DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 25, 2026 has been entered.
Claims 17-53 are pending and being examined. Claim 19 is amended.
New Rejection
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
2. Claims 17-53 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite(s) a kit comprising a biological sample comprising one or more of the first set of human biomarkers isolated from a human subject that as renal cell carcinoma (RCC) or is at risk of having RCC, wherein the biological sample is selected from blood, PBMC, blood cells, serum, plasma, biopsy tissue, tissue, urine, intestinal mucosa, or saliva. Thus, the claims are direct to a kit comprising a biological sample from an RCC patient that contains naturally occurring biomarker proteins. This judicial exception is not integrated into a practical application because the biological sample is not used in a method or altered in any way. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional separate items claimed in the kit (assay cartridge, capture antibodies, labeled detection antibodies, vials, containers, calibrator proteins, diluents) do not change the biological sample from what occurs in nature.
MPEP 2106.04(c) states:
A. Product Claims
Where the claim is to a nature-based product produced by combining multiple components (e.g., a claim to “a probiotic composition comprising a mixture of Lactobacillus and milk”), the markedly different characteristics analysis should be applied to the resultant nature-based combination, rather than its component parts. For instance, for the probiotic composition example, the mixture of Lactobacillus and milk should be analyzed for markedly different characteristics, rather than the Lactobacillus separately and the milk separately. See subsection II, below, for further guidance on the markedly different characteristic analysis.
Where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to “a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt”), the markedly different characteristics analysis should be applied only to the nature-based product limitation. For instance, for the yogurt starter kit example, the Lactobacillus would be analyzed for markedly different characteristics. The container and instructions would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B if needed) if it is determined that the Lactobacillus does not have markedly different characteristics from any naturally occurring counterpart and thus is a product of nature exception. See, e.g., Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948) (although claims 7, 8, 13 and 14 recited an inoculant comprising a bacterial mixture and a powder base, only the bacterial mixture was analyzed).
In the instant case, the biological sample taken from the human subject that has RCC or is at risk of having RCC is a nature-based product. The claimed kits are directed to a combination of the nature-based biological sample product with non-nature-based elements (assay cartridge, capture antibodies, labeled detection antibodies, vials, containers, calibrator proteins, diluents). According to MPEP 2106.04(c), the markedly different characteristics analysis should be applied only to the nature-based product limitation. The markedly different characteristics analysis compares the nature-based product limitation to its naturally occurring counterpart in its natural state. In the instant case, the biological sample comprised in the kit is taken directly from the subject and is not altered, therefore the biological sample is not markedly different from what occurs in nature. According to Step 2A Prong One analysis, the biological sample is a product of nature exception.
According to Step 2A Prong Two analysis, the claims as a whole do not integrate the exception into a practical application. The claims do not use the biological sample or incorporate it into a practical application (see MPEP 2106.04(d)).
According to Step 2B analysis, the claims do not amount to significantly more than the judicial exception. The additional items contained in the claimed kits do not add an improvement to the biological sample itself, and do not alter or transform the biological sample into something different or something significantly more (see MPEP 2106.05).
Maintained Rejections
Claim Rejections - 35 USC § 103
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.
3. Claim 17-23, 26, 29-33, 36-41, 46, 47, and 49-53 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2005/0142033, Glezer et al (Meso Scale Technologies); in view of Gowan et al (Assay and Drug Development Technologies, 2007, 5:391-401); Grund et al (Molecular Pharmacology, 2008, 73:1394- 1404, published online February 5, 2008; IDS); Wako BioWindow (http://www.wako-chem.co.jp) published August 2008; Chabowski et al (Molecular and Cellular Biochemistry, 2006, 288:201-212); Onay-Besikci et al (Basic Res. Cardiol. 2007, 102:436-444); WO 2018/127707, Dephino et al, Published April 2008; US Patent Application Publication 2004/0265938, Remacle et al; Adnane et al (METHODS IN ENZYMOLOGY, 2006, Vol. 407:597-612); Murphy et al (American Journal of Pathology, 2006, 169:1875-1885); Larkin et al (Therapeutics and Clinical Risk Management, 2006, 2:87-98); as evidenced by Cell Signaling Technology antibodies #9102 and #9101 (printed January 2025).
Glezer teaches a kit comprising an assay cartridge for conducting a plurality of assays, said cartridge comprising a flow cell having an inlet, an outlet or a detection chamber, said inlet, detecting chamber, or outlet defining a flow path through said flow cell, said detection chamber comprising a plurality of binding domains comprising a plurality of capture antibodies specific to human biomarkers, said cartridge further comprising, in one or more compartments, a set of labeled detection antibodies specific for said human biomarkers. Glezer teaches a kit comprising a multi-well assay plate comprising a plurality of wells, each well comprising a plurality of discrete binding domains comprising a plurality of capture antibodies specific to human biomarkers. Glezer teaches the discrete binding domains are positioned on an electrode well and the electrodes are capable of immobilizing assay reagents such as binding reagents on electrodes, wherein the binding reagents are proteins or antibodies, and they are attached to ECL tags/labels ([10-15]; [17]; [162-289]; [296-458]; [663-693]; [716-728]; [858-862]; Figures 2-41).
Glezer teaches ECL immunoassay using multi-well plates and multi-analyte immunoassays in multi-well plates, wherein wells of multi-well plates were coated with capture antibodies specific for an epitope on a human protein of interest, the antibodies are coated onto an active working electrode surface of each well and allowed to dry, samples containing protein for testing are added to the wells, diluents containing a ECL-labeled detection antibody are added to wells, then ECL read buffer is added to detect the labeled antibodies bound to the immobilized protein and measured by a sector image; wherein each well contains four discrete binding domains to detect four different human proteins ([173]; [684]; [723]; [780-783]; [858-862]; [67-71]; Figures 26-30 and 35).
Glezer teaches the plurality of binding domains are particles ([133]; [155]; [163-165]; [174]; [176]; [354]).
Glezer teaches the kit comprises additional assay reagents provided in compartments of said cartridge, wherein said additional assay reagents include diluents, calibrators, and ECL read buffer ([725]; [778]; [857]).
Glezer teaches the kit comprises containers comprising one or more assay reagents ([20]; [720]).
Glezer suggests their kit can be used to test a variety of samples that contain an analyte of interest, such samples as biological samples, cells, tissue, blood, serum, plasma, and cell proteins ([656]; [716]). Glezer suggests their kit can be used to test the activities of phosphorylases, phosphatases, and kinases ([657]).
Glezer does not teach:
the human biomarkers comprise or consist of total Akt, phosphorylated ERK1/2 and AMPKa1 phosphorylated at amino acid 174 (wherein “consist of” means exclusion of other biomarkers including pAkt, total ERK 1/2, total AMPKa1, or AMPKa1 phosphorylated at amino acid residue 285);
the calibrators are calibrator proteins;
the containers are vials;
the biological sample is from a patient who has renal cell carcinoma, or is at risk of RCC, and who was treated with sorafenib.
Gowan et al teach two duplex multi-well microplate assays (cartridges) by Meso Scale Discovery (MSD®), wherein one assay detects total and phosphorylated forms of AKT, and the other assay detects total and phosphorylated forms of GSK3β, wherein the assay plates comprise wells (detection chambers) having a plurality of binding domains comprising a set of capture antibodies to the total form of protein and a set of capture antibodies to the phosphorylated form of the protein, further comprising ECL labeled detection antibodies, buffer, diluent, binding domains positioned on an electrode, and analyzed on SECTOR™ 6000 instrument by MSD®. Gowan teaches measuring biomarkers in biological samples in response to treatment in order to identify molecular targets of patient therapies and tumor responses to therapies, and teach the biomarkers they assessed are known to be associated with cancers (Introduction).
Grund et al teach Meso Scale Discovery 96-well multi-spot plates for detecting total/phopho-Akt or total/phopho-Erk comprising calibrator proteins, ECL labeled antibodies, ECL read buffer, diluent, wherein the wells on the plates comprise discrete binding domains coated with capture antibodies that bind to Akt and phospho-Akt or Erk and phospho-Erk; wherein the proteins, detection antibodies, and labeling reagent are in containers, wherein the binding domains are positioned on an electrode within said well, wherein the kit comprises an assay cartridge for conducting a plurality of assays. Grund et al teach the plates were read using the SECTOR™ imager 6000 (Materials and Methods; Figure 2).
Wako BioWindow teaches a commercially available R&D Proteome Profiler™Human Phospho-Kinase Array Kit (p. 10-11) that comprises a multi-well assay and antibodies for detecting levels of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated AMPK alpha 1 at threonine 174, and teaches assessing biomarkers in subject biological samples.
Chabowski teaches detecting all of total Akt, pAkt, pERK1/2, and AMPK phosphorylated at T174 for the purpose of detecting cellular pathway activation in fatty acid metabolism in the heart (abstract) and demonstrates utilizing commercially available antibodies for detection of total Akt, pERK1/2, and AMPK phosphorylated at T174 (Methods, Materials, p. 203, col. 1).
Onay-Besikci demonstrates detecting total Akt, pAkt, and AMPK phosphorylated at T174 with commercially available antibodies and visualizing proteins using ECL Western blotting kit on biological samples from subjects (p. 438, col. 1, “Electrophoresis and immunoblotting”).
Biomarkers comprise total Akt, phosphorylated ERK1/2 and AMPKa1 phosphorylated at Thr174:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to utilize total Akt, pERK1/2, and AMPK phosphorylated at T174 as the protein analytes in the kit of Glezer, along with their capture antibodies. One would have been motivated to and have a reasonable expectation of success to because: (1) Glezer suggests their kit can be used to test the activities of phosphorylases, phosphatases, and kinases; (2) Gowan and Grund demonstrate that total Akt, pAkt, and pERK1/2 are biomarkers already successfully incorporated into Meso Scale Discovery 96-well multi-spot plate kits; (3) Wako BioWindow teaches a commercially available kit that comprises a multi-well assay and antibodies for detecting levels of phosphorylated ERK1/2 and phosphorylated Akt with phosphorylated AMPK alpha 1 at threonine 174 (R&D Proteome Profiler™Human Phospho-Kinase Array Kit); (4) Onay-Besikci and Chabowski provide motivation for combining detection of all of total Akt, pERK1/2, and AMPK T174 phosphorylation to study the activities associated with AMPK activation and the heart, and teach antibodies for their detection are commercially available.
Biomarkers CONSIST of total Akt, phosphorylated ERK1/2 and AMPKa1 phosphorylated at Thr174, excluding total Akt, pErk 1/2, total AMPKa1, and AMPKa1 phosphorylated at residue 174:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to make an assay cartridge comprising capture and detection reagents to any subset of biomarkers from the prior art, including a subset consisting of total Akt, pERK1/2, and AMPK phosphorylated at T174, as the protein analytes in the kit of Glezer. One would have been motivated to and have a reasonable expectation of success to because: (1) Glezer suggests their kit can be used to test the activities of phosphorylases, phosphatases, and kinases; (2) Gowan and Grund demonstrate that total Akt, pAkt, and pERK1/2 are biomarkers already successfully incorporated into Meso Scale Discovery 96-well multi-spot plate kits; (3) Wako BioWindow teaches a commercially available kit that comprises a multi-well assay and antibodies for detecting levels of phosphorylated ERK1/2 and phosphorylated Akt with phosphorylated AMPK alpha 1 at threonine 174 (R&D Proteome Profiler™Human Phospho-Kinase Array Kit); and (4) Onay-Besikci and Chabowski provide motivation for combining detection of Akt, pERK1/2, and AMPK T174 phosphorylation to study the activities associated with AMPK activation and the heart, and teach antibodies for their detection are commercially available. Given the prior art provides motivation to assay cell signaling proteins: total Akt, pERK1/2, and AMPK T174 phosphorylation together, it is well within the level of the skill artisan to take any subset of the known biomarkers to assay their levels, and the kit detecting the subset of biomarkers is expected perform the same function as it would in a kit comprising a larger combination of biomarkers.
Calibrator Proteins:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include calibrator proteins in the assay kit taught by Glezer. One would have been motivated to because: (1) Glezer suggests including calibrators in the kit and teaches using the kit to quantify proteins and phosphorylation using sector image; (2) Gowan and Grund teach calibrating the SECTOR™ imager 6000 instrument for accurately reading the protein levels on the Meso Scale Discovery multi-spot plates. One of ordinary skill in the art would have a reasonable expectation of success including calibrator proteins in the assay kit of Glezer, given calibrating quantitative instruments is standard and Grund et al successfully demonstrate including and using calibrator proteins to measure phospho-proteins including Akt using the same instrument.
Vials:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to utilize vials as the containers disclosed in the kit of Glezer. One would have been motivated to and have a reasonable expectation of success to because vials are well known and established containers for holding reagents such as antibodies, proteins, buffers, and diluents.
Kit further comprises biological sample from human subject having RCC or at risk of RCC and that was administered sorafenib:
Glezer further teaches utilizing the kits for screening biological activity of drugs ([823-824]; [826-827]; [847]). Gowan teaches measuring biomarkers in biological samples in response to treatment in order to identify molecular targets of patient therapies and tumor responses to therapies, and teach the biomarkers they assessed are known to be associated with cancers (Introduction).
Dephino teaches kits and methods for profiling phosphorylation changes in multiple proteins in biological samples of subjects in response to treatment with a receptor tyrosine kinase inhibitor (RTK) and cancer treatments or to predict responsiveness to treatment (p. 3-5; p. 6-7; p. 14-18; p. 44-46; p. 51-52; claims 1-30, 38-51); wherein the subject has renal cell carcinoma (RCC) (p. 6, line 20; p. 46, line 14; claim 17); wherein the biological sample is tissue biopsy, blood, cells, cancer cells (p. 16, lines 9-28; claim 28); wherein the treatment or RTK inhibitor is sorafenib (p. 8, lines 32-33; p. 47, line 13 to p. 48, line 5; p. 64, lines 9-17; claims 44-45); and wherein the kit/method uses phosphorylation state-specific antibodies and/or total-protein detection antibodies; antibodies can be immobilized to support such as plates, arrays, beads, and spotted onto prefigured chips/arrays; a multiplicity of activation state antibodies can be immobilized on a chip to determine the receptor activation state profile for a sample; phosphorylation antibody arrays are commercially available and described in the prior art (p. 8, lines 25-31; p. 30-31; p. 40-42; claims 41-43). Dephino exemplifies contacting cancer cells with RTK inhibitors and detecting phosphorylation changes in AKT and MAPK using antibodies in order to determine the biological response of cells to the RTK inhibitors (Example 4, Figure 3), wherein the antibodies used to detect phosphorylated MAPK were Cell Signaling Technology antibodies #9102 and #9101 (p. 76, lines 15-16) which, as evidenced by Cell Signaling Technology, detect phosphorylated p44/42 MAPK, also known as Erk1/2, therefore Dephino detected phosphorylated Erk1/2. Dephino exemplifies assaying biological cancer tissue/cell samples for phosphorylation states of proteins (Example 6), and describes using commercially purchased antibody arrays for phosphorylation detection (p. 76, lines 20-25).
Remacle teaches kits and methods for simultaneously determining the total and phosphorylated forms of multiple proteins in kinase signaling pathways (cascades) in biological cell samples (abstract; [23-27]; [56-61]; [88-91]). Remacle describes prior art disclosing antibodies immobilized on arrays to detect protein and phosphorylation states in cell lysate samples ([12-21]). Detection of Erk1/2 (MAPK p44/42) phosphorylation to determine cell state is well known ([61]). The detection assay for proteins is conducted using a solid substrate with immobilized capture antibodies that bind the biomarker proteins, such as a protein microarray, and labeled detection antibodies that bind the biomarker proteins, wherein detection antibodies can be phospho-specific, wherein detectable labels include chemiluminescence ([64-92]), wherein the detection assay further comprises a biological sample such as cells, lysates, tissue, blood, serum, and body fluids ([67]; [78-84]); and wherein the assay and kit are used to assess activation states of proteins in cancer and in response to drugs ([85-86]). Remacle exemplifies successfully quantifying total and phosphorylated forms of Akt protein using capture antibodies binding Akt spotted on an array, and using labeled detection antibodies to phospho-Akt or to total Akt (Example 2). Remacle exemplifies successfully quantifying total Akt in a liver cancer cell line treated under different conditions (Example 3). Remacle exemplifies using an array with capture and detection antibodies to detect phosphorylated and total forms of proteins including Akt and Erk1/2 (Example 4), and detecting cell signaling changes in phosphorylation and total protein after treatment of cancer cells with a drug (PMA) (Example 5). Remacle suggests detecting proteins from known signaling pathways (cascades) provided in Tables 1 or 3, wherein Table 1 comprises ERK1/2 and AMPKa1 and Table 3 comprises Akt and ERK1/2 ([34]; [58]; claims 15, 16, 19, 33, 35).
Adnane teaches Sorafenib (BAY 43-9006) is used to treat renal cell carcinoma in humans and targets the RAF/MEK/ERK and VEGFR/PDGFR signaling pathways (abstract; Introduction; Table 1). Adnane demonstrates testing changes in protein biomarker phosphorylation in several cancer cell lines treated with sorafenib to identify the effects of sorafenib on cell signaling, wherein sorafenib decreased Erk1/2 phosphorylation, as detected by phospho-specific antibodies to Erk1/2 (Figure 2). Adnane describes a study measuring the phosphorylation of Erk1/2 in tumor tissue samples after animal treatment with sorafenib, and detected substantial reduction in Erk1/2 phosphorylation in response to sorafenib treatment compared to untreated controls (p. 607; Figure 4). Adnane describes a study measuring the phosphorylation of Erk1/2 in melanoma biopsy samples from a patient before and after sorafenib treatment, wherein treatment significantly reduced phosphorylation of Erk1/2 (Figure 5). Adnane teaches this result showed the ability of sorafenib to distribute well and inhibit the RAF/MEK/ERK pathway in human tumor tissue (p. 607-608). Adnane concludes that sorafenib is a multikinase inhibitor that is highly potent against C-RAF and B-RAF, as well as tyrosine kinases of the VEGF and PDGF receptor families (Conclusion, p. 609).
Murphy also teaches sorafenib inhibits the RAF/MEK/ERK signaling pathways that are activated during tumor angiogenesis (abstract). Murphy tested the effects of sorafenib on tumor cell signaling in vivo for three tumor types including a renal cell adenocarcinoma, and, using phospho-specific detection antibodies, found that sorafenib inhibited Erk1/2 phosphorylation, but did not affect Akt phosphorylation (Figures 4 and 5; Table 1). Murphy demonstrates staining patient renal cell carcinoma biopsy for phosphorylated ErK1/2, teaching cancers typically have ERK1/2 phosphorylation associated with angiogenesis (Figure 6; p. 1882-1883).
Larkin teaches sorafenib is used to clinically treat renal cell carcinoma (see entire paper). Larkin teaches several studies that tested the effects of sorafenib on cancer cell protein signaling pathways, wherein sorafenib was demonstrated to inhibit the RAF/MEK/ERK and VEGFR/PDGFR pathways, and inhibit Erk1/2 phosphorylation (p. 91). Larkin describes studies that detected reduced Erk1/2 phosphorylation in tumor biopsy samples after sorafenib treatment (p. 91, col. 2). Larkin summarizes known targets of sorafenib in Table 1:
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Larkin suggests identifying the mechanism of action for sorafenib in vivo by testing tumor biopsies before and after sorafenib treatment, and identifying the biomarkers of response to therapy (p. 93, col. 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made for the kit of Glezer to further include a biological sample from a human subject having renal cell carcinoma (RCC), wherein the subject was treated with sorafenib. One would have been motivated to and have a reasonable expectation of success to because: (1) Glezer and Gowan teach applying their kit to biological samples in order or assess the total and/or phosphorylated levels of biomarker proteins, as well as to identify the effects of drugs on these biomarker proteins and cell signaling pathways; (2) Dephino suggests testing biological samples from RCC, as well as testing the effects of sorafenib treatment on biomarkers of cell signaling pathways; (3) Remacle suggests applying the kit to assess total and phosphorylation states of proteins in cancer and in response to drugs, and teach known cell signaling pathway proteins to test including Akt, Erk1/2, and AMPKa1; (4) Adnane, Murphy, and Larkin teach it is known RCC is treated with sorafenib and that it inhibits multiple cell signaling pathways, and they demonstrate successfully testing for total and/or phosphorylated forms of biomarker proteins in cancer cells and RCC with and without, or before and after, treatment with sorafenib, including proteins Akt and ERK 1/2; (5) Adnane, Murphy, and Larkin suggest testing the effects of sorafenib on cell signaling pathways in vivo to identify its targets and correlation to therapeutic response. Given: (1) the known need to identify the protein targets and effects of sorafenib on cell signaling pathways in cancer, particularly RCC, (2) the known cell signaling proteins to assess including Akt, Erk1/2, and AMPKa1; (3) the known kits, cartridges, capture and phospho-specific antibodies and methods for detecting these proteins; and (4) the demonstrated success of detecting total and phosphorylated proteins from tumor cells using antibodies, one of skill in the art could have pursued testing and combining biological samples from RCC patients treated with sorafenib with the kit and antibody reagents of the cited combined references above with a reasonable expectation of success.
Response to Arguments
4. Applicants argue that there is a lack of motivation to modify the kits of the cited references and to arrive at the claimed kit. Applicants argue that references teach some, but not all, of the antibodies to the claimed biomarkers. Applicants argue that each of the references teach detecting additional biomarkers that are not required by the claimed kit or are excluded. Applicants argue that the intended analysis of biomarkers in a subject with RCC and optionally being administered sorafenib, are expressly reflected in the independent claims by the inclusion of a biological sample containing the biomarkers as part of the kit. Applicants argued that omitting certain biomarkers from the claimed kit or limiting the kits to a specific "consisting of" subset of biomarkers, as is also required by the independent claims, would require impermissible modification of the cited references. See, Table 2 of the instant specification, which teaches that detection of total Akt (not phosphorylated Akt); phosphorylated Erk 1/2 (but not total Erk 1/2); and p174 AMPKa1 (but not total AMPKa1 or p285), are effective biomarkers or distinguishing sorafenib-resistant subjects from sorafenib-sensitive ones. Applicants argue that absent this data, there is no motivation to select this specific combination of biomarkers. Applicants reiterate that each of the cited references includes antibodies for detecting additional biomarkers, such as phosphorylated Akt, total Erk 1/2, and/or total AMPKa1, which are preferably omitted from the claimed kit. Applicants argue this is based on Applicant's data that shows that these additional biomarkers can confound Applicant's intended use, and furthermore, the exclusion of these biomarkers would modify the kits of the prior art references, thereby rendering them unsatisfactory for their intended purposes of detecting all of the biomarkers
analyzed therein.
5. The arguments have been considered but are not persuasive. Applicants are arguing a method of determining sensitivity of a subject to sorafenib, which is not recited in the claims. The claims are limited to a kit comprising an assay cartridge in multi-spot, multi-well format comprising detection/capture reagents and a human biological sample, and these reagents function the same to detect total Akt, pERK 1/2, and AMPKa1 phosphorylated at residue 174, whether or not they are combined with detection/capture reagents for other markers. These reagents also function the same to detect total Akt, pERK 1/2, and AMPKa1 phosphorylated at residue 174, whether or not they are combined in a kit with biological samples from RCC subjects, at risk subjects (that include anyone with a kidney), or subjects treated with sorafenib.
Examiner maintains that that the cited references teach various subcombinations of all of the detection reagents claimed for total Akt, pERK 1/2, and AMPKa1 phosphorylated at residue 174 biomarkers, demonstrating that they function the same to detect the biomarkers when they are together, or not (excluded from other biomarkers), or when they are combined with other detection reagents. The cited references demonstrated that kits comprising assay cartridges in multi-spot, multi-well assay format utilizing various combinations of known detection and capture antibodies for known biomarkers are both known in the prior art and commercially available.
Applicants are arguing an intended use for the claimed kit for determining sensitivity of a subject to sorafenib. However, an intended use is not given weight for purposes of comparing the claims with the prior art. The claims read on the active ingredients per se, which are the assay cartridge in multi-spot, multi-well assay format, capture and detection antibodies for total Akt, pERK 1/2, and AMPKa1 phosphorylated at residue 174; and a biological sample from a human subject (see MPEP 2111.02).
The cited prior art does not need to teach the same motivation argued by Applicants in order to combine the claimed biomarker detection reagents and arrive at the same claimed kit. MPEP 2144 states: The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon,, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
In the instant case, Examiner stated, in the rejection, reasons provided by the cited art for motivation and reasonable expectation of success to produce the claimed kit that comprises detection and capture reagents for biomarkers comprising Akt, pERK 1/2, and AMPKa1 phosphorylated at residue 174, or consisting of the biomarkers (excluding others).
Contrary to arguments, Applicant's data does not show that detecting additional biomarkers of pAkt, total Erk 1/2, total AMPKa1, and AMPKa1 p285 confound Applicant's intended use for identifying subjects susceptible or resistant to sorafenib. This is evidenced by Table 2 of the instant specification that demonstrates the combined detection of total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 along with pAkt, total ERK1/2, total AMPKa1 and p285, and several other additional biomarkers, still results in detecting increased/decreased/no change levels of total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 proteins indicative of sorafenib resistance or susceptibility. Combining detection of all of these proteins in Table 2 did not change the function of detecting total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 or their correlation to sorafnib response.
6. Applicants argue that an “obvious to try” rationale is not sufficient. Applicants argue there are two classes of situations where “obvious to try” rationale is NOT applicable:
(1) when what would have been "obvious to try" would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful; and
(2) when what was "obvious to try" was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it. Id. (citing In re 'Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir.)). See MPEP § 2143 (I)(E), Example 3.
Applicants argue that one or both of these exceptions apply to the instant case. Applicant argue they have provided a specific recipe of effective biomarkers (i.e., total Akt, phosphorylated Erk1/2, and p174 AMPKa1), to the exclusion of other biomarkers. Applicants argue that the cited references interrogate various individual biomarkers of the claimed kits, but always in combination with additional biomarkers, many of which, as discussed above, are not informative for assessing response to sorafenib treatment. Applicants argue that the claimed kit falls within the exceptions to the "obvious to try" rationale, because the cited references either (1) motivate an endless variation of all parameters or the testing of numerous possible combinations in the hope of arriving at a successful result; and/or (2) provide only general guidance regarding the claimed kit, both of which are exceptions to a finding of obviousness.
Applicants argue that this is further illustrated by the large number of references used to establish the rejection. Although there is no per se prohibition against using a large number of references in a rejection, the context of using the large number of references is important. Applicants argue that the cited references illustrate the broad and virtually unlimited range of biomarkers available to one of skill in the art, and as previously discussed, none of these references individually teach the claimed set of biomarkers, and many of them require biomarkers that are specifically excluded by the instant claims.
7. The arguments have been considered but are not persuasive. Contrary to arguments, there is not an endless variation of all parameters or testing of numerous possible combinations, and this is not a new technology or general approach where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.
With regards to the obvious to try rationale, MPEP 2145 states: “An "obvious to try" rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. " [A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007).”
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, the cited prior art recognizes the need to make a multi-analyte immunoassay in multi-well plates, or a multi-spot assay that can detect the cell signaling activities of phosphorylases, phosphatases, and kinases in a biological sample; the cited prior art provides a finite number of identified combinations and overlapping subcombinations of the known, claimed cell signaling biomarkers detected together in order to assess cell signaling pathways; and the cited prior art provides a reasonable expectation of success to detect the claimed biomarkers together by successfully demonstrating antibodies detecting the claimed biomarkers either individually, in combinations, or in subcombinations, and by demonstrating the claimed biomarkers are already detected in multi-analyte immunoassays. As stated in the rejection:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to make an assay cartridge comprising capture and detection reagents to any subset of biomarkers from the prior art, including a subset consisting of total Akt, pERK1/2, and AMPK phosphorylated at T174, as the protein analytes in the kit of Glezer. One would have been motivated to and have a reasonable expectation of success to because: (1) Glezer suggests their kit can be used to test the activities of phosphorylases, phosphatases, and kinases; (2) Gowan and Grund demonstrate that total Akt, pAkt, and pERK1/2 are biomarkers already successfully incorporated into Meso Scale Discovery 96-well multi-spot plate kits; (3) Wako BioWindow teaches a commercially available kit that comprises a multi-well assay and antibodies for detecting levels of phosphorylated ERK1/2 and phosphorylated Akt with phosphorylated AMPK alpha 1 at threonine 174 (R&D Proteome Profiler™Human Phospho-Kinase Array Kit); and (4) Onay-Besikci and Chabowski provide motivation for combining detection of Akt, pERK1/2, and AMPK T174 phosphorylation to study the activities associated with AMPK activation and the heart, and teach antibodies for their detection are commercially available. Given the prior art provides motivation to assay cell signaling proteins: total Akt, pERK1/2, and AMPK T174 phosphorylation together, it is well within the level of the skill artisan to take any subset of the known biomarkers to assay their levels, and the kit detecting the subset of biomarkers is expected perform the same function as it would in a kit comprising a larger combination of biomarkers.
With regard to arguments that the rejection cites a large number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991) (Court affirmed a rejection of a detailed claim to a candy sucker shaped like a thumb on a stick based on thirteen prior art references.).
Contrary to arguments, the number of cited references does not illustrate the broad and virtually unlimited range of biomarkers available to one of skill in the art, but rather, demonstrates that detection of the claimed biomarkers together, individually, or in subcombinations is well established and routine in the prior art, as are the reagents and cartridge recited in the claimed kits.
8. Applicants argue that the Office alleges that "it is well within the
level of the skill artisan to take any subset of the known biomarkers to assay their levels, and the kit detecting the subset of biomarkers is expected perform the same function as it would in a kit comprising a larger combination of biomarkers" and concludes that Applicant's arguments are ineffectively directed to an "intended use" that is not specifically claimed. Applicants argue the Office appears to reduce the claimed kit to individual elements, i.e., each individual antibody will still bind its target. However, the claims are drawn to a specifically designed collection of antibodies that must be viewed in the aggregate. "[W]hen evaluating the scope of a claim, every limitation in the claim must be considered. Examiners may not dissect a claimed invention into discrete elements and then evaluate the elements in isolation. Instead, the claim as a whole must be considered. See, MPEP § 2103 I. C. citing, e.g., Diamond V. Diehr, 450 U.S.
175, 188-89, 209 USPQ 1, 9 (1981). Applicants argue that when the kit is viewed as an aggregate of antibodies it does not perform the same as the kits of the cited references because the cited references have antibodies that are missing from the claimed kit and/or utilize antibodies that are excluded from the claimed kit. Applicants argue that this collection of claimed antibodies leads to particularly informative means of assessing response to sorafenib treatment that would be confounded by the kits of the cited references. Furthermore, as discussed in MPEP § 2144 II.B. citing In re Edge, 359 F.2d 896, 149 USPQ 556 (CCPA 1966), "[t]he omission of an element and retention of its function is an indicium of nonobviousness." Applicants argue that put another way, even if the cited references are combined and therefore could be capable of carrying out the intended use of the kit, such a combination of kits from the cited art includes more than the number of antibodies required by the claimed kit and identified by Applicant as important for assessing response to sorafenib treatment. Applicants argue that omission of the extraneous antibodies, and retention of diagnostic power, and even improvement thereof, as outlined above, is indica of non-obviousness.
Applicants argue that a specific selection leading to a novel combination of known compositions is patentable, particularly when its use exhibits indicia of non-obviousness. Applicants argue that once Applicant has presented evidence of unexpectedly good results, particularly, as is the case here, where they are directly tied to structural differences between the claims and the art, the results can be applied to the composition per se and need not be restricted to a method or intended use. To do so amounts to reversible error. See, e.g., In re Sullivan, 498 F.3d 1345, 84 USPQ2d 1034 (Fed. Cir. 2007), MPEP 2145, Example 2.
The claimed invention was directed to an antivenom composition comprising F(ab) fragments used to treat venomous rattlesnake bites. The composition was created from antibody molecules that include three fragments, F(ab)2, F(ab) and F(c), which have separate properties and utilities. There had been commercially available antivenom products that consisted of whole antibodies and F(ab)2 fragments, but researchers had not experimented with antivenoms containing only F(ab) fragments because it was believed that their unique properties would prevent them from decreasing the toxicity of snake venom. The inventor, Sullivan, discovered that F(ab) fragments are effective at neutralizing the lethality of rattlesnake venom, while reducing the occurrence of adverse immune reactions in humans. On appeal of the examiner's rejection, the Board held that the claim was obvious because all the elements of the claimed composition were accounted for in the prior art, and that the composition taught by that prior art would have been expected by a person of ordinary skill in the art at the time the invention was made (the case was examined under pre-AIA 35 U.S.C. 103) to neutralize the lethality of the venom of a rattlesnake.
Appellant did not concede that the only distinguishing factor of its composition is the statement of intended use and extensively argued that its claimed composition exhibits the unexpected property of neutralizing the lethality of rattlesnake venom while reducing the occurrence of adverse immune reactions in humans. The Federal Circuit found that such a use and unexpected property cannot be ignored - the unexpected property is relevant and thus the declarations describing it should have been considered. Nonobviousness can be shown when a person of ordinary skill in the art would not have reasonably predicted the claimed invention based on the prior art, and the resulting invention would not have been expected. All evidence must be considered when properly presented.
Applicants argue that such is the case here. The Office provided references encompassing antibodies that detect the claimed biomarkers and with other biomarkers, however, the instant specification discloses that the detection of total Akt, pERK1/2, and p174 AMPKa1 without detection of pAkt, total ERK1/2, total AMPKa1 or p285, is effective for distinguishing sorafenib-resistant subjects from sorafenib-sensitive ones. Applicants argue that the cited references do not provide guidance for selecting and excluding specific biomarkers in order to achieve an effective diagnostic/prognostic result reported by Applicant. Applicants argue that reliance of a general motivation to combine known compositions because a "kit detecting the subset of biomarkers is expected perform the same function as it would in a kit comprising a larger combination of biomarkers" is no longer sufficient to sustain a prima facie case of obviousness, at least because In re Sullivan establishes that results obtained from use of the composition must be considered, even when the claims are directed to a composition and even where the use is not specifically claimed. Applicants argue that dependent claims such as 46, 47, and 51-53 provide increasing specificity of elements that are related to the intended use, particularly the nature of the sample that will be analyzed by the antibodies.
9. The arguments have been carefully considered but are not persuasive. The fact patterns in In re Sullivan are not commensurate in scope with the fact patterns in the instant application, and the arguments directed to the decision in In re Sullivan are not persuasive. In the case of In re Sullivan, the claimed composition at issue consisted of antivenom Fab fragments that exhibited the unexpected property of neutralizing the lethality of rattlesnake venom while reducing the occurrence of adverse immune reactions in humans. The Fab antivenom composition differed from the prior art commercial antivenom composition in that the prior art composition comprised intact antibodies (whole antibodies) and F(ab)2 fragments. Prior art researchers had not experimented with antivenoms containing only Fab fragments because it was believed that their unique properties would prevent them from decreasing the toxicity of snake venom, therefore would not function as antivenom. The prior art did not recognize the unexpected functions of a composition consisting of Fab to neutralize antivenom and to reduce the occurrence of adverse immune reactions in humans.
In the instant case, Applicants have not persuasively argued that the specifically claimed combination of antibodies detecting total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 possess an unexpected function or advantage when separated from antibodies binding to pAkt, total ERK1/2, total AMPKa1, and AMPKa1 phosphorylated at 285 in a kit. The specifically claimed combination of antibodies perform the same function detecting total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 whether they are isolated from, or combined with, other detection antibodies. Their protein-binding function remains predictably the same as that taught by the cited prior art. Therefore, there is no new, unexpected function or advantage gained or previously unappreciated by separating the claimed combination of antibodies from other detection antibodies in a kit.
Further, the instantly claimed detection antibodies are the same as the detection antibodies taught by the cited prior art. Unlike in In re Sullivan, the Fab antivenom was structurally distinct from the composition of whole antibody + F(ab)2 fragments taught by the prior art. This is not the case here. The claimed combination of antibodies detecting total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 are the same as the prior art antibodies and will still detect total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 whether there are other detection antibodies present or not in the kit. Further, the claimed combination of antibodies detecting total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 will still provide the same information of increased or decreased total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 protein levels in a biological sample whether or not other detection antibodies are present in the kit. Therefore, their argued function in identifying subjects as susceptible or resistant to sorafenib does not change in the presence of other detection antibodies. This is evidenced by Table 2 of the instant specification that demonstrates the combined detection of total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 along with pAkt, total ERK1/2, total AMPKa1 or p285, and several other additional biomarkers still results in detecting increased/decreased/no change levels of total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 proteins indicative of sorafenib resistance or susceptibility. Combining detection of all of these proteins in Table 2 did not change the function of detecting total Akt, pERK1/2, and AMPKa1 phosphorylated at 174 or their correlation to sorafnib response (Table 2):
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The instant specification discloses that all of the detected proteins in Table 2 provide a signature pattern for characterizing RCC tumors, and suggests individual markers, combinations of markers, and subsets of markers can be used for determining sorafenib sensitivity. Even when detecting all of the combined proteins in Table 2, the specification still recognizes total Akt, pERK1/2, and AMPKa1 p174 function to characterize RCC tumors as sorafenib responsive or non-responsive:
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Nowhere does the specification provide evidence that the claimed combination of antibodies functions differently in protein detection and characterizing protein expression in RCC samples when excluded from other detection antibodies in a kit. Unlike in in re Sullivan, one of ordinary skill in the art would have reasonably predicted a kit comprising or consisting of the claimed combination of detection antibodies based on the cited prior art.
10. Claims 24, 25, 27, 28, 34, 35, 42, and 43 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2005/0142033, Glezer et al (Meso Scale Technologies); Gowan et al (Assay and Drug Development Technologies, 2007, 5:391-401); Grund et al (Molecular Pharmacology, 2008, 73:1394- 1404, published online February 5, 2008; IDS); Wako BioWindow (http://www.wako-chem.co.jp) published August 2008; Chabowski et al (Molecular and Cellular Biochemistry, 2006, 288:201-212); Onay-Besikci et al (Basic Res. Cardiol. 2007, 102:436-444); WO 2018/127707, Dephino et al, Published April 2008; US Patent Application Publication 2004/0265938, Remacle et al; Adnane et al (METHODS IN ENZYMOLOGY, 2006, Vol. 407:597-612); Murphy et al (American Journal of Pathology, 2006, 169:1875-1885); and Larkin et al (Therapeutics and Clinical Risk Management, 2006, 2:87-98); as evidenced by Cell Signaling Technology antibodies #9102 and #9101 (printed January 2025); as applied to claims 17-23, 26, 29-33, 36-41, 46, 47, and 49-53 above, and further in view of WO 2007/040559, Gamez, published 2007.
Glezer; Gowan; Grund; Wako BioWindow; Chabowski; and Onay-Besikci (the combined references) teach the Meso Scale Discovery multi-spot plates, capture and detection antibodies, and calibrator proteins for use in an ECL assay kit as set forth above.
The combined references do not teach the calibrator proteins are in liquid form or lyophilized.
Gamez teaches the calibration proteins for an electrochemiluminescent assay can be lyophilized and lyophilization of proteins is well known in the art for the preservation and stability of proteins. Gamez teaches the lyophilized calibration proteins can be comprised in a kit with a multi-well plate and detectably labeled antibodies for electrochemiluminescent assay (abstract; p. 1-7; [40-41]; [54-88]; claims 1-26, 57-93, 113-118).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include a lyophilized blend of the proteins or a liquid formulation of proteins as a calibrator in the assay of the combined references. One would have been motivated to in order to have standards to calibrate the SECTOR™ imager 6000 instrument for accurate protein quantification. One of ordinary skill in the art would have a reasonable expectation of success because the use of standards or calibrator proteins stored as lyophilized or liquid are conventional in the art for calibrating protein levels in immunoassays, as taught by Gamez.
Response to Arguments
11. Applicants argue that the additional reference cited in the second rejection fails to remedy the deficiencies argued for the first rejection under 35 USC 103(a).
12. The arguments have been considered but are not persuasive. The references cited in the first rejection do not have the deficiencies argued for the reasons stated above.
13. Conclusion: No claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642