DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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 negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 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 1, 5, 6, 8, 10, 16, 18, 19, 20, 21 and 22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kallergi et al (Breast Cancer Research 13:R59, published 10 June 2011; cited on IDS) in view of Garcia-Blanco et al (US 2013/0209493, cited on IDS).
With regard to claim 1, Kallergi described an experiment in the section entitled “Twist and vimentin expression on CTCs of early stage and metastatic breast cancer patients”, beginning on page 5 and illustrated in figure 2 and table 2. Specifically, Kallergi tested for expression of CK, Twist and vimentin on CTCs “using PBMC cytospin preparations from these patients”. Table 2 clearly shows the identification and distribution of four subgroups of CTCs for each patient: Vim+CK+, Vim-CK+, Twist+CK+ and Twist-CK+. Kallergi expressed the proportions of subgroups as percentages; see “Twist and vimentin expression on CTCs of early stage and metastatic breast cancer patients”, beginning on page 5: “…the proportion of double-positive [CK+/Twist+] CTCs was lower in patients with early stage breast cancer than in patients with metastatic breast cancer (53% versus 97%, respectively…”; “…the proportion of double-positive [CK+/vimentin+] CTCs was lower in patients with early stage cancer than in those with metastatic disease (56% versus 74%...”.
Based on Kallergi’s conclusion that cells expressing Twist and vimentin are higher in patients with metastatic disease, it would have been obvious to perform Kallergi’s assay to monitor patients with early stage disease for indications of metastasis or metastatic potential, so that appropriate treatment or changes in treatment could be initiated.
With regard to claim 16, breast cancer qualifies as both a solid tumor and, in these patients, a malignant tumor.
With regard to claim 8, as noted above, Kallergi detected CK, vimentin and Twist.
With regard to claim 10, Kallergi detected these markers by immunofluorescence.
With regard to claim 20, as noted above, based on Kallergi’s conclusion that cells expressing Twist and vimentin are higher in patients with metastatic disease, it would have been obvious to perform Kallergi’s assay to monitor patients with early stage disease for indications of metastasis or metastatic potential (i.e. risk of metastasis), so that appropriate treatment or changes in treatment could be initiated.
With regard to claim 18, since vimentin (according to Applicant’s claim 8) is a mesenchymal marker, Kallergi’s Table 2 is an implicit comparison of the numbers of epithelial CTCs (CK+/vimentin-) and the numbers of mesenchymal CTCs (CK+/vimentin+).
With regard to claim 21, as noted above, Kallergi tested for expression of Twist (an EMT marker), and Vimentin (a mesenchymal marker).
With regard to claim 22, while Kallergi did not test for E-cadherin, Kallergi noted (page 2, column 1, first full paragraph): “Downregulation of epithelial markers such as cytokeratin and E-cadherin and upregulation of mesenchymal markers such as vimentin, N-cadherin and cadherin 11 characterise the EMT process.” Additionally, Kallergi noted (same column, last paragraph): “Expression of vimentin is characteristic of epithelial cells undergoing the EMT process and is related to reduced expression of E-cadherin and upregulation of N-cadherin…”. As Kallergi was interested in characterizing the EMT process, and tested for vimentin as a mesenchymal marker, it would have been obvious to additionally test for E-cadherin as an epithelial cell marker, since based on Kallergi’s teachings it would have provided an expected inverse correlation to the expression of vimentin. It would also have been obvious to test E-cadherin as an alternative to, or in addition to, CK, as Kallergi taught both were epithelial markers.
The only limitations not disclosed explicitly or implicitly, or otherwise suggested by the disclosure of Kallergi are (i) that the particular experiment described (in the section entitled “Twist and vimentin expression on CTCs of early stage and metastatic breast cancer patients”, beginning on page 5 and illustrated in figure 2 and table 2) included steps a and b of claim 1, and (ii) the expression of the proportions of the CTC subgroups as a “ratio”, rather than a percentage, as recited in claims 1 and 18.
Regarding the first difference, and with regard to claims 5, 6 and 19, it is noted that in a different experiment (section entitled “Vimentin and Twist are coexpressed in CTCs of breast cancer patients”, beginning on page 6), Kallergi obtained blood from breast cancer patients (page 2, last paragraph). Then, Kallergi isolated PBMCs and CTCs from the blood samples using density gradient centrifugation (page 2, last paragraph). Then, Kallergi depleted the resulting cell suspension of hematopoietic cells using anti-CD45 antibody (section entitled “Immunomagnetic separation of CTCs”, beginning at the bottom of page 3 and concluding on page 4). Then, Kallergi applied the enriched CTC cell sample to slides and stained with antibodies (immunofluorescence) to cytokeratin (an epithelial marker, according to Applicant’s claim 8), Vimentin (a mesenchymal marker, according to Applicant’s claim 8), and Twist (an epithelial-to-mesenchymal transition marker (EMT), according to Applicant’s claim 8) (section entitled “Immunomagnetic separation of CTCs”, beginning at the bottom of page 3 and concluding on page 4).
However, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include this immunodepletion step for Kallergi’s other experiment (section entitled “Twist and vimentin expression on CTCs of early stage and metastatic breast cancer patients”, beginning on page 5), because Kallergi taught that this would “enrich the samples with CTCs” (page 4, left column, last statement). Therefore, one would have been motivated to add this step in order to enrich the sample with CTCs, thereby increasing the likelihood of detection of CTCs, as well as increasing the number of analyzed CTCs, thereby improving the accuracy of the results due to a larger sample size, a basic concept of statistical analysis.
With regard to expressing proportions of CTC subtypes as a “ratio” rather than a “percentage”, Garcia-Blanco, who also taught detection of biomarkers, including epithelial mesenchymal transition (EMT) markers on CTCs (see abstract). In Table 6, pages 15-16 (see Table legend), Garcia-Blanco expressed the proportion of CTCs co-expressing cytokeratin and vimentin as both a ratio and a percentage.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to express the proportions of CTC subgroups in Kallergi’s Table 2 as either percentages or ratios, since Garcia-Blanco demonstrated that these were simply two different manners of expressing the data.
Claim 15 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kallergi et al (Breast Cancer Research 13:R59, published 10 June 2011; cited on IDS) in view of Polansky (US 2004/0023207; cited on IDS).
Kallergi taught antibodies (i.e. “markers”) for detecting cytokeratin (an epithelial marker), vimentin (a mesenchymal marker) and Twist (an epithelial-to-mesenchymal transition (EMT) marker); see section entitled “Double-immunofluorescence confocal laser-scanning and ARIOL scanning microscopy”, page 3, left column, indicating mouse A45-B/B3 antibody (for detecting cytokeratins CK8, CK18 and CK19), and rabbit anti-Twist and anti-vimentin antibodies. In addition, Kallergi taught fluorescently-labeled secondary antibodies, which constitute “means for detecting” the binding of the primary antibodies (the markers) to CTCs (id.).
Kallergi did not teach putting these reagents into a “kit”. Kallergi also did not teach including in such kit “instructions” as recited in the claim.
Polansky taught (paragraph [0919]): “Well known advantages of commercial kits include convenience and reproducibility due to manufacturing standardization, quality control and validation procedures.”
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to put the reagents disclosed by Kallergi into a kit to obtain the advantages of kits pointed out by Polansky.
With regard to the “instructions”, the MPEP at 2112.01-III explains why nonfunctional printed matter, including instructions in a kit, does not distinguish over otherwise identical prior art. In In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004), the Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed, explaining "[i]f we were to adopt [applicant’s] position, anyone could continue patenting a product indefinitely provided that they add a new instruction sheet to the product."
Claim 9 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kallergi et al (Breast Cancer Research 13:R59, published 10 June 2011; cited on IDS) in view of Garcia-Blanco et al (US 2013/0209493, cited on IDS) as applied to claims 1, 5, 6, 8, 10, 16, 18, 19, 20, 21 and 22 above, and further in view of Yang (US 2014/0308669, cited on IDS).
The teachings of Kallergi and Garcia-Blanco have been discussed. Kallergi did not teach exposing the CTCs isolated by the method to a pharmaceutical composition.
Yang taught (paragraph [0039]): "In addition, CTCs can be used to study responses of cancer cells to therapeutic pressure, and discover novel biomarkers and drug targets for cancers." Also at paragraph [0071] (emphasis added): "The results obtained from the physical, chemical, and molecular analysis of CTCs can provide valuable information for various applications including, but not limited to, evaluating condition of the cancer patient, assessing or predicting cancer progression, assessing or predicting treatment response of the cancer patient, cancer prognosis, screening targets for cancer drugs, predicting treatment outcome, discovering novel biomarkers, and understanding response of cancer cell to therapeutic pressure."
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to expose the CTCs identified by the method suggested by the combined teachings of Kallergi and Garcia-Blanco to pharmaceutical agents in order to study the responses of cancer cells to therapeutic pressure and to screen for novel cancer drugs.
Claim 17 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kallergi et al (Breast Cancer Research 13:R59, published 10 June 2011; cited on IDS) in view of Garcia-Blanco et al (US 2013/0209493, cited on IDS) as applied to claims 1, 5, 6, 8, 10, 16, 18, 19, 20, 21 and 22 above, and further in view of Skelley (US 2014/0154703, cited on IDS).
The teachings of Kallergi and Garcia-Blanco, and the reason to use Kallergi’s method to monitor tumor progression, have been discussed. Although implicit in “monitoring” tumor progression is the testing of multiple samples taken at different times, Kallergi did not expressly state to do so.
Skelley taught (paragraph [0253]): “The enumeration of the rare cell subtype(s) at two different points in time can be used to monitor treatment. For example, if the number of circulating cancer stem cell (a subtype of CTCs) increases between a first sample collected before therapy or at the beginning of treatment and a second sample collected at a later point in time (for example, after treatment), it can be concluded that the treatment is not helpful. Similarly, a baseline of circulating cancer stem cells in determined at the end of a treatment regimen and a subsequent sample obtained has an increase number of circulating cancer stern cells; there can be an indication of cancer relapse.”
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to perform the method suggested by the combined teachings of Kallergi and Garcia-Blanco on multiple samples taken at different time points both to monitor for metastasis or metastatic potential, or, as suggested by Skelley, to monitor treatment.
Conclusion
No claims are free of the prior art.
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/SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681