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 .
DETAILED ACTION
The amendment filed January 6, 2026, is acknowledged and has been entered. Claims 131-132 have been amended. Claims 133-142 have been newly added.
Claims 131-142 are pending.
Grounds of Rejection Withdrawn
Applicant’s amendments have obviated or rendered moot the grounds of rejection set forth in the previous Office action.
Effective Filing Date of Claims
Amended claim 131 is not supported in provisional application nos. 62/258,781, 62/314,174, or 62/379,094. Accordingly, the effective filing date of claims 131-142, (claim 132-142 depend ultimately from claim 131) is November 22, 2016.
New Grounds of Rejection
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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 131-132, 134 and 137-142 are rejected under 35 U.S.C. 103 as being unpatentable over US2015/0210769 to Freeman et al., (“Freeman;” IDS) as evidenced by WO2014/160160 (PTO-892) and Matsunobu et al (Int. J. Onc., 28:307-314, 2006, IDS).
Freeman teaches anti-PD-1 antibodies (nivolumab and pembrolizumab) and their use to treat cancer. See entire document, e.g., Abstract and [0517]. In one embodiment, the anti-PD-1 antibody is administered along with an FGFR2 inhibitor which can be an antibody or antibody-drug conjugate that binds FGFR2 to treat gastric cancer. E.g. [0654]-[0655]. The “mAb 12425” antibody taught by Freeman specifically as an option for combination (concurrent or sequential) therapy with the anti-PD-1 antibody to treat a limited number of cancers, including gastric cancer, is an antibody that binds to FGFR2-IIIb, as evidenced by WO2014/160160 at Table 4 on page 113. Furthermore, the antibody can have a N197A mutation which would make is afucosylated. E.g. [0397] and [0515].
The anti-PD-1 antibody of Freeman can be administered in combination not only with other drugs, but also in combination with other anti-PD-1 and anti-PD-L1 antibodies, including the anti-PD-1 antibody nivolumab and pembrolizumab and the antibodies can be administered at 10 mg/kg once every 1, 2, 3 or 4 weeks. E.g., [0512]-[0518].
Freeman does not teach detecting overexpression in KGFR/FGFR2-IIIb in at least 10% of cancer cells by immunohistochemistry (IHC) in a gastric cancer sample (see abstract and pages 309-311).
Matsunobu et al teach methods of detecting KGFR/FGFR2-IIIb by immunohistochemistry (IHC) in a gastric cancer sample where when at least 10% of the cancer cells express KGFR/FGFR2-IIIb by any intensity are deemed positive (see abstract and pages 309-311).
Accordingly, with respect to the claims one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the time of the invention to detect KGFR/FGFR2-IIIb by immunohistochemistry (IHC) in a gastric cancer sample and administer an anti-PD-1 antibody, such as nivolumab and pembrolizumab along (concurrent or sequential) with an antibody or antibody-drug conjugate that binds FGFR2-IIIb which is afucosylated to treat gastric cancer in patients that have a gastric cancer with an IHC signal of 2+ or 3+ in at least 10% of cancer cells because with a higher level (2+ or 3+) staining would be expected to be more responsive to an antibody that binds FGFR2-IIIb. Notably, while Matsunobu et al do not specifically classify the IHC staining level, determining antigen staining by IHC is commonly done in cancer samples and staining levels such as 2+ and 3+ are commonly determined as is known in the art. Then with respect to the claimed dosages and timing in claims 139-142, as Freeman teaches such limitations for treating cancer, one of skill in the art would see these limitations as combining prior art elements according to known methods to yield predictable results which involve simple substitution of one known element for another to obtain predictable results.
Accordingly, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
Claims 131-142 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/017600 to Harding et al. (“Harding;” IDS) or Gemo et al., AACR Poster # 5446, April 2014 (“Gemo;” IDS) in view of US2015/0210769 to Freeman et al., (“Freeman;” IDS) as evidenced by WO2014/160160 (PTO-892).
Harding teaches afucosylated anti-FGFR2-IIIb antibodies and their use in methods of treating cancer. See entire document, e.g., Abstract. The cancers that can be treated with the anti-FGFR2-IIIb antibody include gastric cancers that overexpress FGFR2-IIIb. E.g., [0016], [0174], see also Example 4 at [0206]-[0214].
Expression of FGFR2-IIIb on the cancer is determined by immunohistochemistry (IHC) and scored as 0, 1+, 2+, 3+ using an anti-FGFR2-IIIb antibody such as “GAL-FR21.” E.g. Example 6 at [0218]-[0221] as well as [0017], [0174]-[0177]. FGFR2-IIIb is overexpressed if the IHC score is 2+ or 3+. E.g. [0017], [0177].
The exemplified anti-FGFR2IIIb antibody is a humanized antibody that comprises the same CDRs (SEQ ID NOS: 6-11), VH (SEQ ID NO: 4), VL (SEQ ID NO: 5), HC (SEQ ID NO: 2), and LC (SEQ ID NO: 3) as recited in the instant SEQ ID NOS. E.g. [0109]-[0123], [0141]. The afucosylated antibody has enhanced ADCC, and mediates better killing of cancer cells than does a fucosylated anti-FGFR2 antibody. E.g., [0007], [0112], [0159], and Example 5 at [0215]-[0217].
The anti-FGFR2 antibody dose can be optimized for the indication, but Harding teaches that in general the antibody can be administered in a range of 0.5-20 mg/kg. E.g., [0181]. The dosing frequency is also as needed, but can be once every two weeks. E.g., [0182].
Harding teaches that the antibody can be used in combination with other anti-cancer agents. E.g., [0183] and Example 6. As shown in Figures 4 and 5, combining the humanized, afucosylated anti-FGFR2 antibody with either paclitaxel or cisplatin/5-FU enhanced the effectiveness against gastric cancer.
While Harding focuses on full length antibodies, Fv, scFv, Fab, etc. are also taught as options. E.g., [0046].
Gemo provides essentially the same disclosure as found in Harding, but in poster form. See entire poster. While the CDR, VH, VL, HC, and LC sequences of the anti-FGFR2 antibody “FPA144” are not described in the Gemo poster, those sequences appear to be inherent to the FPA144 antibody, which as shown in the middle column, top, panel and the last column, top panel of the poster has the same functional attributes as the humanized, afucosylated anti-FGFR2 antibody of Harding, including enhanced ADCC via “glycoengineering” and additive activity against gastric cancer cells in a tumor model.
Gemo additionally teaches that FPA144 was expected to have a more favorable toxicity profile than other FGFR2 inhibitors because it is specific for FGFR2 and does not inhibit other FGFRs. E.g., Abstract.
Neither Harding nor Gemo teaches treating gastric cancer by administering an anti-FGFR2-IIIb antibody in combination with a PD-1/PD-L1 antibody.
Freeman teaches anti-PD-1 antibodies (nivolumab and pembrolizumab) and their use to treat cancer. See entire document, e.g., Abstract and [0517]. In one embodiment, the anti-PD-1 antibody is administered along with an FGFR2 inhibitor which can be an antibody or antibody-drug conjugate that binds FGFR2 to treat gastric cancer. E.g. [0654]-[0655]. The “mAb 12425” antibody taught by Freeman specifically as an option for combination (concurrent or sequential) therapy with the anti-PD-1 antibody to treat a limited number of cancers, including gastric cancer, is an antibody that binds to FGFR2-IIIb, as evidenced by WO2014/160160 at Table 4 on page 113. Furthermore, the antibody can have a N197A mutation which would make is afucosylated. E.g. [0397] and [0515].
The anti-PD-1 antibody of Freeman can be administered in combination not only with other drugs, but also in combination with other anti-PD-1 and anti-PD-L1 antibodies, including the anti-PD-1 antibody nivolumab and pembrolizumab and the antibodies can be administered at 10 mg/kg once every 1, 2, 3 or 4 weeks. E.g., [0512]-[0518].
Freeman does not teach detecting overexpression in KGFR/FGFR2-IIIb in at least 10% of cancer cells by immunohistochemistry (IHC) in a gastric cancer sample (see abstract and pages 309-311).
Matsunobu et al teach methods of detecting KGFR/FGFR2-IIIb by immunohistochemistry (IHC) in a gastric cancer sample where when at least 10% of the cancer cells express KGFR/FGFR2-IIIb by any intensity are deemed positive (see abstract and pages 309-311).
Accordingly, with respect to the claims one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the time of the invention to in view of the teachings of Harding or Gemo in view of Freeman, to combine the afucosylated (i.e., “glycoengineered”) anti-FGFR2 antibody of Harding or Gemo with the anti-PD-1 antibody of Freeman, either alone or in combination with another anti-PD-1 antibody such as nivolumab or pembrolizumab (as also taught by Freeman), in methods of treating gastric cancer wherein patients that have a gastric cancer with an IHC signal of 2+ or 3+ in at least 10% of cancer cells because with a higher level (2+ or 3+) staining would be expected to be more responsive to an antibody that binds FGFR2-IIIb. Each of Harding, Gemo, and Freeman teach inhibiting FGFR2 with an anti-FGFR2-IIIb antibody for treating gastric cancer and Freeman teaches the claimed combination of an inhibitor of PD-1/PD-L1 with the anti-FGFR2-IIIb antibody. Harding teaches the particular anti-FGFR2 antibody recited by sequence identifiers as in the instant claims, and it appears the antibody taught by Gemo is the same antibody as that taught in Harding. The antibody of Harding/Gemo had enhanced ADCC activity, a property that would facilitate killing of cancer cells expressing FGFR2. Gemo teaches that, given the specificity of their antibody for FGFR2-IIIb, it would be expected to be less toxic than antibodies such as that taught by Freeman, which bound not only FGFR2-IIIb, but also FGFR4. The ordinary artisan would therefore have been motivated to substitute the antibody of Harding/Gemo in the combination therapy of Freeman with the expectation of reduced toxicity. Alternatively, the ordinary artisan would have been motivated to apply the combination therapy taught by Freeman to the methods of treating gastric cancer taught by Harding/Gemo since Freeman teaches adding an anti-PD-1 antibody to any of a variety of anti-tumor therapies, including inhibiting FGFR2 in gastric cancer, was beneficial. Since the antibody of Harding was taught to be useful for treating the same type of cancer but expected to have reduced toxicity compared to the antibody taught by Freeman for use in combination therapy, the ordinary artisan would have expected the combination of the anti-PD-1 antibody of Freeman and the anti-FGFR2-IIIb antibody of Harding to provide an improved combination therapy.
Harding and Gemo both also teach screening for FGFR2 expression on the cancer using IHC. And while the references do not expressly require expression on at least 10% of the tumor cells to administer to patients, it was routine in the art to set such a minimum. For example, as noted above, Freeman teaches considering the percentage of positive cells and their relative staining intensity in generating an H-score for PD-L1 expression. Each of Harding, Gemo, and Freeman teach that monitoring expression levels of molecules of interest by IHC can be helpful in identifying patients that may respond to treatment because their tumor expresses high levels of the target molecule. Lastly, selecting effective doses and dosing regimens for each component would have been routine in the art for the ordinary artisan, particularly in view of the dose and timing ranges taught by Harding and Freeman.
Given the different modes of action, Harding’s and Gemo’s teaching of enhanced results when the anti-FGFR2 antibody was combined with other anti-cancer agents, and Freeman’s express teaching to combine antibodies that inhibit PD-1/PD-L1 with an antibody that inhibits FGFR2-IIIb, the ordinary artisan before the effective filing date of the claimed invention would have had a reasonable expectation that the combination would result in an improvement in treating at least gastric cancer that overexpressed FGFR2. Gemo additionally notes the favorable toxicity profile of their anti-FGFR2 antibody. The rationale to substitute one antibody with an improved toxicity profile for another antibody to the same molecule, as well as the rationale to combine two known therapies to obtain a predictable improvement in a method of treating, is each consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143.
Accordingly, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
Claim Rejections – 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. It must be signed in compliance with 37 CFR 1.321(b).
Claims 131-142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of US10172937 (IDS) in view of WO2015/017600 to Harding et al. (“Harding;” IDS), Gemo et al., AACR Poster # 5446, April 2014 (IDS) and US2015/0210769 to Freeman et al., (IDS) as evidenced by WO2014/160160 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims render obvious the instant claims. The patented claims encompass methods of treating gastric cancer by administering the same anti-FGFR2-IIIb antibody as recited in the instant claims. E.g., patented claims 3 and 25 particularly. The patented claims also recite IHC scoring that is the same intensity as recited in the instant claims. E.g., claims 4, 27, and 31. And while the patented claims do not recite that the expression is on 10% of the tumor cells, that threshold does not provide a patentable distinction for the reasons discussed above in the related rejection under 35 U.S.C. 103. Likewise, while the patented claims do not recite co-administering a PD-1/PD-L1 inhibitor, that combination is also an obvious alternative for the reason set forth above in the rejection under 35 U.S.C. 103 regarding the teachings of Harding and/or Gemo in view of Freeman and the same reasoning for the other limitations is also incorporated herein. Therefore, the claims are not patentably distinct from the patented claims.
Claims 131-142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of US11091555 (IDS) in view of WO2015/017600 to Harding et al. (“Harding;” IDS), ), Gemo et al., AACR Poster # 5446, April 2014 (IDS) and US2015/0210769 to Freeman et al., (IDS) as evidenced by WO2014/160160 (IDS).
The patented claims recite methods of treating gastric cancer by administering the same afucosylated anti-FGFR2-IIIb antibody as recited in the instant claims in combination with modified FOLFOX6 chemotherapy. The patented claims do not recite also administering an anti-PD-1 antibody that is nivolumab or pembrolizumab. But for the reasons of record, the teachings of Harding and/or Gemo in view of Freeman provide motivation to combine an anti-PD-1 antibody that can include the anti-PD-1 antibodies nivolumab or pembrolizumab with other anti-cancer therapeutics for treating gastric cancer. The same reasoning for the other limitations set forth above in the rejection under 35 U.S.C. 103 is also incorporated herein. Therefore, the claims are not patentably distinct from the patented claims.
Claims 131-142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-59 of US11235059, in view of WO2015/017600 to Harding et al. (“Harding;” IDS), Gemo et al., AACR Poster # 5446, April 2014 (IDS) and US2015/0210769 to Freeman et al., (IDS) as evidenced by WO2014/160160 (IDS).
The patented claims recite the same afucosylated anti-FGFR2-IIIb antibodies as recited in the instant methods. The patented claims do not recite administering the anti-FGFR2-IIIb antibodies in combination with an anti-PD-1 antibody that is nivolumab or pembrolizumab for treating gastric cancer. But for the reasons of record, Harding and Gemo teach that such anti-FGFR2-IIIB antibodies can be used to treat gastric cancer; Freeman provides motivation to combine an anti-PD-1 antibody that can include the anti-PD-1 antibodies nivolumab or pembrolizumab with other anti-cancer therapeutics for treating gastric cancer. The same reasoning for the other limitations set forth above in the rejection under 35 U.S.C. 103 is also incorporated herein. Therefore, the claims are not patentably distinct from the patented claims.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner can normally be reached on Monday through Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
February 6, 2026