DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I and species election of CDRs SEQ ID NOs: 49, 50, 51, 129, 130 and 131 in the reply filed on 12/18/2025 is acknowledged.
Claims 82, 94, 106 and 107 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/18/2025.
Claims 75, 77-81, 83, 97-105 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 79 is objected to because of the following informalities: Claim 79 appears to contain an inadvertent typographical error for not including “or” between part (i) and part (ii). Appropriate correction is required. The claim will be examined as having part (i) OR parti (ii).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 78 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 78 recites the limitation of having a heavy chain constant region comprising amino acid sequence as set forth in SEQ ID NOs: 226 to SEQ ID NO: 228, however SEQ ID NO: 227 is an IgG4 constant region comprising the S228P and L235E mutations, and does not comprise one or more substitutions at positions His310, His433, His436, and Ile253 as is required by claim 75 from which it depends. Therefore, SEQ ID NO: 227 does not fall within the scope of claim 10. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 75, 77-81, 83, 97-105 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 sequences recited in claim 99, 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. The claims further comprise a non-protein agent conjugate and humanized framework regions having at least 80% identity to sequences recited in instant claim 97.
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. Furthermore, Figure 1 of Oosterwijk et al. discloses the framework regions which have 100% to instantly claimed SEQ ID NOs: 57-60 and 137-140, however it is noted performing routine humanization using different framework sequences is well known in the prior art. 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.
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, 77-81, 83, 97-105 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.
Conclusion
Claims 75, 77-81, 83, 97-105 are rejected.
No Claim is allowed.
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/Meera Natarajan/Primary Examiner, Art Unit 1643