DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/28/2025 has been entered.
Priority
This application is a U.S. National Stage (371) application of PCT/CN2022/078965 filed on 03/03/2022 which claims priority to Foreign Application No. CN202111584011.5 filed on 12/22/2021.
Claim Status
Claims 1-3 and 5 are cancelled at the Applicant’s request. Claims 4 and 6 are currently amended, and the Applicant notes that no new material is added.
Thus, claims 4 and 6 are pending and are under examination.
Maintained Rejections
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art (PHOSITA) to which the claimed invention 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 35 U.S.C. 103 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.
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (CN104360049 A) in view of Wang et al. (Cytometry. 2021;99:273–277, Accepted: 16 November 2020), Monteiro et al. (US 2019/0265232 A1) and Mahnke et al. (Eur. J. Immunol. 2013. 43: 2797–2809).
Regarding claims 4 and 6, Zhao teaches an immunophenotyping kit for identifying a subset of T lymphocytes (Abstract; claims, claim 4; [0002]; [0009]).
Zhao teaches that the kit consists of antibodies labeled by different fluorescent labels (claims, claim 4).
Zhao teaches that composition 1 consists of an anti-CD45 antibody ([0201]), an anti-CD3 antibody (Abstract), an anti-CD4 antibody (Abstract), an anti-CD8 (Abstract) antibody, an anti-CD45RO antibody ([0133]; [0310]).
Zhao teaches using the following fluorescent markers: FITC, BV510, BV421, PE and APC ([0041]; [0137]).
Zhao further classifies the T helper cells into double negative T cells, gamma T cells, helper naïve T cells, helper depleted T cells, helper central memory T cells, helper effector memory T cells by using the following antibodies : anti-CD3, anti-CD4, anti-CD45RA and anti-CD27 ().
Regarding claims 4 and 6, Zhao does not teach using the following antibodies: an anti-CD25 antibody, an anti-CD127 antibody, an anti-CD197 antibody, an anti-CD28 antibody, and an anti-CD95 antibody to further classify T cells.
Zhao does not teach using the following fluorescent labels: APC-Cy7, BV650, BV605, BV785 and Alexa Fluor 700.
Zhao does not teach the staining pattern of regulatory T cells.
Zhao does not teach using anti-CD197 (CCR7) nor anti-CD45RO antibodies.
Zhao does not use CD45RO along with CCR7 (CD197) to classify cytotoxic T cell populations.
Regarding claims 4 and 6, Wang teaches using an anti-CD25 antibody and anti-CD127 antibody (Page 274, right column, first paragraph; Table 2, “CD25”, “CD127”).
Wang teaches using an anti-CD28 and anti-CD95 antibodies (Page 274, right column, second paragraph, “CD28”; Table 2, “CD28”; “CD95”).
Wang teaches using an anti-CD197 or CCR7 antibody (Page 274, right column, first and second paragraphs, “CCR7”; Table 2, “CCR7”).
Wang teaches using the following fluorescent labels: APC-Cy7, BV605 and BV650 (Table 2, “APC-Cy7”, “BV605”, “BV650”).
Wang teaches that a cell surface marker of CD3+CD4+CD25+CD127- indicates a regulatory T cell (Table 2, “CD25”, “CD127”, “Regulatory T-cell Lineage”).
CD3+ and CD4+ are common T cell markers that are also used by Wang to detect cells (Table 2, “CD3”, “CD4”, “T-cell lineage”).
Wang teaches using CD197 (CCR7) and CD45RO- along with CD3 and CD4 to classify helper T cells (Page 274, right column, first paragraph, “Conventional CD4+ T cells can be divided into naïve and memory T cells using CCR7 and CD45RO, respectively”).
Wang also uses CD28 as a co-stimulation marker and CD 95 as an activation marker (Table 2, “CD28”, “CD 95”).
Wang further teaches that conventional memory CD4+ T cells can be further divided into distinct Th cell subpopulations (Page 274, right column, first paragraph).
Wang used CD45RO, CCR7 (CD197), CD28 and CD95 along with CD3 and CD8 to identify six CD8+ cytotoxic T-cell subpopulations: naïve T cells, T memory stem cells, central memory T cells (TCM), “transitional” memory cells (TTM), effector memory T cells (TEM), and terminal effector cells TTE (Page 274, right column, second paragraph).
Regarding claims 4 and 6, Monteiro teaches using the following fluorescent labels: BV785 and Alexa Fluor 700 (Page 4, [0027]).
Regarding claims 4 and 6, Mahnke teaches the subsets of memory T cells (Figure 1, Panel B).
Mahnke teaches that human T cells differentiation should be delineated using a minimum set of canonical markers such as CD45RO, CCR7(CD197), CD28 and CD95 (Page 2799, right column, last paragraph and page 2800, left column, first paragraph).
Mahnke teaches that six subsets of T cells would be identified with such a classification: TN for naïve T cells, TSCM for stem cell memory T cells, TCM for central memory T cells, TTM for transitional memory T cells, TEM for effector memory T cells and TTE for terminal effector T cells (Page 2800, left column, first paragraph).
Mahnke teaches using other molecules to further classify T cells (Page 2800, left column, first paragraph). A skilled artisan would have known that to study T cells, CD3 is used as a defining marker as noted before by Zhao (Abstract) and to further differentiate helper from cytotoxic T cells, CD4 and CD8 surface markers are to be used as it has been noted by Mahnke (Page 2804, second paragraph, “Cytotoxicity was thought to be limited to CD8+ T cells (hence they were named “cytotoxic T lymphocytes” or “CTLs”), while CD4+ T cells were considered to be mostly cytokine-producing cells (hence named helper or TH cells)”.
It would have been obvious for a PHOSITA before the effective filing date of the application to combine marker antibodies of Wang over Zhao’s kit to develop a kit for identifying subsets of T lymphocytes because Wang noted that in clinical research the changes in helper T cell subsets have attracted a lot of attention, especially in autoimmune diseases and cancer (Page 274, right column, first paragraph) and even stated that Conventional memory CD4+ T cells can be further divided into distinct helper T cell subpopulations (Page 274, right column, first paragraph). The skilled artisan would have been even more motivated to combine the fluorescent labels of Monteiro with the methods of Wang and Zhao because Monteiro further looked at phenotypic markers of T cells to further help in the diagnosis of an inflammatory autoimmune disease (Page 4, [0031-0032]). The skilled artisan would have combined T cell subset classification of Mahnke with the methods of Monteiro, Wang and Zhang because Mahnke proposed using a unified model of human memory T-cell differentiation along with a set of canonical markers to be used for their delineation (Page 2798, left column, first paragraph). Thus, a skilled artisan would have been motivated to combine the above methods into the kit of Zhao because such a kit for immunophenotyping T lymphocytes would have been used to provide information for different diseases that can assist a physician in making an informed decision about the health status of a patient (Abstract; [0007] and [0009]). A PHOSITA would have had a reasonable expectation of combining the methods of Mahnke, Monteiro, Wang and Zhao because the claimed methods are all directed to immunotyping subsets of T cells.
Overall, it would have been obvious for a skilled artisan to combine the marker antibodies of Wang, the fluorescent labels of Monteiro and the memory T cell classification of Mahnke with the kit of Zhao to achieve a specific and accurate immunophenotyping of T cells subsets because it can provide valuable information for the healthcare provider for treatment and vaccination purposes for example.
Response to Arguments
Applicant's arguments filed on 04/28/2025 have been fully considered but they are not persuasive.
The Applicant traversed to using Mahnke, Monteiro, Wang and Zhao in the previous rejection of claims 4 and 6 under 35 U.S.C. 103.
The Applicant first alleged that when evaluating the "inventive step" of an invention, the technical solutions should be considered as a whole. In particular, in the claim 4 and claim 6 of the present invention, the Applicant alleged that each antibody conjugated to a specific fluorescent label should be taken as a whole, and that claim 4 does not discloses a solution of using only ten antibodies, but a solution of using ten antibodies, each of which is conjugated with a specific fluorescent label.
The Applicant further alleged that although the Examiner asserts that the references disclose ten antibodies and ten fluorescent labels, the Applicant alleged that NONE of the references used in 103 rejection of claims 4 and 6 discloses the ten specific combinations of the antibodies and the fluorescent labels.
The Applicant further alleged that according to the identification of the present application, the ten specific combinations of the antibodies and the fluorescent labels are inventively designed to avoid the complex and less reliable compensation as much as possible, for example, in the present application.
The Applicant admits that Mahnke, Monteiro, Wang and Zhao only separately mentioned the use of part of the fluorescent labels of the present application, but alleged that Mahnke, Monteiro, Wang and Zhao never teach the combination of the ten fluorescent labels conjugating to the ten antibodies as a whole for the identification of subsets of T cells to avoid the compensation as stated above.
In addition, the Applicant further alleged that the antibodies and fluorescent labels of the present application are NOT randomly combined and that it has been inventively designed so as to obtain a more clear and precise results for the identification of subsets of T cells.
The Applicant concludes by alleging that Mahnke, Monteiro, Wang and Zhao neither disclose the simultaneous use of the specific ten combinations of antibodies and fluorescent labels of the present application at once, nor teach the technical effect achieved by the present application.
The instant case is a clear example of routine optimization within the prior art conditions or through routine experimentation. The Comparative examples that the Applicant presented in their arguments of 04/28/2025 are clear examples for optimizing the conditions for immuno-phenotyping of T Lymphocyte subgroups.
In order to properly support a rejection on the basis that an invention is the result of "routine optimization", the examiner must make findings of relevant facts, and present the underpinning reasoning in sufficient detail. The articulated rationale must include an explanation of why it would have been routine optimization to arrive at the claimed invention and why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range. See In re Stepan, 868 F.3d 1342, 1346, 123 USPQ2d 1838, 1841 (Fed. Cir. 2017). See also In re Van Os, 844 F.3d 1359,1361,121 USPQ2d 1209, 1211 (Fed. Cir. 2017) ("Absent some articulated rationale, a finding that a combination of prior art would have been ‘common sense’ or ‘intuitive’ is no different than merely stating the combination ‘would have been obvious.’"); Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355, 1362, 119 USPQ2d 1822 (Fed. Cir. 2016) ("[R]eferences to ‘common sense’ … cannot be used as a wholesale substitute for reasoned analysis and evidentiary support … ."). In the instant case, Wang noted that in clinical research the changes in helper T cell subsets have attracted a lot of attention, especially in autoimmune diseases and cancer (Page 274, right column, first paragraph). Wang even stated that conventional memory CD4+ T cells can be further divided into distinct helper T cell subpopulations (Page 274, right column, first paragraph). A skilled artisan would have been motivated to combine the methods of Mannke and Wang with Monteiro method because Monteiro further looked at phenotypic markers of T cells to further help in the diagnosis of an inflammatory autoimmune disease (Page 4, [0031-0032]). A skilled artisan would have been motivated to combine the above methods into the kit of Zhao because such a kit for immunophenotyping T lymphocytes would have been used to provide information for different diseases that can assist a physician in making an informed decision about the health status of a patient (Abstract; [0007] and [0009]).
The Supreme Court has clarified that an "obvious to try" line of reasoning may properly support an obviousness rejection. In KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, 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 the product 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."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, Wang noted that in clinical research the changes in helper T cell subsets have attracted a lot of attention, especially in autoimmune diseases and cancer (Page 274, right column, first paragraph) and stated that conventional memory CD4+ T cells can be further divided into distinct helper T cell subpopulations (Page 274, right column, first paragraph). A skilled artisan would have been motivated by the success of Zhao’s kit to combine with the different methods of Wang, Monteiro and Mahnke to further immunophenotype the subpopulations of T lymphocytes.
The Applicant alleged that none of the references teaches the instant invention. However, the Applicant is reminded to look at the teachings of references in combination as it has been noted in the MPEP. Regarding the rejection of claims under 35 U.S.C. 103 and in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case and when combined, the references of Mahnke, Monteiro, Wang and Zhao teach all of the antibodies and fluorescent tags of the instant invention and with an incentive to combine and optimize as noted above the instant invention is reached.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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