DETAILED ACTION
The Claim amendments filed 7/27/2026 are acknowledged and entered into the record.
Accordingly, Claims 82, 94, 106-107 have been previously withdrawn.
Claims 75, 77, 78, 80-81, 83, 100, 102-105 are pending and will be examined on the merits.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 75 is objected to because of the following informalities: Claim 75 recites “Ile253His435” when referring to choosing one or more amino acid residues at specific positions. His435 was already recited in the list of positions. The grouping of the two is unclear when the claim already states “one or more”. Appropriate correction is required. Additionally, Claim 75 comprises two sentences with a period after SEQ ID NO: 131 and another period at the end of the claim. Additionally, the amendment appears to be missing identification of the variable heavy chain (VH). Appropriate correction is required.
Claim 77 is objected to for text spacing leaving large gaps in line 3 between “heavy”, “chain”, and “region”. Appropriate correction is requested.
Claim 102 is objected to for not including a space between “Gln” and “residue in line 2. It also appears to be restating the substitutions. Appropriate correction is required.
Claim Rejections Maintained - 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.
Claim(s) 75, 77, 78, 80-81, 83, 100, 102-105 are rejected under 35 U.S.C. 103 as being unpatentable over Oosterwijk et al. (WO2002/062972, cited on IDS filed 12/23/2021) in view of Elrifi et al. (WO2007/065027, cited on IDS filed 12/23/2021) and Hartmann et al. (WO2014/177460, cited on IDS filed 12/23/2021).
The claims are drawn to an anti-CAIX antibody comprising a heavy chain constant region having one or more mutations as compared to wild-type at positions H310, H433, H435, and I253 and comprising VH CDRs having SEQ ID NOs: 49-51 and VL CDRs having SEQ ID NOs: 129-131 and VH/VL SEQ ID NOs: 52 and 132 respectively, wherein the antibody has reduced FcRn binding affinity as compared to wild-type. The claims are further drawn to a VH constant region comprising substitutions S228 and L235.
Oosterwijk et al. teach discloses chimeric and humanized anti-CAIX (G250) antibodies. Oosterwijk et al. G250 antibody has the same CDRs as the Girentuximab antibodies recited in the instant application (see figure 1). The VH chain encoded by SEQ ID NO: 52 of the instant application has the same sequence as the VH chain disclosed in Oosterwijk et al., and the VL chain encoded by SEQ ID NO: 132 of the instant application has the same sequence as the VL chain disclosed in Oosterwijk et al. The antibodies taught by Oosterwijk et al. include single-chain Fv antibody fragments, and they may be conjugated with radioactive isotopes (see page 5 last paragraph, page 6 last paragraph). Oosterwijk et al. teach the CAIX (G250) antibodies can be used in the treatment of renal cell carcinoma. Oosterwijk et al. does not teach the constant region substitutions recited in the instant claims. This deficiency is made up for by Elrifi et al. and Hartmann et al.
Elrifi et al. discloses various anti-CAIX antibodies and method of making said antibodies. Elrifi et al. teaches anti-CAIX scFvFc antibody fragments carrying the Fc mutations H310A/H435Q have been constructed, because antibodies carrying the H310A/H435Q double mutations (named scFvFc DM) show superior tumor imaging in vivo due to disrupted interaction with FcRn and reduced serum half-life. The anti-CAIX scFvFc DM antibodies are labelled with ¹²⁴Iand ⁶⁴Cu using a chelating agent (i.e. DOTA), and said antibodies are used for microPET imaging on mice bearing RC-52 tumor. The radiolabeled antibodies are considered to inherently have reduced toxicity because of their shorter serum half-life (see page 53, page 55, Examples 1-3, claim 29). Elrifi et al. further discloses methods of treatment comprising administering anti-CAIX (G250) antibodies.
Hartmann et al. discloses a range of Fc mutations which lead to reduced affinity of the modified antibodies for human FcRn and thereby reduced serum half-life, such as the triple mutations I253A/H310A/H435A. The exemplified antibody (anti-VEGF/anti-ANG-2 bispecific) comprising the I253A/H310A/H435A mutations further contains the mutations P329G/L234A/L235A which removes binding of the antibody to FcγRIIIA. Hartmann et al. further discloses FcRn-binding abolished antibodies further comprising the S228P/L235E mutations. The antibodies can be further conjugated to other moieties, such as drug moieties. Hartmann et al. also discloses a method of producing the modified antibody using expression vectors and cell expression systems. The antibodies disclosed in Hartmann et al. would inherently have reduced toxicity when the antibodies are used in radioimmunotherapy, wherein the toxicity is associated with longer-term residence of radioisotope in the circulation (see Example 1, Example 3, pages 48-57,page 97, pages 115-116, page 133, page 140).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the constant regions of the anti-CAIX antibody Girentuximab, to be applied in radioimmunotherapy based on the teachings of Oosterwijk et al., Elrifi et al. and Hartmann et al. Elrifi et al. teaches a chimeric anti-CAIX (G250) mAb having H310A/H435Q mutations resulted in reduced FcRn binding and shortened serum half-life and therefore superior tumor imaging in vivo when conjugated to radioisotopes. Therefore, in the light of Elrifi et al., it would be immediately obvious that there is a desire to shorten the serum half-life of any given anti-CAIX antibody by Fc modifications to reduce FcRn binding affinity order to reduce toxicity and achieve superior tumor imaging in vivo), when the antibody is radiolabeled and used in radio imaging or radioimmunotherapy. It is obvious that the H310A/H435Q modifications used in Elfiri et al. can be applied to a different anti-CAIX antibodies, and there are several available anti-CAIX antibodies, including Girentuximab, which is taught by Oosterwijk et al. having the same instantly claimed CDR/VH/VL sequences. The skilled person would expect that such Fc modification will lead to reduced FcRn binding affinity, shortened half-life, superior tumor imaging and lower toxicity of the resulting anti-CAIX antibody. Different antibody formats (e.g. scFv, Fab etc.) are known in the art and the skilled person can optimize it through routine experimentation. Additionally, modifications in the Fc region for reduced affinity for Fc gamma receptors for hinge stabilization, as taught by Hartmann et al., these modifications (S228 and L235) are commonly used in antibody engineering, therefore obvious. It does not appear that the addition of these mutations confer any surprising advantages to how the present invention works. The specification has not shown a surprising advantage when a mutation affecting Fc gamma binding is further included in addition to mutations affecting FcRn binding in terms of superior pharmacokinetics. Therefore, the features added by these claims are considered obvious in view of the teachings of Oosterwijk, Elrifi et al. and Hartmann et al.
Response to Arguments
Applicant's argue in the response filed 7/27/2026 that Oosterwijk does not teach substitutions at His310 or His435 and does not indicate reducing serum half-life would be desirable. Applicants further argue Elrifi’s imagining-driven disclosure does not apply to any anti-CAIX antibody because improving imaging contrast and delivering a therapeutic radiation dose to a tumor are materially different objectives. Applicants argue none of Oosterwijk, Elrifi, or Hartmann teaches that tumor accumulation would be preserved despite reduced half-life, and therefore there was no reasonable expectation of success that the girentuximab antibody modified at His310 and His435 would retain tumor directed function. These arguments have been fully considered but they are not persuasive.
Oosterwijk et al. teach the therapeutic anti-CAIX antibody, girentuximab, that may be used for renal cell carcinoma and Elrifi et al. teach other anti-CAIX antibodies used in renal cell carcinoma therapy comprising the claimed H310/H435 substitutions. Both references teach the anti-CAIX antibodies may be conjugated to cytotoxic agents and therefore would benefit from reduced FcRn binding and shorter half-life to reduce toxicity as stated in the maintained rejection set forth above. Therefore, although Oosterwijk et al. does not explicitly teach motivation to reduce serum half-life, one of skill in the art would know that modifying therapeutic antibodies as instantly claimed could be beneficial. Furthermore, the instant claims are drawn to a product and not a method of treatment. The rejection of record is hereby maintained.
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 75, 77, 78, 80-81, 83, 100, 102-105 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 75-95 of copending Application No. 18/646,281 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and those of copending application 18/646,281 are both drawn to the same anti-CAIX antibody, Girentuximab, having the same constant region mutations as well as conjugated to a radiolabel.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s request in the response filed 7/27/2026 the provisional rejection be held in abeyance pending further prosecution of the copending application. Therefore, the rejection of record is hereby maintained, have been fully considered but they are not persuasive.
Conclusion
Claims 75, 77, 78, 80-81, 83, 100, 102-105 are rejected.
No Claim is 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.
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/Meera Natarajan/Primary Examiner, Art Unit 1643
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