protein G with a molecular weight of 17 kDa, this does not indicate the manner of truncation (remarks page 8). Applicant argues Fowler does not teach protein G having at least one less antibody binding site than a full length protein G, as recited at claim, Applicant arguing this is because Fowler’s principle of operation is maximum binding.
However, this argument is not persuasive, there is no evidence of record to support that the truncated protein G of Fowler (the commercially available recombinant protein G having MW 17000) is distinct from the truncated protein G presently claimed. Further, based on the cited prior art of record, both full length and truncated forms of protein G were well known, available and known to be usable for antibody binding (for binding IgG). Fowler’s reference teaching their protein G only binding through the Fc binding region, see Prober, teaching truncated forms that bind the Fc region, these forms lacking Fab binding sites. Applicant’s argument is not persuasive, because based on the cited prior art, there does not appear to be a distinction between the truncated protein G of the prior art and that as recited by Applicant.
Applicant further remarks (page 8) that Prober does not remedy this deficiency. Applicant argues that while Prober’s truncated protein G may be more specific for IgG relative to, e.g., IgA, etc., a binding affinity of Prober’s truncated protein G to IgG would be reduced relative to a binding affinity of Prober’s truncated G in native form. Applicant’s argument is acknowledged, however, regardless of which is expected to exhibit a better or reduced binding affinity, the fact remains that both native and truncated forms of the protein were known and used, prior to Applicant’s effective filing date, for binding and detection of IgG. Both native and truncated forms were taught for this purpose, and as a result, the use of either is not considered unobvious. There does not appear to be a critical difference between the use of the native or the truncated forms of this protein for binding and detection of IgG.
At remarks page 8, Applicant argues that one having ordinary skill in the art would not considered Prober’s truncated Protein G’ as a substitute for Protein G of Sayoko because the binding affinity would have been expected reduced, and as a result would have expected to result in a decreased sensitivity. Applicant argues there is no motivation to try such a substitution as set forth in the rejection in view of NPL document by Ligand (biochemistry) retrieved only, cited in IDS entered 11/27/2023. Applicant argues that this argument was not previously addressed by the Office, asserting that Ligand discloses that greater binding affinity gives greater sensitivity in binding assays, as is represented by the graph reproduced in remarks at page 9. Applicant argues the modification would be expected to decrease sensitivity (suggesting it would be expected that the truncated form would show a decrease in affinity) (see remarks page 9).
However, referring to the cited art in detail previously and above, Sayoko in view of Fowler and Prober together suggests a truncated form of the protein binding IgG at the Fc region (Fowler teach the recombinant protein bind through its constant Fc region, Prober teaching a truncated form omitting the Fab binding region, and having Fc binding region). It is the case that the protein binding at the Fc region is a high affinity binding event, see cited merely as evidence to support this position in response to remarks, Millipore Sigma, “Protein G and Protein A Bind to Different IgG, https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/protein-biology/protein-pulldown/protein-a-g-binding?srsltid=AfmBOoqb0_mF5Rv6N9D2nBmEjbX3yuW0btY376E8gxFTfJtJt8Hp8VVc [Accessed: 09/29/2025] (see first line referring to “high affinity of protein G and protein A for the Fc region”). Considering the truncated protein G taught by the cited prior art in the rejection is truncated protein G exhibiting binding for the Fc region, it would be expected that this would exhibit binding at a high affinity. As a result, while higher affinity is expected to improve sensitivity based on Applicant’s submitted evidence “Ligand”, these arguments are not persuasive considering that the truncated form of protein G, exhibiting Fc binding, would be expected to exhibit high affinity binding.
At remarks page 10, Applicant further argues the additional grounds of rejection, further citing Montero-Julian and Chiapetta, Applicant argues neither of these references addresses the above argued deficiencies as they are silent as to “[a] method for increasing sensitivity of determining antibody concentration in a liquid sample” (see through remarks page 11). However, this argument is not persuasive for the reasons discussed in detail above.
Applicant also argues the additional grounds of rejection at remarks pages 12-14, the rejection citing Sayoko et al. in view of Alleman et al., Prober, and as evidenced by Selenko et al. Applicant argues the combination of the cited art does not address all the limitations as claimed. Specifically (remarks page 13) Applicant argues one of ordinary skill in the art would have predicted that the substitution would have reduced binding affinity, thereby rendering Sayoko’s method to be less effective. Applicant argues that it would be expected that the modification result in reduced binding affinity, referring to Ligand as evidence (consistent with citation/reference to Ligand discussed in remarks above). However, this argument is not persuasive for the same reasons as discussed in detail previously above. As noted above, both native and truncated forms of protein G were known and used (and available to those of ordinary skill in the art) for binding and detection of IgG. Further, protein G binding to the Fc region was considered high affinity binding. Also, Allemann et al. at para [0069]-[0073] (examples of suitable Fc-binding components include proteins having binding affinity for the Fc-region of antibodies, such as natural or recombinant protein G or A or recombinant fusion protein A/G). At para [0074] Allemann et al. teach additional Fc-binding components include fragments of these proteins, such as a fragment of the B1 domain of protein G, see Allemann teaching this as a commercially available protein.
At remarks pages 14-15 Applicant further argues the additionally cited reference (Berlin, Li ) do not cure the asserted deficiencies, however, see response to arguments as detailed above, the combination of the cited art indicated above does address the limitations of the claims.
For all of these reasons, Applicant’s arguments are not persuasive, and the rejections are maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677