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 .
Claims 1-6 and 9-20 are pending.
Claims 1-5 and 10-20 are withdrawn as directed to non-elected inventions as discussed in further detail in the office action dated 01/31/2025.
Claims 7-8 are cancelled.
Claims 6 and 9 are under examination on the merits.
Withdrawn Claim Rejections
The rejections of claims 7-8 presented in the office action dated 01/31/2025 are withdrawn as moot in light of the 06/02/2025 cancellation of claims 7-8. The rejections of claims 6 and 9 under 35 USC §102 are withdrawn as addressed by the 06/02/2025 amendments to the claims. The rejections of claims 6 and 9 under 35 USC §103 over Franzoni et al are withdrawn as redundant.
Claim Interpretation
Applicant is advised that the recitation of biomarker permutations (where P signifies positive and N signifies negative such that P:P is positive: positive and P:N is positive: negative) as recited in light of the 06/02/2025 claim amendments are being interpreted to be requires as listed alternatives by the claim, not as preferred embodiments.
Newly Necessitated Claim 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 6 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shutz et al (Identification of novel dendritic cell subset markers in human blood. Biochem Biophys Res Commun. 2014 Jan 10;443(2):453-7. doi: 10.1016/j.bbrc.2013.11.112. Epub 2013 Dec 7. PMID: 24321550) in view of Liu et al (A min-max combination of biomarkers to improve diagnostic accuracy. Stat Med. 2011 Jul 20;30(16):2005-14. doi: 10.1002/sim.4238. Epub 2011 Apr 7), Hegde et al (CD44 mobilization in allogeneic dendritic cell-T cell immunological synapse plays a key role in T cell activation. J Leukoc Biol. 2008 Jul;84(1):134-42. doi: 10.1189/jlb.1107752. Epub 2008 Apr 3), and Li et al (Aberrant CD200/CD200R1 expression and function in systemic lupus erythematosus contributes to abnormal T-cell responsiveness and dendritic cell activity . Arthritis Res Ther 14, R123 (2012). https://doi.org/10.1186/ar3853).
Shutz et al teach that human PBMC were isolated from buffy coats of healthy blood donors after informed consent by Ficoll-Paque (Pharmacia, Germany) density gradient centrifugation. Blood DC were enriched in some experiments in a two-step immunomagenetic purification process using the Blood Dendritic Cell Isolation Kit II (Miltenyi Biotec) according to the manufacturer’s instructions (see section 2.1). Then, in order to acquire a sufficient high number of human DC, including the rare mDC2 subset we first systematically screened DC-enriched PBMC preparations from buffy coats of healthy blood donors. Human DC-enriched PBMC samples were subsequently stained with consensus DC subset surface markers (CD1c, CD141, BDCA-2) and a lineage cocktail to unambiguously exclude contaminating non-DC (Fig 1A). Shutz et al combined multiparameter DC subset staining method with 332 different PE-labelled surface monoclonal antibodies to identify novel subset markers. Isotype-specific FMO controls were used to precisely evaluate the specificity for surface staining for each DC subset. The initial analysis revealed the presence of eight novel DC subset candidate markers CD26, CD85a, CD109, CD172a, CD200, CD200R, CD275 and CD301 (Fig 1B). Additionally, the analysis included previously reported DC subset markers, such as CD123 and CD45RA for pDC and CD32, CD64 and FcεRI for mDC1 providing an internal control. Note that Figs 1C-D show biomarker expressed on the DCs (presumed to include regulatory DCs given the DC breakdown depicted) including biomarkers CD172α and CD200R. Note that Schutz et al teach that DCs were separated in a two-step immunomagenetic purification process using the Blood Dendritic Cell Isolation Kit II (Miltenyi Biotec; which is a magnetic labeling system for the concurrent isolation of plasmacytoid and myeloid dendritic cells from human PBMCs) according to the manufacturer’s instructions (see for example the Cell separation and enrichment of blood DC section).
Schutz et al does not explicitly separating DCregs from a cell population based upon the presence of CD44 and CD200R (separation of CD200R and CD44 P:P cells).
However, Hegde et al teach that CD44 expression by dendritic cells (DCs) is required for formation of DC-T cell tight junctions/function immunological synapses (see for example the abstract).
Hegde et al do not explicitly teach the use/function of CD200R on DCs.
However, Li et al teach that patients with systemic lupus erythamatosis (SLE) had a decreased proportion of CD200R1+ cells (including plasmacytoid DCs, and myeloid DCs (see the final paragraph of the Increased CD200 but decreased CD200R1 expression by CD4+ T cells and dendritic cells in SLE patients subsection of the results at pg. 4 or 17)). Li et al further teach that decreased expression of CD200R1 in SLE may contribute to the defective generation of Tregs (see the final paragraph of the CD200 signaling rescues the defective generation of CD4 + CD25highFoxP3+ T cells (Tregs; also called regulatory T-cells) in SLE patients subsection of the results at pg. 6 or 17).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Schutz et al, Lui et al, Hegde et al, and Li et al. The artisan would have been motivated to make and use the invention as claimed because Li et al and Hegde et al teach that CD200R and CD44 are expressed on the surface of DCs and are required for DC-T cell interaction and generation of functional Tregs. Additionally, Liu et al teach that diagnostic accuracy, as measured by the area or partial area under the ROC curves, can be substantially improved by combining multiple biomarkers.
Therefore, one of ordinary skill in the art would have been motivated to select for cells positive for CD200R and CD44 in order to increase the specificity of the method of Schutz for enriching not only for DCs, but for enriching for DCs able to interact with T-cells to generate functional Tregs. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Reponses:
A. Applicant argues that the amendment of claim 6 to add a step of separation (of regDCs from the cell population) is sufficient to overcome the rejection of claims 6-9 under 35 USC §101.
Response: The high level of generality used to recite the newly added separation step suggests that Applicant does not deem the process of separation to be inventive. Moreover, the high degree of generality fails to integrate the recited judicial exceptions and does not add ‘significantly more’ so as to overcome the rejections of record under 35 USC §101, which are maintained at this time.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Minas et al (Is the CD200/CD200 receptor interaction more than just a myeloid cell inhibitory signal? Crit Rev Immunol. 2006;26(3):213-30. doi: 10.1615/critrevimmunol.v26.i3.20) teach that phenotypic analysis revealed that the receptor recognized by OX102 was expressed by cells of the myeloid lineage. Thus, the distribution of OX2 (CD200) and its receptor (CD200R has similarities with the CD47-CD172a (SIRP-α) interaction in that CD47 is widely distributed, and its receptor CD172a is mostly expressed by myeloid cells. Signaling via CD172a has been shown to downregulate myeloid cells through tyrosine phoshatases SHP1 and SHP2.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST.
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supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678