DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The examiner of this application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Sharon Wen, Group Art Unit 1641, Technology Center 1600.
In view of the Brief filed on 11/12/2025, PROSECUTION IS HEREBY REOPENED. New rejections are set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below:
Applicant’s amendment, filed 12/20/2024, has been entered.
Claims 4, 15-17, 22, 24, 26, 28, 30-36 are pending and currently under examination they read on a method for treating a human having a colon/colorectal/rectal cancer comprising:
1) selecting a human patient having a level of expression of placental growth factor PlGF 1 and PlGF2 in plasma sample that is lower than 17 pg/mL and 2) administering ziv-aflibercept.
All previous rejections have been withdrawn. New grounds of rejections are set forth herein.
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.
Claims 4, 15-17, 22, 24, 26, 28, 30-36 are rejected under 35 U.S.C. 103 as being unpatentable over Lambrechts (Br J Cancer 2015 113:1027–1034; cited in IDS) in view of F. Hoffmann-La Roche (EP2311865A1; reference of record) as evidenced by VELOUR study (NCT00561470 2012-09-27).
Lambrechts teaches methods of treating patients with metastatic colorectal cancer (mCRC) using aflibercept-containing therapy. Lambrechts further recognizes that aflibercept is approved for use in combination with the FOLFIRI ((Irinotecan, 5-Fluorouracil, and Leucovorin (aka folinic acid)) regimen for patients previously treated with an oxaliplatin-containing regimen, as established by the VELOUR study. Thus, Lambrechts teaches administering ziv-aflibercept at 4 mg/kg in combination with irinotecan (180 mg/m²), leucovorin (400 mg/m²), and 5-fluorouracil at a total dose of 2800 mg/m² (400 mg/m² bolus followed by 2400 mg/m² continuous infusion) as the standard aflibercept/FOLFIRI regimen for metastatic colorectal cancer as evidenced by VELOUR study (see NCT00561470 Intervention/Treatment).
Lambrechts further teaches obtaining circulating plasma samples from patients before treatment and measuring baseline placental growth factor (PlGF) levels, followed by serial measurements after treatment, in order to evaluate PlGF as a biomarker associated with response to aflibercept therapy (see, e.g., Figure 2). As shown in Figure 2, Lambrechts demonstrates that baseline plasma PlGF is measured prior to initiation of aflibercept treatment and that circulating PlGF levels increase following administration of aflibercept, thereby establishing PlGF as a pharmacodynamic biomarker in aflibercept-treated metastatic colorectal cancer patients. Accordingly, Lambrechts teaches both the determination of baseline PlGF levels and the clinical significance of monitoring changes in PlGF during anti-VEGF therapy. Moreover, the baseline PlGF values reported in Figure 2 fall within the same range as the claimed selection criterion, indicating that Lambrechts already evaluated the same patient population from which the claimed subgroup is selected.
Lambrechts does not expressly identify PlGF as PlGF-1 or PlGF-2, nor does it expressly disclose selecting patients based upon a baseline PlGF level of 17 pg/mL or less.
F. Hoffmann-La Roche teaches that PlGF is a recognized biomarker useful for monitoring anti-VEGF therapy and that PlGF levels are routinely determined in biological samples, including blood, plasma, and serum (paragraphs 15, 57). F. Hoffmann-La Roche further teaches comparing measured PlGF levels with predetermined reference or threshold values for patient classification (paragraphs 34-36, 42-47, 59), and explains that such threshold values are established using routine statistical methods, including percentile analyses and receiver operating characteristic (ROC) analyses, to achieve the desired diagnostic or predictive performance (paragraphs 34-40). F. Hoffmann-La Roche additionally teaches determining PlGF or variants thereof (paragraphs 7-15, 30, 33), and monitoring changes in PlGF before and after anti-VEGF therapy to evaluate therapeutic response (paragraphs 60-89). Thus, F. Hoffmann-La Roche demonstrates that the use of baseline PlGF measurements, comparison to reference thresholds, and patient stratification based on those thresholds were well-known techniques in the art.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the threshold-based PlGF evaluation taught by F. Hoffmann-La Roche into the baseline PlGF measurements of Lambrechts in order to stratify or select patients receiving aflibercept therapy. Because Lambrechts already teaches measuring baseline plasma PlGF and demonstrates in Figure 2 that PlGF serves as a pharmacodynamic biomarker in aflibercept-treated patients, and F. Hoffmann-La Roche teaches that interpretation of PlGF measurements is routinely performed by comparison to statistically derived reference or threshold values, the precise numerical cutoff employed for patient selection, including a value of 17 pg/mL, would have constituted nothing more than optimization of a known result-effective variable to obtain a desired level of diagnostic or predictive performance. Selecting such an optimum threshold through routine experimentation would have been well within the ordinary skill in the art.
With respect to the recitation of PlGF-1 and PlGF-2, Lambrechts teaches measuring circulating plasma PlGF, while F. Hoffmann-La Roche likewise teaches determining PlGF or variants thereof in plasma samples (paragraphs 7-15, 30, 33, 57). At the time of the invention, human PlGF was known to exist as only a finite number of identified isoforms, including PlGF-1 and PlGF-2, with PlGF-1 being the predominant circulating soluble isoform. One of ordinary skill in the art would therefore have found it obvious to employ PlGF-1 and PlGF-2 when practicing the biomarker-based methods taught by Lambrechts and F. Hoffmann-La Roche because they represented known and predictable isoforms of the same biomarker. Selection among this finite number of known isoforms would have been an obvious matter of routine optimization with a reasonable expectation of success. Furthermore, because circulating plasma PlGF inherently includes PlGF-1 and 2, Lambrechts’ measurement of plasma PlGF necessarily encompasses measurement of PlGF-1 and 2, even though the specific isoform is not expressly identified.
Accordingly, it would have been obvious to modify the methods taught by Lambrechts in view of F. Hoffmann-La Roche to select metastatic colorectal cancer patients based on baseline circulating plasma PlGF, including PlGF-1 and PlGF-2, using an optimized threshold value such as 17 pg/mL or less, prior to administration of the conventional aflibercept/FOLFIRI treatment regimen.
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention as evidenced by the combined teachings of Lambrechts and F. Hoffmann-La Roche, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 4, 15-17, 22, 24, 26, 28, 30-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11033606 in view of Lambrechts (Br J Cancer 2015 113:1027–1034; cited in IDS) in view of F. Hoffmann-La Roche (EP2311865A1; reference of record) as evidenced by VELOUR study (NCT00561470 2012-09-27).
The combined teachings of the prior art above make obvious all instant claims for the reasons above in the 103, all said discussions there being incorporated here. The addition of the patented claims over related subject matter only further adds to this obviousness.
Patented claims are directed to a method of treating colorectal cancer in a patient comprising administering aflibercept, leucovorin (folinic acid), 5-FU, and irinotecan at dose ranges that cover the doses recited in the present claims. Thus the method directed by the patent claims could benefit from the obvious method which will identify more likely responders as discussed supra. Thus, the combination of the patented claims and prior art renders all instant claims obvious and the instant claims are rejected here.
Claims 4, 15-17, 22, 24, 26, 28, 30-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10501523 in view of F. Hoffmann-La Roche (EP2311865A1; reference of record) as evidenced by VELOUR study (NCT00561470 2012-09-27).
The combined teachings of the prior art above make obvious all instant claims for the reasons above in the 103, all said discussions there being incorporated here. The addition of the patented claims over related subject matter only further adds to this obviousness.
Patented claims are directed to a method of treating colon cancer, colorectal cancer, or rectal cancer in a patient comprising administering aflibercept, folinic acid, 5-FU, and irinotecan at dose ranges that cover those of instant claims, wherein a sample from the patient has a level of IL-8 lower than a reference level. The rest of the patented claims depend on claim 1. Thus, all are treatments of CRC that use the therapeutic regimen of instant claims and so could benefit from the obvious method which will identify more likely responders and lower dose requirements as discussed supra. Thus, the combination of the patented claims and prior art renders all instant claims obvious and the instant claims are rejected here.
Claims 4, 15-17, 22, 24, 26, 28, 30-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11208461 in view of F. Hoffmann-La Roche (EP2311865A1; reference of record) as evidenced by VELOUR study (NCT00561470 2012-09-27).
The combined teachings of the prior art above make obvious all instant claims for the reasons above in the 103, all said discussions there being incorporated here. The addition of the patented claims over related subject matter only further adds to this obviousness.
Patented claim 1 is a method of determining therapeutic efficacy of ziv-afliberceptin a patient with colon cancer, colorectal cancer, or rectal cancer comprising measuring IL-8 expression in a sample, wherein a level of IL-8 lower than a reference level indicates therapeutic efficacy of aflibercept. Thus, the patented claims are prognostic methods using during treatment of the same cancers as instant claims to determine efficacy. The rest of the patented claims depend on claim 1. Thus, all are treatments of CRC that use the therapeutic regimen of instant claims and so could benefit from the obvious method which will identify more likely responders and lower dose requirements as discussed supra. Thus, the combination of the patented claims and prior art renders all instant claims obvious and the instant claims are rejected here.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
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/SHARON X WEN/ Primary Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
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