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 .
1. The Amendment filed October 10, 2025 in response to the Office Action of April 11, 2025, is acknowledged and has been entered. Claims 26-30, 35-39 are pending and being examined. Claims 1-25, 31-34, 40, and 41 are canceled. Claims 26 and 35 are amended and altered in scope as being limited to treating skin melanoma and testing biological samples selected from the group consisting of blood, serum, and plasma. The new limitations required a new search of prior art based on new limitations, necessitating new rejections set forth below.
Priority
2. It is noted that the instant application claims priority to provisional application 62/635620, filed 2/27/2018. Application 62/635620 contemplates measuring levels of progastrin in patient blood samples, including melanoma patients, in order to select patients for treating with immune checkpoint inhibitor therapy when their progastrin level is below a threshold. Slide XIII of the specification of application 62/635620 on page 18 states:
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Application 62/635620 does not identify any threshold, and does not support the instant claims’ threshold of less than 3 pm as recited in claims 26 and 35.
Additionally, Application 62/635620 does not disclose several of the immune checkpoint inhibitors listed in claims 27 and 28. Application 62/635620 discloses slide XIV in the specification on page 19 listing only the following immune checkpoint inhibitors:
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Application 62/635620 does not identify several drugs listed in instant claims 27 and 28, therefore does not fully support the material recited in instant claims 27 and 28.
Therefore, for the sake of the new prior art search for the new claim limitations, the effective priority date of the instant claims is considered to be February 27, 2019, the filing date of PCT/EP2019/054878 that discloses and supports the instantly claimed limitations.
New Rejection
(necessitated by amendments)
Claim Rejections - 35 USC § 103
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.
3. Claim(s) 26-30 and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/114973, Floch, published July 2017; in view of Prieur et al (Journal of Clinical Oncology, May 30, 2017, Vol. 35, Number 15_Suppl: abstract 11545); and Mahoney et al (Clinical Therapeutics, 2015, 37:764-782).
Floch teaches a method for detecting levels of progastrin in cancer patient blood/serum/plasma samples, the method comprising:
Contacting a blood/serum/plasma sample (p. 5; claim 13) from the cancer patient with a first progastrin-binding antibody;
Detecting binding of the first progastrin-binding antibody to progastrin in the sample by immunoassay; and
Determining the concentration of progastrin in the biological sample (p. 9-18);
wherein the cancer patient has skin melanoma (Examples, see Figure 15 below; p. 7 line 6; p. 8, line 1; claims 1-13).
Floch teaches detection of progastrin can also be accomplished using a first anti-progastrin antibody that binds to the C-terminus of progastrin, and a second antibody binding to the N-terminus of progastrin (p. 25-26, 28-29), wherein the C-terminus antibody comprises monoclonal antibody Mab14, produced by hybridoma 2H9F4B7, deposited under the Budapest Treaty at the CNCM, Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris CEDEX 15, France, on 27 December 2016, under reference 1-5158 (p. 26, 29; claims 1-13); and wherein the N-terminus antibody comprises either a polyclonal antibody, or a monoclonal antibody selected from:
(a) mAb3 comprising CDR SEQ ID NOs:4-9 that are 100% identical to the instantly claimed CDR SEQ ID NOs:4-9;
(b) mAb4 comprising CDR SEQ ID NOs:10-15 that are 100% identical to the instantly claimed CDR SEQ ID NOs:10-15;
(c) mAb16 comprising CDR SEQ ID NOs:16-21 that are 100% identical to the instantly claimed CDR SEQ ID NOs:16-21;
(d) mAb19 comprising CDR SEQ ID NOs:22-27 that are 100% identical to the instantly claimed CDR SEQ ID NOs:22-27;
(e) mAb8 comprising CDR SEQ ID NOs:28-33 that are 100% identical to the instantly claimed CDR SEQ ID NOs:28-33; and
(f) mAb13 comprising CDR SEQ ID NOs:34-39 that are 100% identical to the instantly claimed CDR SEQ ID NOs:34-39 (p. 26, 30, claims 1-13; Tables 1-6).
In Example 1, Floch demonstrates detecting plasma levels of progastrin utilizing an ELISA with polyclonal antibodies to progastrin C-terminus for capture on the wells of an assay plate, and biotin-labeled polyclonal antibodies binding to the N-terminus of progastrin for detection.
In Example 2 (Figure 16), Floch demonstrates detecting plasma levels of progastrin utilizing an ELISA with monoclonal antibody mAb14 binding to the C-terminus for capture of progastrin (mAb 14 is produced by hybridoma 2H9F4B7, deposited under the Budapest Treaty at the CNCM, Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris CEDEX 15, France, on 27 December 2016, under reference 1-5158), and with detectably labeled polyclonal antibodies binding to the N-terminus for detection of progastrin.
In Example 3 (Figure 16), Floch demonstrates detecting progastrin levels quantified by ELISA using two monoclonal antibodies: mAb 14 binding the C-terminus of progastrin for capture, and detectably labeled mAb 16 binding the C-terminus of progastrin for detection.
Figure 15:
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Floch determined a median value of 6.45pM progastrin characteristic of melanoma patients, with a range that appears to span ~3 pM to ~12 pM in Figure 15. Floch determined that healthy controls with no cancer had 0 pM of progastrin (Figure 15).
Floch teaches measuring levels of progastrin as a biomarker for early cancer detection, and teaches early detection and diagnosis of cancer is important for the selection of patients to receive appropriate treatment that will benefit them and improve survival (p. 1-5). Floch teaches progastrin is essentially not detectable in samples of subjects who do not develop cancer (Figure 15; p. 3, lines 5-6). Increasing concentrations of progastrin in patient samples indicates worse prognosis for cancer (p. 27).
Floch does not teach treating the melanoma patients with immune checkpoint inhibitor, such as anti-CTLA-4 antibody ipilimumab, anti-PD-1 antibodies pembrolizumab and nivolumab, and/or anti-PD-L1 antibody atezolizumab when detecting a level of progastrin less than 3 pM.
Prieur teaches development of an early cancer screening test using progastrin as a biomarker, teaches it is known that the progastrin gene is activated in almost all types of cancers at the earliest stage of development, and progastrin is secreted by cancer cells. Prieur teaches the problem with detection of cancer in late stages is low survival rates, and teaches their assay can detect progastrin in the blood of persons having cancer at early stage. Prieur teaches measuring blood progastrin levels from patients having various types of cancer utilizing an ELISA comprising polyclonal antibodies for detection, and confirmed that the presence of progastrin is a biomarker for multiple types of cancers. Prieur then measured blood progastrin levels from patients having various types of cancer, including early stages of cancer, utilizing an ELISA comprising polyclonal antibodies and monoclonal antibodies for detection. Prieur determined that their ELISA detected melanoma with a sensitivity of 87%, and all stages of cancers were detected with high specificity of 97.5%. Early stage melanoma was detected at a sensitivity of 68% (Results). Prieur concludes progastrin is a reliable biomarker for early cancer screening, and their ELISA for detection is efficient and available for the clinic.
Mahoney teaches that patients diagnosed with melanoma are successfully treated with immune checkpoint inhibitors that results in improved survival, and summarizes clinical success of anti-CTLA-4 antibody (ipilimumab), anti-PD1 antibodies (nivolumab and pembrolizumab), and anti-PD-L1 antibody (MPDL-3280A, also known as atezolizumab) in the treatment of melanoma (p. 764; p. 767-770; Tables II - V). Mahoney teaches the greatest clinical activity of anti-PD1 and anti-PD-L1 antibodies in unselected cancer patients is in melanoma patients (p. 764, col. 2). Mahoney explains the known mechanisms of how the immune checkpoint inhibitor antibodies function to treat cancer (Figures 1 and 2; p. 767, col. 2). Mahoney teaches the combination of nivolumab + ipilimumab has shown impressive duration and rates of response in melanoma (p. 775, col. 1). Mahoney notes that in one clinical study treating melanoma patients with pembrolizumab, patients with less baseline tumor burden (earlier stage) were more likely to respond to pembrolizumab (p. 769, col. 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat patients diagnosed with melanoma and having detectable progastrin levels in the blood, including levels less than 3 pM, by administering to the patients an immune checkpoint inhibitor therapy such as ipilimumab, nivolumab, pembrolizumab, and/or atezolizumab. One would have been motivated to, and have a reasonable expectation of success to because: (1) Floch and Prieur teach the need for early diagnosis of cancer, including melanoma, in order to provide the appropriate therapy to the cancer patient and to improve survival rates; (2) Floch and Prieur teach and successfully demonstrate that progastrin serves as a biomarker for melanoma diagnosis/detection, and successfully detects early stages of melanoma; (3) Floch established that lack of progastrin (0 pM) indicates no cancer, and presence of progastrin indicates the presence of cancer or risk of developing cancer, and Floch demonstrates successfully detecting levels of progastrin between 0 pM and 3pM in cancer patients using their immunoassay; (4) Mahoney teaches patients diagnosed with melanoma are successfully clinically treated by administration of immune checkpoint inhibitors, including ipilimumab, nivolumab, pembrolizumab, and/or atezolizumab, wherein melanoma patients having lower tumor burden demonstrated improved response to pembrolizumab treatment, and wherein the greatest clinical activity of anti-PD1 and anti-PD-L1 antibodies in unselected cancer patients is in melanoma patients.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Floch and Prieur teach the need for an assay the provides early diagnosis of cancer, including melanoma, in order to provide the appropriate therapy to the cancer patient and to improve survival rates. Floch and Prieur teach the solution for early diagnosis of melanoma is detecting blood levels of progastrin, wherein increasing levels above 0 pM are indicative of cancer including melanoma, and Mahoney teaches the known solution to treating patients diagnosed with melanoma is administering immune checkpoint inhibitors, wherein melanoma patients having lower tumor burden demonstrated improved response to pembrolizumab treatment, and wherein the greatest clinical activity of anti-PD1 and anti-PD-L1 antibodies in unselected cancer patients is in melanoma patients. Given the recognized need to provide early detection and diagnosis of melanoma in order to provide appropriate therapy and increase survival rate, given the known solution for early melanoma detection/diagnosis by detecting levels of progastrin above 0 pM, and given the known solution for treating patients diagnosed with melanoma is administering immune checkpoint inhibitor therapy resulting in improved survival rate, wherein melanoma patients in particular respond beneficially to immune checkpoint inhibitor therapy regardless of selection, one of skill in the art could have pursued selecting patients diagnosed with melanoma and having detectable blood levels of progastrin between 0-3 pM indicative of cancer for treatment with immune checkpoint inhibitor therapy, and treated the melanoma with a reasonable expectation of success.
4. All other rejections recited in the Office Action mailed April 11, 2025 are hereby withdrawn in view of claim amendments.
5. Conclusion: No claim is allowed.
Conclusion
6. 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.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642