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 .
Claim Status
Claims 2-6 and 13 have been cancelled and claims 1, 12, 14, and 17 have been amended, as requested in the amendment filed on 02/13/2026. Following the amendment, claims 1, 7-12, and 14-19 are pending in the instant application.
Claims 1, 7-12, and 14-19 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 7-12, and 14-19 have an effective filing date of September 27, 2019 corresponding to PRO 62/906,906.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 2-6 and 13 were rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial Study ID NCT02447003 (Version from May 2017; herein after referred to as "Keynote-086"; previously cited on PTO-892) in view of non-patent literature by Bauml et. al. (Journal of Clinical Oncology, 2017, 35(14), 1542-1549; herein after referred to as "Bauml"; previously cited on PTO-892) and US 2017/0285037 A1 (previously cited on PTO-892; herein after referred to as "Kulangara"; previously cited on PTO-892) as evidenced by WO 2017/205216 A1 (previously cited on PTO-892; herein after referred to as “Beckmann”; previously cited on PTO-892).
It is noted that claims 2-6 and 13 have been cancelled, rendering their rejection moot. As such, the rejection of claims 2-6 and 13 under 35 U.S.C. 103 as being unpatentable over Keynote-086, Bauml, and Kulangara as evidenced by Beckmann is withdrawn.
Double Patenting - Withdrawn
Claims 1-19 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 10, 12, 15-16, 21-22, 34-36, 38, and 51-52 of copending Application No. 18/720,011 (herein after referred to as "'011") in view of Clinical Trial Study ID NCT02447003 (Version from May 2017; herein after referred to as "Keynote-086"; previously cited on PTO-892), non-patent literature by Bauml et. al. (Journal of Clinical Oncology, 2017, 35(14), 1542-1549; herein after referred to as "Bauml"; previously cited on PTO-892), and/or US 2017/0285037 A1 (previously cited on PTO-892; herein after referred to as "Kulangara"; previously cited on PTO-892) as evidenced by WO 2017/205216 A1 (previously cited on PTO-892; herein after referred to as “Beckmann”; previously cited on PTO-892).
Claims 1-19 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 37 of copending Application No. 18/550,537 (herein after referred to as "'537") in view of Clinical Trial Study ID NCT02447003 (Version from May 2017; herein after referred to as "Keynote-086"; previously cited on PTO-892), non-patent literature by Bauml et. al. (Journal of Clinical Oncology, 2017, 35(14), 1542-1549; herein after referred to as "Bauml"; previously cited on PTO-892), and/or US 2017/0285037 A1 (previously cited on PTO-892; herein after referred to as "Kulangara"; previously cited on PTO-892) as evidenced by WO 2017/205216 A1 (previously cited on PTO-892; herein after referred to as “Beckmann”; previously cited on PTO-892).
Claims 1-19 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-6 of U.S. Patent 10,945,990 (herein after referred to as "'990") in view of Clinical Trial Study ID NCT02447003 (Version from May 2017; herein after referred to as "Keynote-086"; previously cited on PTO-892), non-patent literature by Bauml et. al. (Journal of Clinical Oncology, 2017, 35(14), 1542-1549; herein after referred to as "Bauml"; previously cited on PTO-892), and/or US 2017/0285037 A1 (previously cited on PTO-892; herein after referred to as "Kulangara"; previously cited on PTO-892) as evidenced by WO 2017/205216 A1 (previously cited on PTO-892; herein after referred to as “Beckmann”; previously cited on PTO-892).
Claims 1-19 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-6 of U.S. Patent 11,377,693 (herein after referred to as "'693") in view of Clinical Trial Study ID NCT02447003 (Version from May 2017; herein after referred to as "Keynote-086"; previously cited on PTO-892), non-patent literature by Bauml et. al. (Journal of Clinical Oncology, 2017, 35(14), 1542-1549; herein after referred to as "Bauml"; previously cited on PTO-892), and/or US 2017/0285037 A1 (previously cited on PTO-892; herein after referred to as "Kulangara"; previously cited on PTO-892) as evidenced by WO 2017/205216 A1 (previously cited on PTO-892; herein after referred to as “Beckmann”; previously cited on PTO-892).
With regard to the above-listed claim rejections under nonstatutory double patenting in view of the reference applications/patents and Keynote-086, Bauml, and/or Kulangara, Applicant argues on Pages 5-8 of Remarks (02/13/2026) that:
The claims of copending Application No. 18/720,011 are directed to a method for determining the eligibility of a subject for treatment with an anti-IL T4 and anti-PD-I combination therapy, and does not teach what CPS threshold is appropriate for the treatment of mTNBC with pembrolizumab as monotherapy.
The claims of copending Application No. 18/550,537 are directed to a method of treating cancer with an anti-ILT3 antibody, and does not teach what CPS threshold is appropriate for the treatment of m TNBC with pembrolizumab as monotherapy.
The claims of U.S. Patent 10,945,990 are directed to a method of treating TNBC with the combination of pembrolizumab and eribulin, and does not teach what CPS threshold is appropriate for the treatment of mTNBC with pembrolizumab as monotherapy.
The claims of U.S. Patent 11,377,693 are directed to a method of treating cancer using a gene signature entirely unrelated to CPS scoring, and does not teach what CPS threshold is appropriate for the treatment of mTNBC with pembrolizumab as monotherapy.
It is noted that claims 2-6 and 13 have been cancelled, rendering their rejections moot. Furthermore, the claims of the above-listed reference applications/patents have been reviewed, and Applicant’s arguments are deemed persuasive. As such, the above-listed claim rejections under nonstatutory double patenting are withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1, 7-12, and 14-19 stand as rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial Study ID NCT02447003 (Version from May 2017; herein after referred to as "Keynote-086"; previously cited on PTO-892) in view of non-patent literature by Bauml et. al. (Journal of Clinical Oncology, 2017, 35(14), 1542-1549; herein after referred to as "Bauml"; previously cited on PTO-892) and US 2017/0285037 A1 (previously cited on PTO-892; herein after referred to as "Kulangara"; previously cited on PTO-892) as evidenced by WO 2017/205216 A1 (previously cited on PTO-892; herein after referred to as “Beckmann”; previously cited on PTO-892).
Response to Arguments
Applicant's arguments filed 02/13/2026 (herein after referred to as “Remarks”) have been fully considered but they are not persuasive.
With regard to the maintained claim rejections under 35 U.S.C. 103 and the maintained claim rejections under nonstatutory double patenting, Applicant argues the following on Pages 4-7 of Remarks:
Keynote-086 does not disclose a CPS of ≥10, and person of ordinary skill in the art would not look to Bauml and Kulangara to arrive at the invention as claimed.
Bauml is directed to treatment of head and neck squamous cell carcinoma (HNSCC), and not metastatic triple negative breast cancer (mTNBC). Thus, the deficiencies of Keynote-086 are not remedied by Bauml, as Bauml provides no teaching, suggestion or motivation on how to treat metastatic triple negative breast cancer (mTNBC) with pembrolizumab as monotherapy.
Kulangara teaches methods for determining the eligibility of a subject having a malignancy by determining a CPS score and administering a treatment if the CPS is above a threshold, but Kulangara provides no motivation to arrive at the invention as claimed, namely, how to treat metastatic triple negative breast cancer (mTNBC) with pembrolizumab as monotherapy, wherein the tumor identified as having a combined positive score (CPS) of ≥10 before administration. Instead, Kulangara is directed to how to perform CPS scoring itself (and establish thresholds), not what threshold is appropriate for the treatment of mTNBC with pembrolizumab as monotherapy.
Applicant further argues unexpected, advantageous properties. In the population of patients with PD-L1-positive CPS ≥10 tumors, median overall survival was 12.7 months (95% CI: 9.9 to 16.3) for the pembrolizumab group and 11.6 months (95% CI: 8.3 to 13.7) for the chemotherapy group (see FIG. 4B). Further, the application itself notes that in Keynote-086, [for] participants with previously treated disease, the objective response rate was modest and independent of PD-L1 status. The application as filed thus demonstrates that patients with tumors with the claimed PD-L1 expression may have a greater likelihood of clinical benefit from pembrolizumab monotherapy, and the ordinarily skilled person would not have expected this effect from Keynote-086 in view of Bauml and Kulangara. The combination of these steps ensures that PD-L1 CPS ≥10 biomarker positive subjects with mTNBC will be accurately diagnosed and properly treated with the claimed PD-1 antagonist.
With regard to Applicant’s arguments against the combination of Keynote-086, Bauml, and Kulangara, it is specifically noted that Keynote-086 is relied upon for its teaching regarding the use of pembrolizumab monotherapy in patients with metastatic triple negative breast cancer (mTNBC), and more specifically patients having PD-L1 positive and/or strong positive mTNBC. Thus, Keynote-086 establishes the use of pembrolizumab monotherapy in PD-L1 positive/strong positive mTNBC patients. It was acknowledged that Keynote-086 does not disclose CPS scores for identifying patients for treatment; this deficiency is remedied by the combination of Bauml and Kulangara. Both Bauml and Kulangara disclose CPS scores in the context of metastatic cancer. Bauml indicates that higher PD-L1 expression, and subsequently higher CPS scores, correlate with higher response rates to pembrolizumab monotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC); significantly improved responses in (i) PD-L1 positive patients with a CPS ≥1% versus PD-L1 negative patients with a CPS <1% and (ii) patients with CPS scores ≥50% compared to patients with CPS scores <50%. While it is acknowledged that Bauml is drawn to R/M HNSCC, it is specifically noted that Kulangara discloses that pembrolizumab shows promising effects in a variety of cancers (NSCLC, advanced gastric cancer, advanced bladder cancer, head and neck cancer, classical Hodgkin's lymphoma, and triple-negative breast cancer) and further teaches that clinical trials have indicated that in some tumor indications PD-L1 staining on both tumor and tumor-associated immune cells is associated with clinical outcome and that there is a need to improve tumor tissue scoring methods for identifying patients that will respond effectively to anti-PD-1 therapy; Kulangara specifically teaches methods for determining the eligibility of a subject having a malignancy for treatment with an anti-PD-1 therapeutic agent based on a Combined Positive Score (CPS) for a tumor tissue sample from the subject wherein the subject is eligible for treatment with an anti-PD therapeutic agent when the CPS is above a threshold that can be determined by a ROC curve for best responder/cut off (threshold) correlation and can thus be any applicable CPS value, including but not limited to: 1%; 5%; 10%; 20% 30%; 40%; 50%; 60%, etc., and is specific to the drug used. Kulangara also indicates that a specimen is considered PD-Ll positive if CPS ≥ l% (i.e., equal to or above the threshold value), which is the same cutoff utilized in the study of Bauml. Thus, it is maintained that it would have been obvious to one of ordinary skill in the art that the therapeutic approach to mTNBC comprising administering pembrolizumab to patients having PD-L1 expressing cancer of Keynote-086 could be restricted to patients having higher CPS scores (e.g., CPS ≥10) because higher PD-L1 expression (and higher CPS scores) correspond to higher response rates in PD-L1 positive cancers, as suggested by Bauml, and higher likelihood overall of response to anti-PD-1 therapy, as suggested by Kulangara. Combining prior art elements according to known methods would be expected to yield predictable results; pembrolizumab is indicated for the treatment of mTNBC as disclosed by Keynote-086, and supported by Kulangara, wherein safety and efficacy have already been evaluated by Bauml in a different cancer, and wherein it is suggested, by both Bauml and Kulangara, that increased PD-L1 expression and therefore increased CPS scores increase the likelihood of response and generally correlate with higher response in patients receiving treatment. Kulangara also discloses methods of determining CPS scores and methods of establishing cutoffs based on a ROC curve specific for the drug to be used. The art suggests higher CPS scores indicate treatment with pembrolizumab as a monotherapy, and it would have been within the purview of one having ordinary skill in the art to determine the exact CPS threshold for a given cancer/anti-PD-1 therapeutic.
With regard to the argument of unexpected, advantageous properties, it is noted that evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. Furthermore, it is specifically noted that the active steps of the instantly claimed method are rendered obvious by the combination of Keynote-086, Bauml, and Kulangara. Keynote-086 explicitly teaches the use of pembrolizumab monotherapy in PD-L1 positive/strong positive mTNBC patients. Both Bauml and Kulangara further suggest that PD-L1 expression correlates with response to pembrolizumab monotherapy, wherein patient populations having increased CPS scores are indicated for treatment with pembrolizumab monotherapy, and suggest that higher CPS scores correlate with increased response to pembrolizumab. As such, the data of the instant application as filed demonstrating that patients with tumors with the claimed PD-L1 expression may have a greater likelihood of clinical benefit from pembrolizumab monotherapy is not unexpected. All of the prior art references establish correlations between CPS scores and increased response rates, and it is noted that the data argued by Applicant comparing a pembrolizumab treatment group with a chemotherapy treatment group does not demonstrate unexpected results compared to the closest prior art references, which together suggest that PD-L1 positive cancers are indicated for treatment with pembrolizumab, but also suggest that patients having higher CPS scores correlate with increased response.
In view of the above, the rejection of claims 1, 7-12, and 14-19 under 35 U.S.C. 103 and in view of Keynote-086, Bauml, and Kulangara is deemed proper and is maintained.
Conclusion
Claims 1, 7-12, and 14-19 are pending. Claims 1, 7-12, and 14-19 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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 ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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