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 Status
The amendments and remarks filed on 11/13/2025 are acknowledged.
Claims 1 and 8 are amended.
Claims 2-6, 10, and 12-20 are canceled.
Claims 1, 7-9, 11, and 21 are pending and under examination.
Withdrawn
The previous rejections of claims 1, 7-9, 11, and 21 under 35 U.S.C. 103 are withdrawn. Applicant has amended claim 1 to overcome the rejections. However, the claims remain rejected under 35 U.S.C. 103. See rejections below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/13/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
New Grounds of Rejection Necessitated by Amendment
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.
Claims 1, 9, 11, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Byrd et al., 2001 (12/16/2024 PTO-892) in view of Mueller et al., 2017 (12/16/2024 PTO-892) and Paganessi et al., 2011 (instant PTO-892).
Regarding claims 1 and 21, Byrd teaches administering rituximab to treat patients with B-cell chronic lymphocytic leukemia (CLL; hematologic cancer), and that rituximab demonstrated clinical efficacy and acceptable toxicity with an overall response rate of 45% (treating a hematologic cancer) [see Abstract].
However, Byrd does not teach assessing a level of myeloid inflammation in a tumor of the patient comprising measuring a gene expression level of IFNL2, determining whether the patient should be administered an effective dose of anti-CD19 CAR T-cells with a second therapeutic (i.e. the rituximab of Byrd) at least in part from measuring the gene expression level of IFNL2, or administering the effective dose of anti-CD19 CAR T-cells and the second therapeutic agent if the gene expression level of IFNL2 is above the predetermined level.
Mueller teaches CTL019, an anti-CD19 CAR T-cell [page 2317, left column, first paragraph] and administering CTL019 to patients with B-cell chronic lymphocytic leukemia [see Abstract and page 2318, left column, second paragraph]. Mueller further teaches that CTL019 achieved impressive clinical efficacy, including the expansion and persistence of CTL019 cells, which correlates with response to therapy [see Abstract] and that CTL019 demonstrated an overall response rate of 53%, with 35% complete response, and 19% partial response [page 2317, left column, second paragraph – right column, first paragraph].
Paganessi teaches obtaining peripheral blood (PC) serum from untreated CLL patients and normal healthy donors and measured 54 cytokines protein levels [see page 1, Methods section]. Paganessi further teaches that 16 cytokines had significantly higher expression in CLL samples compared to normal samples, one of which was IL-28A (i.e. IFNL2) [see page 2, Results section; Table 1]. Paganessi also teaches that CLL is not treated until it develops into later stage disease.
Since IFNL2 levels were measured, the measured gene expression level of the IFNL2 is necessarily higher than an unspecified predetermined level.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of the applied references to better identify those patients with B-CLL that would benefit from therapeutic intervention with the named treatments. It would have been obvious to combine the rituximab (second therapeutic agent) of Byrd with the anti-CD19 CAR T-cells of Mueller to treat B-CLL because both are known to treat B-CLL. This follows the logic of MPEP 2144.06 which states “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, it would have been obvious to combine the separate, known compositions for the same purpose of treating B-CLL. It further would have been obvious to measure IFNL2 levels, as taught by Paganessi, because IFNL2 can be used to identify and monitor the B-CLL patients. One would have been motivated to identify the patients that are in need of treatment based on their IFNL2 levels because Paganessi teaches that IFNL2 was significantly higher in CLL patients compared to the levels in normal control patients. Additionally, one would have been motivated to administer the anti-CD19 CAR T-cells and rituximab (second therapeutic agent) if the level of IFNL2 is above some predetermined level because the art indicates that IFNL2 is correlated to a CLL disease state and CLL is not treated until it develops into later stage disease. Therefore, one would want to treat the B-CLL aggressively by using the anti-CD19 CAR T-cells and rituximab (second therapeutic agent) together.
Further, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provide a prima facie case of obviousness, absent convincing evidence to the contrary.
Regarding claim 9, it further would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have used the median value of IFNL2 to be the predetermined level of IFNL2 because the median is the center value of the data and is less likely to be skewed due to any outliers in the IFNL2 levels (see Wikipedia, Median; 03/31/2023, PTO-892). Since the median by definition separates the higher half from the lower half of a set of values, cancers would necessarily have values higher and lower than the median value, and so, the value, whether higher or lower, would still be indicative of cancer. One would recognize that when the value is higher than the median, the patient may have a more aggressive cancer, and therefore should be treated with a more aggressive treatment (i.e. anti-CD19 CAR T-cells and rituximab).
Claim 11 is included in this rejection because Mueller teaches that the number of prior therapies was 1-9 [page 2318, right column, fourth paragraph], thereby indicating that the CAR T-cells were a second line therapy for certain patients.
Claims 1, 7-9, 11, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Byrd et al., 2001 (12/16/2024 PTO-892) in view of Mueller et al., 2017 (12/16/2024 PTO-892) and Paganessi et al., 2011 (instant PTO-892), as applied to claims 1, 9, 11, and 21 above, and further in view of Boissard et al., 2015 (instant PTO-892).
The teachings of Byrd, Mueller, and Paganessi are above.
However, Byrd, Mueller, and Paganessi do not teach quantifying a tumor myeloid cell density in a tumor by measuring levels of CD68+CD163+ cells, and administering the effective dose of anti-CD19 CAR T-cells and the second therapeutic agent (rituximab) if the tumor myeloid density in the tumor is above the predetermined level.
Regarding claims 7-8, Boissard teaches that CLL nurse like cells (NLCs) are characterized by a high level of expression of CD68 and CD163 whereas healthy donor nurse like cells (HD-NLCs) express very little CD163 and CD68 [see Abstract and page 1570, right column, fourth paragraph]. Boissard also teaches that the CLL-NLCs protect CLL cells from death [see Abstract], suggesting that the CD163 high cells have an influence on overall survival and progression-free survival [see page 1570, right column, fourth paragraph]. The teachings therefore imply that the higher the CD163 expression levels in the cells, the more aggressive the disease state with a decrease in overall survival and progression-free survival.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the anti-CD19 CAR T-cells, as taught by Mueller, and the rituximab (second therapeutic agent), as taught by Byrd, to the subject with B-CLL of Paganessi if the tumor myeloid cell density (levels of CD68+CD163+ cells) are above the predetermined myeloid cell density level because Boissard teaches that CD68 and CD163 expression is higher in CLL cells compared to healthy cells and the CD163 high positive cells indicate a more aggressive disease state with a decrease in overall survival and progression-free survival. One would have been motivated to administer the anti-CD19 CAR T-cells and the rituximab if the tumor myeloid cell density (i.e. CD68+CD163+ cells) is above the predetermined level because the art indicates that higher levels are associated with CLL, that the CLL-NLCs protect CLL cells from death, and high levels of expression in the cells correlate with a more aggressive disease state decreasing overall survival and progression-free survival, and therefore, one would want to treat the B-CLL more aggressively by using the anti-CD19 CAR T-cells and the rituximab together.
Conclusion
No claims are allowed.
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.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675