DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Response to Amendment
Applicant's request for reconsideration of the finality of the rejection of the last Office action is persuasive and, therefore, the finality of that action is withdrawn.
Priority
The present application was filed 04/02/2020 and is a division of 14/356,735. Application 14/356,735 was filed as a proper National Stage (371) entry of PCT Application No. PCT/DK2012/000119, filed 11/08/2012, which claims benefit of provisional application No. 61/556,916, filed 11/08/2011. Acknowledgement is also made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. PCTDK2011000131, filed in Denmark on 11/08/2011.
Status of the claims
Claims 17-25 and 31-41 are pending. Claims 26-30 are cancelled. Claims 17, 31, 37 and 40 are amended. Claims 17-25 and 31-41 are examined below.
Withdrawn rejection
After further consideration the rejection under 35 U.S.C. 103 is withdrawn. See new grounds of rejection below.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17-25, 31-37, and 40-41 stand rejected under 35 U.S.C. 112 for the reasons of record, reiterated below.
Claims 17-25, 31-37 and 40-41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 17, 31, and 40 are indefinite because claim 17 recites an “the binding partner present in a reference sample”, claim 31 similarly recites an “the binding partners in a reference sample” and claim 40 recites an “the target in a reference sample”. It is unclear what the reference sample comprises, for example which particular binding partner or target is present in the reference sample, and since the claim is silent regarding the reference sample, one would not be able to use an unknown to determine the amount. Because it is unclear that the reference sample is of the same nature as the binding partner or target, i.e. that the binding agent present in the kit would be capable of specifically binding to the binding partner or target present in the reference sample, therefore the claim language is indefinite.
Claims 18-25 depend on claim 17 and are therefore also indefinite.
Claims 32-37 depend on claim 31 and are therefore also indefinite.
Claim 41 depends on claim 40 and is therefore also indefinite.
Claim 37 recites “wherein the concentration of the binding agent in the composition is greater than a predetermined Kd (dissociation constant) value of the binding agent binding-partner complex”. The recited language is indefinite, because the limitation appears to place a limitation to the amount (the concentration) in terms of an unspecified Kd value; one having ordinary skill cannot readily visualize what concentrations would and would not be encompassed by the recited language, and as such the boundaries of the claim are unclear.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 19 recites the broad recitation “wherein amounts of the first and second binding molecules are in a predetermined ratio”, and claim 17 from which claim 19 depends also recites “a mixture of first binding molecules and second binding molecules in a predetermined ratio in which the second binding molecules are present in a greater amount than the first binding molecules” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 23 depends on claim 19 is therefore also rejected.
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 (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.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 17-20, 22-23, 31-40 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dowd et al., US7396689 (PTO-892, 02/06/2028) in view of Flavell et al. (1998) “Host-mediated Antibody-dependent Cellular Cytotoxicity Contributes to the in Vivo Therapeutic Efficacy of an Anti-CD7-Saporin Immunotoxin in a Severe Combined Immunodeficient Mouse Model of Human T-Cell Acute Lymphoblastic Leukemia”, Cancer Research, 58, pages 5787-5794 (PTO-892 05/08/2024), Linke et al., US20090061422A1 (PTO- 892, 12/01/2022), and Zuk et al., US 4,208,479, 06/17/1980 (PTO-892, 07/27/2023).
Regarding claim 17, Dowd teaches a specifically selective binding reagent which binds an analyte which is or may be present in a sample that is specific for the analyte (first binding molecule; capable of specifically binding to a binding partner in a sample) and further teaches a scaling agent (second binding molecule) which has a binding specificity for the analyte and inhibits binding of a sub-population of the analyte with its corresponding capture agent (both first and second binding molecules capable of binding and competing for said binding). Dowd further teaches that the sample is allowed contact with the scaling agent prior or together with the capture agent and that preferably the capture reagent is bound to a solid support (Dowd, column 3, lines 20-33).
Put another way, Dowd teaches a binding agent comprising a first and a second binding molecule contacting the sample at the same time wherein the first binding molecule can be but is not necessarily bound to a solid support. Dowd further teaches that the scaling agent includes all substances which are able to bind the analyte directly or indirectly and preferably has a high affinity, typically being at least about 107 M-1, 109 M-1, 1010 M-1, and optimally being 1011 M-1 or 1012 M-1 or greater (Dowd, column 3, lines 52-61). Dowd further teaches that the association between the scaling agent and the analyte, e.g., when the analyte is an antigen, is based on highly specific noncovalent interactions between the antigenic determinant, or epitope, of the antigen and the variable-region domain of an antibody molecule used as the scaling agent. Dowd further teaches that the scaling agent can be a monoclonal or polyclonal antibody raised against the analyte or the scaling agent can be another molecule harvested or engineered for the purpose of specifically binding to an analyte (Dowd, column 3, line 63- column 4, line 9). Dowd further teaches that the amount of capture antibody is small relative to the amount of scaling agent employed to adjust the linear range of the assay, so that the molar amount of capture antibody need not be accounted for in the equilibrium conditions (second binding molecules are present in a greater amount than the first binding molecules; Dowd, column 18, lines 18-23). Dowd further teaches introducing a certain amount of the scaling agent to the sample to create a reaction mixture where the total concentration of scaling agent (bound to the analyte and free scaling agent) is preferably greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture (amount of binding agent is sufficient to bind to substantially all units of a binding partner; Dowd, column 5, lines 18-27). Dowd further teaches spiking varied concentrations of cytokines into serum and measuring using a multiplexed immunoassay and adding scaling antibody to scale the concentration of one analyte for detection and further teaches that four of the targets assayed saturate at the high end of the concentration range (a reference sample having a predetermined amount of binding partner; Dowd, column 20, lines 55-65 and Figure 13). As such Dowd teaches an amount of binding agent sufficient to bind to substantially all units of the binding partner in a reference sample having a predetermined amount of the binding partner.
Even though Dowd does not explicitly teach a predetermined ratio of first and second binding molecules, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made from Dowd, to have added the first and second binding molecules in a predetermined ratio in order to ensure that the second binding molecule was present in a greater amount than the first binding molecule because the amount of capture antibody is small relative to the amount of scaling agent and the total concentration of the scaling agent is greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture so that the molar amount of capture antibody need not be accounted for in the equilibrium conditions.
Dowd fails to teach a first binding molecule comprising a binding part and a detectable part and the second binding molecule comprising a binding part. Dowd further fails to teach that the first binding molecule comprises an antibody molecule or derivative thereof, comprising an Fc region, wherein the detectable part comprises the Fc region and the second binding molecules do not comprise a part that can be detected by the detector of the first binding molecules and the second binding molecule does not comprise the Fc region of the first binding molecules. Dowd further does not teach a reference sample that has cells in it.
Flavell teaches an anti-human CD7 antibody, clone HB2 (a binding agent capable of specifically binding to a binding partner comprised in one or more target site) and further teaches a F(ab’)2 fragment (second binding molecule) of the HB2 antibody produced by pepsin digestion of native HB2 antibody, retaining its full immunoreactivity (first binding molecule; Flavell, page 5787, ‘Materials and Methods’, ‘Antibodies and Antibody F(ab’)2 Fragments’, see 2nd paragraph). Flavell further teaches incubating cells with FITC-labeled full length HB2 antibody and adding varying concentrations of the F(ab’)2 fragments to the culture (predetermined ratio; Flavell, page 5788, ‘Binding of HB2 Antibody and ITs to HSB-2 cells’, lines 16-20). Flavell further teaches competitive inhibition by intact HB2 antibody of the binding of molar equivalent amounts of intact and F(ab’)2 antibody (Flavell, page 5788, ‘Results’, 2nd paragraph, lines 1-3 and Table 1). In summary, Flavell teaches a first and second binding molecule, the antibody and the F(ab’)2 fragment, wherein the first binding molecule comprises a binding part and a detectable part (an antibody) and a second binding molecule comprising a binding part (an antibody fragment not comprising an Fc portion). As such, Flavell also teaches that the first binding molecules comprise an antibody comprising an Fc region and that the detectable part comprises the Fc region and the second binding molecule does not comprise the part that can be detected by a detector of the detectable part of the first binding molecules and the second binding molecules do not comprise the Fc region of the first binding molecules. Flavell further teaches staining HSB-2 cells with either F(ab’)2 or intact antibody at a saturating equimolar concentration in order to study binding characteristics of intact and F(ab’)2 antibody to HSB2 cells (Flavell, page 5788, ‘Results’, lines 1-6).
Linke teaches diagnostic markers of breast cancer treatment (Linke, see ‘Title’). Linke further teaches a kit for the analysis of markers comprising antigen and/or antibody titers in a suitable titrated form with concentrations given for easy reference in quantitative applications (page 11, see entire paragraph [0112]). Linke further teaches a control sample such as a cell line in which serial dilutions are undertaken to determine exact concentrations of elevated polypeptide levels (Linke, page 6, paragraph [0069], lines 1-9). Put another way, Linke teaches a kit comprising antibodies in suitably titrated form and also reference samples comprising cells with elevated target levels that are equal to patient samples with elevated target levels.
The advantages of packaging together the necessary reagents in kit form were well known in the art at the time of the invention. For example, Zuk et al. teach that in performing assays it is a matter of substantial convenience, as well as providing significant enhancement in accuracy, to provide the reagents combined in a kit (column 22, lines 20-68).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have included the antibody and F(ab’)2 fragment as taught by Flavell as the capture agent and scaling agent (first and second binding molecule) as taught by Dowd because Dowd teaches a capture agent that is capable of binding an analyte and a scaling agent, that relies on highly specific noncovalent interactions between the antigenic determinant, or epitope, of the antigen and the variable-region domain of an antibody molecule, and that specifically binds the same analyte and competes for binding with the capture agent. Flavell teaches a F(ab’)2 fragment with the same specificity as the capture antibody which competes with said antibody for binding and as such it would be an obvious substitution of one art known pair of binding molecules (capture molecule and antibody as in Dowd) with another, both recognized for the same purpose, both binding to the same analyte and competing for such binding with each other both suitable for the same purpose of inhibiting binding of the other binding molecule to the analyte in the sample. The ordinarily skilled artisan would have been motivated to do so, because the antibody and F(ab)2 fragment of Flavell performs the same function as the capture molecule and scaling agent of Dowd, namely competing for the binding of an analyte in a sample.
Although Dowd and the prior art above does not teach their competing reagents provided together in the form of a kit composition, in light of the teachings of Zuk et al. regarding the advantages of providing reagents combined in a kit, as well as well-known advantages of providing reagents in this form for the purposes of commercial sale, it would have been prima facie obvious to combine together the necessary reagents (i.e., the capture agent such as the full length antibody and the scaling agent such as the derivative of said antibody lacking the Fc portion), in kit form.
It would have further been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the reference sample of Dowd to have included cells as taught by Linke because of the teaching of Linke that cell lines with different levels of target analytes are equal to patient samples with elevated target levels and Dowd teaches control samples spiked with target to determine if the target concentration saturates the range of the assay. As such it would have been obvious to comprise a reference sample that are equal to patient samples with elevated target levels in order to determine if the target in patient samples would saturate the assay.
The ordinary artisan would have a reasonable expectation of success modifying Dowd with Flavell and Linke because the all three comprise antibodies or fragments thereof to detect analytes in a sample.
Regarding claim 18, Dowd teaches means for measuring the detectable signal (Dowd, column 7, lines 40-43).
Regarding claim 19, Dowd teaches that the amount of capture antibody is small relative to the amount of scaling agent employed to adjust the linear range of the assay, so that the molar amount of capture antibody need not be accounted for in the equilibrium conditions (second binding molecules are present in a greater amount than the first binding molecules; Dowd, column 18, lines 18-23).
Even though Dowd does not explicitly teach a predetermined ratio of first and second binding molecules, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have added the first and second binding molecules in a predetermined ratio in order to ensure that the second binding molecule was present in a greater amount than the first binding molecule. One of ordinary skill in the art would be motivated to do so, so that the molar amount of capture antibody need not be accounted for in the equilibrium conditions.
Regarding claim 20, Dowd teaches that the scaling agent can be a monoclonal or polyclonal antibody raised against the analyte (Dowd, column 3, line 63- column 4, line 9).
Regarding claim 22, Dowd and the cited art above as applied to claim 17 also applies to claim 22.
Flavell teaches an anti-human CD7 antibody, clone HB2 (first binding molecule) and further teaches a F(ab’)2 fragment (second binding molecule) of the HB2 antibody produced by pepsin digestion of native HB2 antibody, retaining its full immunoreactivity (Flavell, page 5787, ‘Materials and Methods’, ‘Antibodies and Antibody F(ab’)2 Fragments’, see 2nd paragraph).
Regarding claim 23, Dowd teaches that the analyte will be a member of a naturally-occurring binding pair, e.g. carbohydrate and lectin, hormone and receptor, complementary nucleic acids and the like and that analytes of particular interest include antigens, antibodies, proteins, carbohydrates, haptens, drugs, hormones, hormone metabolites, macromolecules, toxins, bacteria, viruses, enzymes, tumor markers, nucleic acids, and the like (Dowd, column 3, lines 42-50).
Regarding claim 31, Dowd and the cited art above teach a kit comprising a binding agent comprising a first and second binding molecule, wherein the first binding molecule comprises an antibody molecule comprising an Fc region and the second binding molecule does not comprise an Fc region, substantially as claimed.
Dowd further teaches introducing a certain amount of the scaling agent to the sample to create a reaction mixture where the total concentration of scaling agent (bound to the analyte and free scaling agent) is preferably greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture (binding agent is sufficient to bind to at least 51% of the binding partners; Dowd, column 5, lines 18-27). Dowd further teaches spiking varied concentrations of cytokines into serum and measuring using a multiplexed immunoassay and adding scaling antibody to scale the concentration of one analyte for detection (in a reference sample having a predetermined amount of binding partner; Dowd, column20, lines 55-65 and Figure 13).
As explained previously in detail above, Linke teaches diagnostic markers of breast cancer treatment (Linke, see ‘Title’). Linke further teaches a kit for the analysis of markers comprising antigen and/or antibody titers in a suitable titrated form with concentrations given for easy reference in quantitative applications (page 11, see entire paragraph [0112]). Linke further teaches a control sample such as a cell line in which serial dilutions are undertaken to determine exact concentrations of elevated polypeptide levels (Linke, page 6, paragraph [0069], lines 1-9). Put another way, Linke teaches a kit comprising antibodies in suitably titrated form and also reference samples comprising cells with elevated target levels that are equal to patient samples with elevated target levels.
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the reference sample of Dowd to have included cells as taught by Linke because of the teaching of Linke that cell lines with different levels of target analytes are equal to patient samples with elevated target levels.
The ordinary artisan would have a reasonable expectation of success modifying the reference sample of Dowd with that of Linke because the because both Dowd and Linke teach a reference sample for analyte detection by antibodies or antibody fragments.
Regarding claim 32 and 33, Dowd teaches an assay for IL-1B analyte and an anti-IL-1B antibody as scaling agent (Dowd, column 9, lines 9-13).
Regarding claim 34, Dowd and the cited art above as applied to claim 31 also applies to claim 34.
Flavell teaches an anti-human CD7 antibody, clone HB2 (first binding molecule) and further teaches a F(ab’)2 fragment (second binding molecule) of the HB2 antibody produced by pepsin digestion of native HB2 antibody, retaining its full immunoreactivity (Flavell, page 5787, ‘Materials and Methods’, ‘Antibodies and Antibody F(ab’)2 Fragments’, see 2nd paragraph).
Regarding claims 35 and 36, Dowd and the cited art above as applied to claim 31 also applies to claim 35.
Flavell teaches an anti-human CD7 antibody, clone HB2 (first binding molecule) and further teaches a F(ab’)2 fragment (second binding molecule) of the HB2 antibody produced by pepsin digestion of native HB2 antibody, retaining its full immunoreactivity (Flavell, page 5787, ‘Materials and Methods’, ‘Antibodies and Antibody F(ab’)2 Fragments’, see 2nd paragraph). Flavell further teaches competitive inhibition by intact HB2 antibody of the binding of molar equivalent amounts of intact and F(ab’)2 antibody (Flavell, page 5788, ‘Results’, 2nd paragraph, lines 1-3).
Regarding claim 37, Dowd teaches that the scaling agent is present in high concentrations relative to analyte concentrations in order to reduce the available analyte concentration by a fractional amount corresponding to a constant (scaling coefficient) and the residual amount of analyte remaining as free analyte is the quantity of analyte that is then measured (Dowd, column 2, line 67- column 3, line 6). Dowd further teaches that due to the equilibrium nature of association and dissociation between scaling agent and analyte in solution, the sample can be expected to maintain a finite amount of unbound, i.e., free analyte, which is then readily detectable in the detection phase (Dowd, column 9, lines 53-55). Dowd further teaches that the total concentration of scaling agent is preferably greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture and that in some embodiments the scaling agent is at least nine times greater than the free analyte and the product of free analyte and the scaling coefficient is less than one ninth. Dowd further teaches that the dynamics of the method of the invention can be modeled according to the laws of mass action, which are predictable, quantifiable and can thus be exploited to tailor an immunoassay for a particular analyte (Dowd, column 11, lines 60-64). As such Dowd teaches a concentration of the binding agent that is high enough so that there is a finite amount of analyte due to the equilibrium nature of association and dissociation between scaling agent and analyte and as such the scaling agent is present at a concentration greater than the Kd value of the binding agent-binding partner complex (Dowd, column 5, lines 24-31).
Regarding claim 38, Dowd and the cited art above as applied to claim 17 also applies to claim 38.
Dowd teaches a specifically selective binding reagent which binds an analyte, which is or may be present in a sample, that is specific for the analyte (first binding molecule; capable of specifically binding to a binding partner in a sample) and further teaches a scaling agent (second binding molecule) which has a binding specificity for the analyte and inhibits binding of a sub-population of the analyte with its corresponding capture agent (both first and second binding molecules capable of binding and competing for said binding). Dowd further teaches that the sample is allowed contact with the scaling agent prior or together with the capture agent and that preferably the capture reagent is bound to a solid support (Dowd, column 3, lines 20-33). Put another way, Dowd teaches a binding agent comprising a first and a second binding molecule contacting the sample at the same time wherein the first binding molecule can but is not necessarily bound to a solid support. Dowd further teaches that the scaling agent includes all substances which are able to bind the analyte directly or indirectly and preferably has a high affinity, typically being at least about 107 M-1, 109 M-1, 1010 M-1, and optimally being 1011 M-1 or 1012 M-1 or greater (Dowd, column 3, lines 52-61). Dowd further teaches that the association between the scaling agent and the analyte, e.g., when the analyte is an antigen, is based on highly specific noncovalent interactions between the antigenic determinant, or epitope, of the antigen and the variable-region domain of an antibody molecule used as the scaling agent. Dowd further teaches that the scaling agent can be a monoclonal or polyclonal antibody raised against the analyte or the scaling agent can be another molecule harvested or engineered for the purpose of specifically binding to an analyte (Dowd, column 3, line 63- column 4, line 9). Put another way, Dowd teaches introducing both the first and second binding molecules at the same time. Dowd further teaches that the amount of capture antibody is small relative to the amount of scaling agent employed to adjust the linear range of the assay, so that the molar amount of capture antibody need not be accounted for in the equilibrium conditions (second binding molecules are present in a greater amount than the first binding molecules; Dowd, column 18, lines 18-23). Dowd further teaches introducing a certain amount of the scaling agent to the sample to create a reaction mixture where the total concentration of scaling agent (bound to the analyte and free scaling agent) is preferably greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture (amount of binding agent is sufficient to bind to substantially all units of a binding partner; Dowd, column 5, lines 18-27). Dowd further teaches spiking varied concentrations of cytokines into serum and measuring using a multiplexed immunoassay and adding scaling antibody to scale the concentration of one analyte for detection (a reference sample having a predetermined amount of binding partner; Dowd, column20, lines 55-65 and Figure 13). As such Dowd teaches an amount of binding agent sufficient to bind to substantially all units of the binding partner in a reference sample having a predetermined amount of the binding partner.
Even though Dowd does not explicitly teach a predetermined ratio of first and second binding molecules, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have added the first and second binding molecules in a predetermined ratio in order to ensure that the second binding molecule was present in a greater amount than the first binding molecule because the amount of capture antibody is small relative to the amount of scaling agent and the total concentration of the scaling agent is greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture so that the molar amount of capture antibody need not be accounted for in the equilibrium conditions.
Dowd fails to teach a first binding molecule comprising a binding part and a detectable part and the second binding molecule comprising a binding part. Dowd further fails to teach that the first binding molecule comprises an antibody molecule or derivative thereof, comprising an Fc region, wherein the detectable part comprises the Fc region and the second binding molecules do not comprise a part that can be detected by the detector of the first binding molecules and the second binding molecule does not comprise the Fc region of the first binding molecules. Dowd further does not teach a reference sample that has cells in it.
Flavell teaches an anti-human CD7 antibody, clone HB2 (a binding agent capable of specifically binding to a binding partner comprised in one or more target site) and further teaches a F(ab’)2 fragment (second binding molecule) of the HB2 antibody produced by pepsin digestion of native HB2 antibody, retaining its full immunoreactivity (first binding molecule; Flavell, page 5787, ‘Materials and Methods’, ‘Antibodies and Antibody F(ab’)2 Fragments’, see 2nd paragraph). Flavell further teaches incubating cells with FITC-labeled full length HB2 antibody and adding varying concentrations of the F(ab’)2 fragments to the culture (predetermined ratio; Flavell, page 5788, ‘Binding of HB2 Antibody and ITs to HSB-2 cells’, lines 16-20). Flavell further teaches competitive inhibition by intact HB2 antibody of the binding of molar equivalent amounts of intact and F(ab’)2 antibody (Flavell, page 5788, ‘Results’, 2nd paragraph, lines 1-3 and Table 1). In summary, Flavell teaches a first and second binding molecule, the antibody and the F(ab’)2 fragment, wherein the first binding molecule comprises a binding part and a detectable part (an antibody) and a second binding molecule comprising a binding part (an antibody fragment not comprising an Fc portion). As such, Flavell also teaches that the first binding molecules comprise an antibody comprising an Fc region and that the detectable part comprises the Fc region and the second binding molecule does not comprise the part that can be detected by a detector of the detectable part of the first binding molecules and the second binding molecules do not comprise the Fc region of the first binding molecules. Flavell further teaches staining HSB-2 cells with either F(ab’)2 or intact antibody at a saturating equimolar concentration in order to study binding characteristics of intact and F(ab’)2 antibody to HSB2 cells (binding agent sufficient to bind substantially all units of the binding partner present in the sample; Flavell, page 5788, ‘Results’, lines 1-6). Flavell also teaches that the first binding molecules comprise an antibody comprising an Fc region and that the detectable part, detected by the detector, i.e. the FITC-label, comprises the Fc region and the second binding molecule does not comprise the part that can be detected by a detector of the detectable part of the first binding molecules and the second binding molecules do not comprise the Fc region of the first binding molecules. As such Flavell teaches a detectable agent specific for the Fc region of the first binding molecule.
Linke teaches diagnostic markers of breast cancer treatment (Linke, see ‘Title’). Linke further teaches a kit for the analysis of markers comprising antigen and/or antibody titers in a suitable titrated form with concentrations given for easy reference in quantitative applications (page 11, see entire paragraph [0112]). Linke further teaches a control sample such as a cell line in which serial dilutions are undertaken to determine exact concentrations of elevated polypeptide levels (Linke, page 6, paragraph [0069], lines 1-9). Put another way, Linke teaches a kit comprising antibodies in suitably titrated form and also reference samples comprising cells with elevated target levels that are equal to patient samples with elevated target levels.
The advantages of packaging together the necessary reagents in kit form were well known in the art at the time of the invention. For example, Zuk et al. teach that in performing assays it is a matter of substantial convenience, as well as providing significant enhancement in accuracy, to provide the reagents combined in a kit (column 22, lines 20-68).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have included the antibody and F(ab’)2 fragment as taught by Flavell as the capture agent and scaling agent (first and second binding molecule) as taught by Dowd because Dowd teaches a capture agent that capture an analyte and a scaling agent, that relies on highly specific noncovalent interactions between the antigenic determinant, or epitope, of the antigen and the variable-region domain of an antibody molecule, and that specifically binds the same analyte and competes for binding with the capture agent. Flavell teaches a F(ab’)2 fragment with the same specificity as the capture antibody which competes with said antibody for binding and as such it would be an obvious substitution of one art known pair of binding molecules (capture molecule and antibody as in Dowd) with another, both recognized for the same purpose, both binding to the same analyte and competing for such binding with each other both suitable for the same purpose of inhibiting binding of the other binding molecule to the analyte in the sample. The ordinarily skilled artisan would have been motivated to do so, because the antibody and F(ab)2 fragment of Flavell performs the same function as the capture molecule and scaling agent of Dowd, namely competing for the binding of an analyte in a sample.
Although Dowd and the prior art above does not teach their competing reagents provided together in the form of a kit composition, in light of the teachings of Zuk et al. regarding the advantages of providing reagents combined in a kit, as well as well-known advantages of providing reagents in this form for the purposes of commercial sale, it would have been prima facie obvious to combine together the necessary reagents (i.e., the capture agent such as the full length antibody and the scaling agent such as the derivative of said antibody lacking the Fc portion), in kit form.
It would have further been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the reference sample of Dowd to have included cells as taught by Linke because of the teaching of Linke that cell lines with different levels of target analytes are equal to patient samples with elevated target levels and Dowd teaches control samples spiked with target to determine if the target concentration saturates the range of the assay. As such it would have been obvious to comprise a reference sample that are equal to patient samples with elevated target levels in order to determine if the target in patient samples would saturate the assay.
The ordinary artisan would have a reasonable expectation of success modifying Dowd with Flavell and Linke because the all three comprise antibodies or fragments thereof to detect analytes in a sample.
Regarding claim 39, Dowd and the cited art above as applied to claim 38 also applies to claim 39.
Flavell teaches an anti-human CD7 antibody, clone HB2 (first binding molecule) and further teaches a F(ab’)2 fragment (second binding molecule) of the HB2 antibody (Flavell, page 5787, ‘Materials and Methods’, ‘Antibodies and Antibody F(ab’)2 Fragments’, see 2nd paragraph).
Regarding claim 40, Dowd and the cited art above teach a kit comprising a binding agent comprising a first and second binding molecule, wherein the first binding molecule comprises an antibody molecule comprising an Fc region and the second binding molecule does not comprise an Fc region, substantially as claimed.
Dowd further teaches introducing a certain amount of the scaling agent to the sample to create a reaction mixture where the total concentration of scaling agent (bound to the analyte and free scaling agent) is preferably greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture (binding agent is sufficient to bind to at least 51% of the binding partners; Dowd, column 5, lines 18-27). Dowd further teaches spiking varied concentrations of cytokines into serum and measuring using a multiplexed immunoassay and adding scaling antibody to scale the concentration of one analyte for detection (in a reference sample having a predetermined amount of binding partner; Dowd, column20, lines 55-65 and Figure 13).
As explained previously in detail above, Linke teaches diagnostic markers of breast cancer treatment (Linke, see ‘Title’). Linke further teaches a kit for the analysis of markers comprising antigen and/or antibody titers in a suitable titrated form with concentrations given for easy reference in quantitative applications (page 11, see entire paragraph [0112]). Linke further teaches a control sample such as a cell line in which serial dilutions are undertaken to determine exact concentrations of elevated polypeptide levels (Linke, page 6, paragraph [0069], lines 1-9). Put another way, Linke teaches a kit comprising antibodies in suitably titrated form and also reference samples comprising cells with elevated target levels that are equal to patient samples with elevated target levels.
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the reference sample of Dowd to have included cells as taught by Linke because of the teaching of Linke that cell lines with different levels of target analytes are equal to patient samples with elevated target levels.
The ordinary artisan would have a reasonable expectation of success modifying the reference sample of Dowd with that of Linke because the because both Dowd and Linke teach a reference sample for analyte detection by antibodies or antibody fragments.
Claim 21 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dowd et al., in view of Flavell et al. , Linke et al., and Zuk et al., as applied to claim 17 above, and further in view of Buchwalow IB et al. (2010) “Chapter 7; Multiple Multicolor Immunoenzyme Staining”; In: Buchwalow I, Böcker W, eds. Immunohistochemistry: Basics and Methods. Berlin, Germany: Springer-Verlag; pages 61-67 (PTO-892, 05/08/2024).
Regarding claim 21, Dowd and the cited art above teach a kit comprising a binding agent comprising a first and second binding molecule, wherein the first binding molecule comprises an antibody molecule comprising an Fc region that is detectable and the second binding molecule does not comprise an Fc region that is detectable, substantially as claimed.
Dowd and the cited art above fails to teach first and second binding molecules that are antibodies comprising different Fc regions.
Buchwalow teaches that using a pair of primary antibodies raised in two different species or raised in the same species but with different IgG isotypes allows for simultaneous immunoenzymatic double staining by using a mixture of a pair of secondary enzyme-labeled antibodies against corresponding IgG species or IgG isotypes. Buchwalow further teaches that this allows for co-localization of antigens (Buchwalow, page 61, see ‘7.1. Simultaneous Immunoenzymatic Double Staining’, 1st paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the kit of Dowd to have used a first and second binding molecule with different Fc regions because of the teaching of Buchwalow that this allows for simultaneous immunoenzymatic staining of the two antibodies. As such, Buchwalow teaches a method that allows the confirmation of the specificity of both antibodies for the same antigen, ensuring competitive binding of the antibodies of the kit. The ordinary artisan would be motivated to do so, because Buchwalow teaches that using two labeled antibodies also allows for confirmation that both binding molecules bind the same target. As such, two binding molecules of Buchwalow are a suitable alternative to those of Dowd in view of Flavell, because the detector only detects the detachable part of one of the binding molecules and is therefore an equivalent way of achieving the same goal, each are two ways of detecting one of two binding partners specific for the same antigen in a sample.
The ordinary artisan would have a reasonable expectation of success, because Buchwalow teaches using antibodies to detect antigen in a sample, the same method as applied by Dowd and Linke.
Claims 24 and 25 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dowd et al., in view of Flavell et al. , Linke et al., and Zuk et al., as applied to claim 17 above, and further in view of Olsen et al. (2008) “Acute Leukemia Immunohistochemistry: A systematic Diagnostic Approach”, Archives of Pathology & Laboratory Medicine, 132, 3, pages 462-475 (PTO-892, 05/08/2024).
Regarding claim 24, Dowd and the cited art above teach a kit substantially as claimed.
Dowd does not teach a kit comprising a reference material which is one or more histological samples comprising cells with predetermined amounts of said one or more target sites.
Olsen teaches lymphoid markers, such as CD7, should be distinguished in Acute myeloid leukemia, because some have a significantly better prognosis (Olsen, page 466, 2nd column, 6th paragraph, lines 8-12). Olsen further teaches that flow cytometry is a powerful method to detect acute leukemia, but has several limitations, such as the need for fresh cells or tissues, limited morphologic correlation and lack of assessment of viable cells (Olsen, page 462, 2nd paragraph, lines 5-9 and table 1, page 463). Olsen further teaches that immunohistochemistry is a universally accessible technique that can be rapidly and accurately applied to leukemia diagnosis and is particularly useful for analyzing cells too fragile for processing. Olsen further teaches that immunohistochemistry reveals architectural features and estimates tumor cellularity in paraffin sections (Olsen, page 463, lines 3-8). As such Olsen teaches analyzing CD7 expression in histological samples by immunohistochemistry.
Linke teaches a kit for the analysis of markers comprising antigen with concentrations given (page 11, paragraph [0112], lines 1 and 8). The method comprises using samples suitable for immunohistochemistry (claim 15, line 2). Linke further teaches that antigen preparations in suitable titrated form, with concentrations (claim 24), provide easy reference for quantitative applications (claim 25; Linke, page 11, paragraph [0112], line 14).
It would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made, to have modified the kit as taught by Dowd and the cited prior art, to further include reference material that is one or more histological samples, because of the teaching of Olsen that, even though there are other powerful methods to detect leukemia, they have several limitations and that immunohistochemistry is a universally accessible technique that can be rapidly and accurately applied and is particularly useful for analyzing cells too fragile for processing. It would have been obvious to modify the kit to include reference material for such histological staining as taught by Linke, because of the teaching of Linke that antigen preparations in suitable titrated form with concentrations, comprising those suitable for immunohistochemistry, provide easy references for quantitative applications.
The ordinary artisan would have had a reasonable expectation of success providing the reagents together as a kit because Olsen teaches staining the target (CD7) using immunohistochemistry and Linke teaches that a method suitable for immunohistochemistry comprises antigen preparation for easy reference for quantitative applications.
Regarding claim 25, Dowd teaches introducing a certain amount of the scaling agent to the sample to create a reaction mixture where the total concentration of scaling agent is preferably greater than or equal to the high end expected initial concentration of the high concentration analyte in the reaction mixture (Dowd, column 5, lines 18-27). Dowd further teaches that the amount of capture antibody is small relative to the amount of scaling agent employed (amounts of first and second binding molecules are predetermined; Dowd, column 18, lines 18-23). Dowd further teaches that due to the equilibrium conditions established by the laws of mass transfer, the amount of free analyte remaining in solution in the presence of scaling agent is predictable and finite and can be measured as a quantitative indicator of the initial concentration of the analyte in the sample (quantitative evaluation; Dowd, Abstract, lines 25-30).
Claim 41 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dowd et al., in view of Flavell et al. , Linke et al., and Zuk et al., as applied to claim 40 above, and further in view of Sturgeon et al., National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Clinical Practice: Quality Requirements, Clinical Chemistry, Volume 54, Issue 8, 1 August 2008, Pages e1–e10 (PTO 892, 07/27/2023), Gown AM, Current issues in ER and HER2 testing by IHC in breast cancer. Modern pathology. 2008 May 1;21:S8-15 (PTO 892, 07/27/2023), and Kao et al., US PGPUB 20110165087A1 (PTO-892, 07/27/2023).
Regarding claim 41, Dowd and the cited art above teach a kit comprising a first binding molecule comprising an antibody molecule comprising an Fc region and a second binding molecule capable of binding the same target, wherein the second binding molecule dos not comprise the Fc region of the first binding molecule and wherein the first binding molecule and the second binding molecule are in a predetermined ration and in which the second binding molecules are present in a greater amount than the first binding molecule and a detectable agent specific for said Fc region of said first binding molecule, substantially as claimed.
Dowd and the cited art above does not teach that the target is Her2 protein.
Sturgeon teaches, regarding the hook effect, that high-dose hook effect is a recognized type of interference that can lead to risk of method-related errors in tumor marker results, see teaching laboratories should have in place, defined protocols for identifying specimens that have “hooked”, that tumor marker concentrations range over several orders of magnitude and for any tumor marker may exceed the capacity of the solid phase, that failure to recognize high tumor marker concentrations constitutes a critical clinical error (see page e1, Abstract, and supplementary material, page 9, Table 5).
Gown teaches that HER2 is expressed at low levels in normal epithelia and overexpressed in certain cancers. Gown further teaches that determination of HER2 status in breast cancer is an important prognostic and predictive marker and HER2 overexpression is an independent prognostic marker of clinical outcome (Gown, page 10, lines 13-22) and that the accuracy of diagnostic assays for HER2 in breast cancer is extremely important (Gown et al., page 11, 2nd column, lines 11-13).
Kao et al. teaches HER2 comparing trastuzumab (anti-HER2 antibody; Kao et al. page 10, paragraph [0119], lines 12-14) against trastuzumab Fab’ fragment (lacking the Fc region, see Kao et al. Figure 3) by immunostaining of fixed cell lines (Kao et al., page 8, paragraph [0101] lines 1-10). Kao et al. further teaches that trastuzumab Fab’ fragments find HER2 as avidly and selectively as intact trastuzumab IgG (Kao et al., page 10, paragraph [0125], lines 4-6).
It would have been prima facie obvious to one having ordinary skill in the art at the time of the claimed invention, to have modified the capture agent and the scaling agent of Dowd, such to be binding molecules specific and competing for the target HER2 (namely HER2 monoclonal antibodies), in order to provide reagent to combat hook effect affecting detection of the tumor related biomarker HER2. In particular, one having ordinary skill would have been motivated to modify the reagent of Dowd in order to detect HER2 because it was known in the art at the time that the high dose hook effect is an interference that can affect the detection of tumor related antigens (Sturgeon), that specifically determination of HER2 status in breast cancer is an important prognostic and predictive marker and HER2 overexpression is an independent prognostic marker of clinical outcome (Gown), and that the accuracy of diagnostic assays for HER2 in breast cancer is extremely important (Gown).
Put another way, the modification to rely on HER2 monoclonal antibody (as in Gown) in place of the capture agent (as in Dowd) would have been a simple substitution of one binding reagent for another. In particular, it was known that the hook effect can interfere with the detection of targeted antigens, particularly that it can interfere with tumor related antigen detection (Sturgeon). Further, HER2 is a well-known, art-recognized tumor antigen (Gown), that the importance of proper detection of this marker is important to clinical outcome (Gown), further that the accuracy of diagnostic assays for HER2 in breast cancer is extremely important (Gown). Considering the base composition (composition comprising binding agent that is a scaling agent with a binding agent that is a capture antibody) was well known in the art at the time to combat the interference of high dose analytes with assay results and that HER2 is a clinically important marker that requires proper detection, it would have been obvious to have modified the reagents of Flavell such to provide the reagents specific for HER2, and the results would have been predictable, namely the modification would provide reagent/composition capable of accounting for assay interference introduced by the presence of high HER2 concentration.
Further, one having ordinary skill in the art would have had a reasonable expectation of success modifying the reagents of Dowd to instead provide competing binding reagents specific for HER2, because Dowd teaches their technique is used to remove interference by high concentration analytes in a sample and Flavell’s technique is used to test binding interference of a F(ab’)2 fragment with an intact antibody, and because competing antibody reagents that bind avidly and that compete with one another are known to those of skill in the art (see as in Kao).
Even further, it would have been obvious, when modifying the reagent of Flavell (for CD7) to be reagent for HER2, to have used competing antibody reagents such as that taught by Kao (trastuzumab, an anti-HER2 antibody and trastuzumab Fab’) as a an obvious matter to try, particularly because Flavell teach the requirements of said reagent be that they bind the same target and that they compete, because Kao teach trastuzumab antibody and Fab’ bind avidly and selectively, and therefore would be expected to compete, and the teaching of Dowd of a method of adjusting the concentration of an analyte to match a known working range of detection of an assay system using a scaling agent which competitively binds the target and reduced the concentration of the analyte in the assay.
One having ordinary skill in the art would have a reasonable expectation of success because Kao is teaching a specific example of binding reagent that meet the descriptive requirements for combating hook effect as taught by Kao (and as such, the reagents would be expected to work for HER2 the way that Flavell’s antigen binding molecules compete for binding for CD7 and therefore would also be expected to work in the assay of Dowd).
Response to Arguments
Applicant’s arguments, see page 8, line 10- page 13, filed 11/07/2025, with respect to the rejections of claims 17-25 and 31-41 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the teaching of Dowd of a scaling agent specific for the same antigen and competing with the capture antibody for binding to the antibody.
Regarding the argument starting on page 8 that Dowd does not have the scaling agent and the capture agent in a composition together at a predetermined ratio prior to contacting with the sample, Dowd does teach contacting the sample with the scaling agent prior or together with the capture agent (Dowd, column 3, lines 20-33, see rejection under 35 USC 103 above).
Applicant further argues that no prima facie case of obviousness exists to modify Flavell with the teaching of Dowd. However, the new rejection does make a prima facie case that it would be obvious to use the antibody and antibody fragment of Flavell in the invention of Dowd as this would be an obvious substitution of one art known pair of binding molecules (capture molecule and antibody as in Dowd) with another, namely that of Flavell. This would not render Dowd unsatisfactory for its intended purpose.
Applicant further argues on page 10 that, regarding claim 21, the teaching of Buchwalow of using antibodies having different Fc regions, clearly relates to the detection of two different antigens which is inapposite to the claims, which require that both antibodies are specific for the same antigen.
This argument is not persuasive.
Buchwalow teaches that two antibodies having two different Fc regions can be distinguished from each other by the Fc region and as explained previously in detail above in the rejection of claim 21, this would allow one of ordinary skill in the art to allow individual detection of each antibody type and as such confirm specific binding of each antibody type for the same antigen.
Regarding the argument on page 13 that Flavell in view of Dowd, Zuk, and Linke in view of Sturgeon, Gown, and Kao fails to overcome the deficiency in the combination of Flavell, Dowd, and Zuk, see the new grounds of rejection above.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677