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 .
Election/Restrictions
Applicant’s election of group I, CXCR3 and CD8, anti-PD-1, hepatocellular carcinoma (HCC), CXCR3+CD45R0O+CD8+effector memory T (Tem) cell population and CXCR3+CD45R0O+CD8+CCR7- effector memory T (Tem) cell population in the reply filed on 10/21/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In view of the species election being consistent with group II the groups are rejoined to the extent they read on the elections.
Claims 19-20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invnetion, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/21/2025.
Priority
The most recent filing receipt has no priority claim. Thus the instant application is being afforded 4/13/2023 as the filing date.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/19/2023 is being considered by the examiner.
Claim Objections
Claims 1-18 are objected to because of the following informalities:
Claim 1 is objected to as it recites “CXCR3, CD45RO, CCR7, CD8, HLADR, ITGAX (CDIlc), and CD86” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 2 is objected to as it recites “CXCR3, CD45RO, CCR7, CD8, HLADR, CD86, and CD14” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 9 is objected to as it recites “TNFR2” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 10 is objected to as it recites “TNFR2” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Improper Markush Group
Claims 1-18 are rejected under the judicially approved ‘‘improper Markush grouping’’ doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719–20 (CCPA 1980). A Markush claim contains an ‘‘improper Markush grouping’’ if: (1) the species of the Markush group do not share a ‘‘single structural similarity,’’ or (2) the species do not share a common use. Members of a Markush group share a ‘‘single structural similarity’’ when they belong to the same recognized physical or chemical class or to the same art-recognized class. However, when the Markush group occurs in a claim reciting a process or a combination (not a single compound), it is sufficient if the members of the group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. See MPEP § 803.02.
Here each species is considered to be a method detecting immune cell population markers.
The recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection of different genes. Each gene that could be detected is itself located in a separate region of the genome and has its own structure. The nature of genes is they are differentially expressed in different tissues. The genes recited in the instant claims, and the methods which detect them, do not share a single structural similarity since each consists of a different nucleic acid sequences that occurs at a different location in the human genome. The only structural similarity present is that all genes are nucleic acid molecules or proteins. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated immune cell population. The association between the claimed genes is not considered as ‘property’ as the association is a statistical construct, it is a conclusion based on analysis of a specific population and may not be present in subject outside of the population assayed. Further there is no evidence the association was known in the prior art. While the instant specification asserts the genes have a common function of being correlated with the asserted phenotype, the association between the claimed gene is not clear from their very nature. If the instantly claimed genes are placed in a group with an equal number of genes, the skilled artisan could not differentiate those associated with a phenotype from those that are not associated with a phenotype. Thus the one of skill in the art could not identify those genes that are asserted to be associated with the phenotype by their very nature. Thus the instant claims have not met the requirements of a proper Markush group.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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.
Claim(s) 1-2, 5-8, 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chow (Immunity 50, 1498–1512, June 18, 2019), Han (EBioMedicine 48 (2019) 169–177) and Zhulai (Scand J Immunol. 2022;95:e13129).
With regards to claims 1-2, 5-8, 17-18 Chow teaches, “CD8+ T cells play a vital role in tumor eradication through the production of cytotoxic molecules, such as perforin and granzyme, and cytokines, such as interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a) (Martı´nez-Lostao et al., 2015). Indeed, the presence of high densities of CD8+ T cells within tumor tissue is a favorable prognostic indicator in many cancers (Fridman et al., 2012). However, it is well established that the microenvironment of tumors is frequently immunosuppressive, rendering CD8+ T cells dysfunctional and promoting tumor progression (Speiser et al., 2016). In particular, immune checkpoints, such as the programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway (PD-1-PD-L1), have been exploited by tumors as a critical immunosuppressive mechanism to evade T cell immunity (” (1498, 1st column). Chow teaches, “CXCR3 Is Necessary for an Effective Response to PD-1 Blockade Therapy” (1500, 1st column). Chow teaches, “A Functional CD8+ T Cell Response after PD-1 Blockade Is Dependent on CXCR3.”
Han teaches, “we report that the percentage of CXCR3+ T cells in blood
changes in a specific pattern during multiple infusions of anti-PD-1 antibody. Mass cytometry with peripheral blood mononuclear cells (PBMCs) periodically collected from patients before and after receiving a periodic infusion of pembrolizumab revealed significant alterations in the constitution of lymphocytes, especially in CXCR3+ T cells. Interestingly, a lower percentage of CXCR3+ T cells in blood indicated a better therapeutic effect in patients receiving pembrolizumab. Consistently, CXCR3 blockade led to tumor hyperprogression in mice. Thus, the amount of peripheral CXCR3+ T cells may be a novel and potential predictive biomarker for the efficacy of anti-PD-1 therapy.” (page 170, 1st column. Top) Han teaches, “In conclusion, dynamic changes in CXCR3+ T cells in blood is a potential biomarker for predicting anti-PD-1 therapy response.”(176, 2nd column, top).
With regards to 11-12, Zhulai teaches heptacellular carcinoma (table 2, page 3, 1st column, top).
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to detect immune cells expressing CD8 and CXCR3 in cancer subjects and treat cancer subjects with immune cells expressing CD8 and CXCR3 in cancer subjects. The artisan would be motivated as Han and Chow teach CD8 and CXCR3 are makers for anti-PD1 in cancer response. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to detect and treat cancer.
While the prior art of Chow and Han demonstrate a correlation of immune cells expressing CD8 and CXCR3 were implicated in anti-PD1 response and Han teaches detection of CD45RO+, they do not specifically teach CXCR3+CD8+CD45RO+ cells.
However, Zhulai teaches, “The prognostic value of CD3+, CD45RO+CD8+, mast cells and granzyme B+CD8+ cells for the response to PD-1 inhibitors is reported” (page 3, 1st column. Last full paragraph).
Therefore it would have been prima facie obvious to detect CXCR3+CD8+CD45RO+ memory T cells and treat with anti-PD1. The artisan would be motivated to determine if the CD45RO+ is an additional marker identifying subjects likely to respond to anti_PD1 therapy. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to detect known markers and treat on a known correlation of CXCR3 and CD8 as required for response to anti_PD1.
Claim(s) 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over 1-2, 5-8, 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chow (Immunity 50, 1498–1512, June 18, 2019), Han (EBioMedicine 48 (2019) 169–177) and Zhulai (Scand J Immunol. 2022;95:e13129) as applied to claims 1-2, 5-8, 17-18 above, and further in view of Quazi (Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 November 2021 doi:10.20944/preprints202111.0529.v1)
While the prior art of Zhulai ,Chow and Han demonstrate a correlation of immune cells expressing CD8 and CXCR3 were implicated in anti-PD1 response, they do not specifically teach the use of a TNFR2 inhibitor.
However, Qauzi teaches, “Combined or Monotherapy of TNFR2 with immune checkpoint inhibitor is an appealing approach in cancer immunotherapy.”(page 2) Quazi teaches, “TNFR2 enhances cancer cell survival and tumor growth by stimulating the activation and multiplication of Tregs, a key checkpoint in antitumor immu ne responses. By blocking the expression of TNFRII through antibody antagonist, the proliferation of Tregs can be suppressed which may initially induce apoptosis to cancer cells.” (page 3, bottom)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use anti-THFNRII antibodies in addition to anti-PD1 in subjects with cancer. The artisan would be motivated as Qauzi suggest anti-THFNRII antibodies in combination with anti_PD1 induces apoptosis in cancer cells. The artisan would have a reasonable expectation of success as the artisan is using known treatments of cancer in subjects identified as having CD* and CXCR3 which are known to be correlated with response to anti-PD1.
Summary
No claims are allowed.
The claim is being interpreted as requiring the detection of at least one of the recited genes and treating the subjects which have the genes. Thus if the genes are not detected it outside the scope of the claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683