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 .
Response to Amendment
The Amendment filed 30 April 2026 is acknowledged. Applicant has currently amended claims 1, 31, 38, and 39. Claims 2, 4, 6-7, 32-34, 40, and 41 are canceled. New claims 42 and 43 are added.
Claim Status
Claims 1, 8-11, and 31, 35-39, and 42-43 are pending and under examination in the instant office action.
Withdrawal of Objections
The objection to the drawings for reference to color not in the greyscale drawings is withdrawn in view of the amendment to the specification.
The objection to the specification for reference to color not in the greyscale drawings is withdrawn in view of the amendment to the specification.
Withdrawal of Rejections
The rejections of claims 2, 4, 6-7, 32-34, 40, and 41 are moot in view of the cancellations of the claims.
The rejection of claims 1, 2, 4, 6-11, and 31-38, and 40-41 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 2, 4, 6-11, and 31-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the amendment to the claims.
The rejection of claims 38-41 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of imaging a tumor expressing PSCA in vivo, does not reasonably provide enablement for a method of imaging a generic, singular cancer cell in vivo is withdrawn in view of the amendment to the claims and Applicants Remarks dated 4/30/2026. Applicant argues that the preamble of claim 8 “A method of imaging a cancer cell in vivo” is not limiting because it is in the preamble and the claim fully and intrinsically sets forth all of the limitations of the claimed invention, such that the preamble is merely an intended use and non-limiting. This is partially persuasive
The rejection of claims 1, 2, 6-11, 31, 33-34 and 35-41 under 35 U.S.C. 103 as being unpatentable over WO2007108321 to Wu et. al. published 27 September 2007 (Of record, IDS dated 7/10/2023), US 20120034228 to Kufer et. al. published 9 February 2012, Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329, CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation), Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (Of record, IDS dated 7/10/2023); and Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 is withdrawn in view of the amendment to the claims.
The rejection of claims 4 and 32 under 35 U.S.C. 103 as being unpatentable over WO2007108321 to Wu et. al. published 27 September 2007 (Of record, IDS dated 7/10/2023), US 20120034228 to Kufer et. al. published 9 February 2012, Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329, CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation), Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (Of record, IDS dated 7/10/2023); and Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 as applied to claims 1 and 31 above, and further in view of Diebolder, Philipp, et al. "Generation of “LYmph Node Derived Antibody Libraries”(LYNDAL) for selecting fully human antibody fragments with therapeutic potential." MAbs. Vol. 6. No. 1. Taylor & Francis, 2014 is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 2, 6-11, 31, 33-34, and 35-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10-11, 13-17, 29, 31, 32 of U.S. Patent No. 8940298 in view of US 20120034228 to Kufer et. al. published 9 February 2012, Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329, CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation), Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (Of record, IDS dated 7/10/2023); and Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 2, 6-11, 31, 33-34, and 35-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10-11, 13-17, 29, 31, 32 of U.S. Patent No. 9527919 (Of Record, cited in IDS dated 7/10/2023) in view of US 20120034228 to Kufer et. al. published 9 February 2012, Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329, CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation), Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (Of record, IDS dated 7/10/2023); and Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 2, 6-11, 31, 33-34 and 35-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 8940871 (Of record, IDS dated 7/10/2023) in view of WO2007108321 to Wu et. al. published 27 September 2007 (Of record, IDS dated 7/10/2023), US 20120034228 to Kufer et. al. published 9 February 2012, Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329, CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation), Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (Of record, IDS dated 7/10/2023); and Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 39 and 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 39, the recitation of “ wherein the detectable marker comprises one or more radioactive isotopes selected from the group consisting of […] or haptens and proteins” is indefinite because it is unclear what are the boundaries of “comprising” “selected from the group consisting of”. For example, it appears that the limitation “fluorescent dyes” is part of the group of one of more radioactive isotopes. Additionally, the lack of an oxford comma in the phrase “or haptens and proteins” makes it unclear whether “haptens and proteins” are considered to be one element of the list together or a separate detectable marker. The examiner recommends amending the conjunctions and the punctuation to make it clear which elements are part of the list “wherein the detectable marker comprises” and which elements are part of the “one or more radioactive isotopes selected from a group consisting of” and to make the elements of each Markush Group distinct.
Regarding claim 42, the phrase “the recombinant anti-PSCA scFv-Fc fusion protein” is indefinite because the claim does not depend from any other claim, and therefore there is no antecedent basis for the recombinant anti-PSCA scFv-Fc fusion protein. For the purposes of expedited prosecution, claim 42 will be examined as if it is dependent on independent claim 31, which comprises an anti-PSCA scFv-Fc fusion protein and a first peptide.
Response to Arguments
The Remarks filed 4/30/2026 have been fully considered but are not persuasive. In regard to claim 39, the claim is still indefinite because the amendments have made the different groups of detectable markers and radionuclides unclear, as described above.
Claim Rejections - 35 USC § 102- New, necessitated by amendment
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 31, and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over WO2009032949 to Wu et. al. published 12 March 2009.
Claim interpretation: Claim 31 recites a recombinant anti-PSCA scFv-Fc fusion protein comprising a first peptide, the first peptide comprising a VH domain and a VL domain of an anti-PSCA antibody having an amino acid comprising SEQ ID NO: 2 or SEQ ID NO: 3; therefore, the claim requires only an anti-PSCA scFv-Fc fusion protein comprising a peptide comprising the VH and VL domain of the anti-PSCA antibody of SEQ ID NO: 2 or 3, which are residues 1-112 and 128-233 of SEQ ID NO: 2 or 3, respectively.
Regarding claims 31 Wu 2009 teaches an anti-PSCA parental scFv antibody of SEQ ID NO: 6 comprising a VH of SEQ ID NO: 6 residues 124-235 of SEQ ID NO: 6 [0024] that are identical to the VH of SEQ ID NOs: 2 and 3 residues 1-112 and a VL of SEQ ID NO: 6 residues 1-106 100% identical to instant SEQ ID NOs: 2 and 3 residues 128-233. Wu et. al. teaches that the embodiments include a variety of engineered antibody formats including scFv-Fc [0008], [0011], . Wu et. al. teaches “the invention provides an antigen binding protein construct selected from the group consisting of a minibody, a diabody, scFv and scFv-Fc wherein the selected construct has V.sub.L and V.sub.H domains that are substantially identical to the V.sub.L and V.sub.H domains of 2B3 or an scFv variant designated herein as Al 1, A2, or C5” [0016] (A2 is equivalent to SEQ ID NO: 6; [0012]).
Regarding claims 35-37, Wu et. al. teaches radionuclides attached to the antibodies for imaging or therapeutics such as toxins or drugs for tumor targeting [0009], [0013], [0018].
Claim Rejections - 35 USC § 103- New, necessitated by amendment
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.
The factual inquiries 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 1, 8-11, 38-39, and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over WO2009032949 to Wu et. al. published 12 March 2009; US 20120034228 to Kufer et. al. published 9 February 2012 (PTO-892 12/1/2025); Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329 (PTO-892 12/1/2025); U.S. 20130244341 to Pfizenmaier et. al. published 19 September 2013 (IDS 7/101/2023); CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation) (PTO-892 12/1/2025); Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (IDS dated 7/10/2023); Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 (PTO-892 12/1/2025); and U.S. 20060134709 to Stavenhagen et. al. published 22 June 2006.
Regarding claim 42, the teachings of Wu et. al. in regards to claim 31 are in the 102 rejection above.
Regarding claims 1, 38, and 42, Wu 2009 teaches an anti-PSCA parental scFv antibody of SEQ ID NO: 6 comprising a VH of SEQ ID NO: 6 residues 124-235 of SEQ ID NO: 6 [0024] that are identical to the VH of SEQ ID NOs: 2 and 3 residues 1-112 and a VL of SEQ ID NO: 6 residues 1-106 100% identical to instant SEQ ID NOs: 2 and 3 residues 128-233. Wu et. al. teaches that there are a variety of engineered antibody formats including scFv-Fc and that the overall size, shape, and domain composition of the agent can be varied to suit the final application. Wu et. al. teaches dimeric formats such wherein two scFvs are each linked to a CH3 domain (See Fig. 1; reads on “form a homodimer”). Wu et. al. teaches “the invention provides an antigen binding protein construct selected from the group consisting of a minibody, a diabody, scFv and scFv-Fc wherein the selected construct has V.sub.L and V.sub.H domains that are substantially identical to the V.sub.L and V.sub.H domains of 2B3 or an scFv variant designated herein as Al 1, A2, or C5” (A2 is equivalent to SEQ ID NO: 6; [0016]). SEQ ID NO: 6 has a peptide between the VH an the VL linker comprising the amino acid sequence GSTGGGSGGGSGGS.
Regarding claims 8-11, Wu et. al. teaches radionuclides attached to the antibodies for imaging or therapeutics such as toxins or drugs for tumor targeting [0009], [0013], [0018].
Regarding claim 38, Wu et. al. teaches a method of imaging tumors in vivo comprising administering the antibodies of the invention [0007], [0009], [0022], [0094-0095].
Regarding 39, Wu et. al. teaches the method of imaging tumors wherein the antibody is linked to a detected markers and teaches example radionuclides 111I and 18F [0013], [0094-0095].
Wu 2009 does not teach the scFv in the VH-VL order as in SEQ ID NO: 2 or SEQ ID NO: 3. This deficiency is resolved by Weatherill et. al. and Kufer et. al.
Weatherill et. al. teaches engineering of scFv fragments for antigen binding and stability to determine where disulfide bonds might most improve scFv biophysical characteristics (Discussion, p 328 left column bottom- right column ¶1). Weatherill et. al. teaches “ scFv are comprised of a vH and vL, where the C-terminus of a first variable region domain is connected to the N-terminus of the second by means of a flexible peptide linker. scFv have been described in both vL–vH (LH) and vH–vL (HL) orientations. Some studies have shown no difference in binding activity and expression between the two orientations (Rajagopal et al., 1997) whereas others have shown the LH orientation to be both superior (Desplancq et al., 1994; Luo et al., 1995) and inferior (Albrecht et al., 2006) to HL for expression or antigen binding” (p. 321 right column ¶1). Weatherill et. al. demonstrates that out of six scFvs tested “[m]ost scFv showed little or no preference with regard to variable region orientation in terms of both yield and propensity to form monomer” (p. 322 left column ¶3). Weatherill teaches “Most of the scFv expressed appear to be equally functional in either orientation, but scFv 3 produced substantially more monomer and scFv 2 was ∼4°C more stable in the LH orientation while scFv 1 appeared to be slightly less capable of forming monomer in the LH orientation.” (p. 329 left column, ¶2).
Kufer et. al. teaches an anti-PSCA scFv as part of a PSCAxCD3 bispecific antibody (SEQ ID NOs: 385 and 389) wherein the scFv is oriented in the VH-VL orientation, and wherein the VH and VL of the scFv are 96.7% and 98.9% identical to the anti-PSCA VH and VL of Wu 2009:
Query Match 96.7%; Score 582; Length 233;
Best Local Similarity 96.4%;
Matches 108; Conservative 3; Mismatches 1; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
|||||||||||||||||||||||||||||||||||||||||||||||||||||| ||:||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSS 112
|||||||||:|||||||||||||||||||||||||||||||||:||||||||
Db 61 VPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS 112
Query Match 98.9%; Score 546; Length 233;
Best Local Similarity 99.1%;
Matches 105; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 128 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 187
Qy 61 FSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIK 106
|||||||||||||||||||||||||||||| |||||||||||||||
Db 188 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIK 233
It would have been obvious to make an scFv-Fc as taught by Wu et. al. using an scFv in VH-VL format because the VH-VL and VL-VH formats are obvious variants of one another and as taught by Weatherill and Kufer a person of ordinary skill in the art would reasonably believe that the particular VH and VL of Wu 2009 would work in this format because a highly similar antibody maintains PSCA binding.
Wu et. al. in view of Weatherill and Kufer does not teach the anti-PSCA scFv-Fc protein with the peptide linker GGGGSGGGGSGGSAQ as in instant SEQ ID NOs: 2 and 3 residues 113-127.
This deficiency is resolved by U.S. 20130244341 to Pfizenmaier et. al.
Pfizenmaier et. al. teaches a 15 residue scFv linker of SEQ ID NO: 13 which comprises GGGGSGGGGSGGSAQ identical to SEQ ID NOs: 2 or 3 residues 113-127.
It would have been obvious, at the instant time of filing, to use SEQ ID NO: 13 of Pfizenmaier in order to benefit from a known variant of a glycine/serine rich linker as taught by Wu 2009. This would have a reasonable expectation of success because Wu 2009 teaches that a person of ordinary skill in the art can vary linkers of the VH and VL and SEQ ID NO: 13 is a known variant of a GS linker for use in an scFv.
Wu 2009 in view of Weatherill, Kufer, and Pfizenmaier does not teach the sequence of the Fc domain of the scFv-Fc protein. This deficiency is partially resolved by Li et. al.
Li et. al. teaches an improved IgG2 antibody hinge wherein the “hinge region lacks Glu216Arg217Lys218 amino acids and the Cys219 and/or Cys220 contains amino acid substitution and/or deletion” (Abstract). Li et. al. teaches that, although IgG2 is less susceptible to protease digestion than other isotypes such as IgG1, the upstream hinge region sequence “ERK” comprises protease target cut sites and can result in degradation of the antibody (p. 1, last ¶). Li et. al. teaches that deleting the protease restriction sites of Glu 216 Arg 217 Lys 218 (EU index) and simultaneously replacing or deleting the two amino acids in the upstream hinge to “obtain a uniform and stable IgG2 antibody product” (p. 2, first ¶). Li et. al. teaches the full-length antibody comprising SEQ ID NO: 5 comprising the mutant Fc sequence.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to combine the anti-PSCA scFv-Fc fragment with the protease resistant IgG2 hinge of Li et. al. in order to benefit from the protease-resistant hinge and IgG2 Fc domain as taught by Li et. al., resulting in an anti-PSCA scFv-Fc with a truncated hinge and Fc domain and a method of imaging a cancer cell in vivo comprising the anti-PSCA scFv-Fc with the truncated hinge. The scFv-Fc sequence of Wu et. al. in view of Weatherill, Kufer, and Pfizenmaier, comprising the Fc hinge of Li comprises the following sequence:
RESULT 1
AASEQ2_06242026_121713
Query Match 99.4%; Score 2425; DB 1; Length 456;
Best Local Similarity 99.3%;
Matches 453; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
Qy 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
Qy 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
Qy 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKP 300
||||||||||||||||||||||||||||||||||||||||||||||||||:|||||||||
Db 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKP 300
Qy 301 REEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
|||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||
Db 301 REEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
Qy 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
Qy 421 VDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
||||||||||||||||||||||| ||||||||||||
Db 421 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 456
This would have a predictable effect because an artisan would expect that the protease-resistance would improve any Fc-containing protein to prevent severing the antigen-binding portion from the Fc portion (comprising the effector domain or labeling moiety for effective labeling or therapeutic effect).
Wu 2009 in view of Weatherill, Kufer, Pfizenmaier, and Li does not teach the scFv-Fc domain comprising SEQ ID NO: 3. As shown in the alignment above, the difference between the modified Wu 2009 scFv-Fc and instant SEQ ID NO: 3 is 3 point mutations in the IgG2 Fc domain: H310A, H435Q, and V282M.
This deficiency is resolved by Kenanova et. al., Stapleton et. al., and Stavenghagen et. al.
Kenanova et. al. teaches anti-CEA scFv-Fc fusion proteins with the human IgG1 isotype comprising mutations in order to alter the binding to FcRn in order to modulate the half-life of the receptors (Abstract). Kenanova et. al. teaches that compared to other scFv-Fc mutations, 125I and 131I-labeled scFv-Fc fragment comprising the H310A and H435Q mutations was cleared the fastest from the blood (Fig. 4, Table 2). This increased turnover in the blood resulted in better distinction between tumor-to-nontarget ratios in microPET scans of mice when administered a 124I-labeled scFv-Fc of 11.7:1 as compared to 0.6:1 for wildtype (Fig. 6, p. 628 left column) and that “Among the scFv-Fc proteins used in the imaging studies, the H310A/H435Q mutant showed a superior ability to quickly localize to the tumor site and clear from the circulation (p. 630 left column, ¶1). Kenanova et. al. teaches that “instead of producing one fragment with one distinct pharmokinetic profile, we can produce several fragments with the same format exhibiting broadly different pharmacokinetic characteristics. Thus, one can choose a format that would best suit a specific in vivo application” and that the scFv-Fc format can be tailored to clear from the serum as quickly as a minibody (p. 628 right column, ¶2).
Stapleton et. al. teaches that both IgG1 and IgG2 are reported to have similar fractional catabolic rates and half-lives of 21-28 days, “indicating that FcRn is able to rescue IgG1 and IgG2 equally efficiently from lysosomal degradation” (p. 2 ¶1). Additionally, “IgG1 and IgG2 are not known to differ in their affinities for FcRn or known IgG-FcRn contact residues” (p. 2 ¶2). Stapleton et. al. report “Recently, we also found no evidence for any preference for either light chain isotype or IgG2 hinge isomer (formed by different disulphide-bridge formations between cysteines in the upper IgG2-hinge and the light chains), indicating that the difference in hinge flexibility reported by Dillon et al.34 does not affect FcRn function26. We have also recently generated a IgG variant lacking Fc-receptor effector functions by engrafting IgG2- and IgG4-derived amino acids onto IgG1 (Δnab35), which still binds FcRn” (p. 2 ¶2).
Stavenhagen et. al. teaches Fc variant regions that stimulate increased effector cell function by increased FcR interaction, including the variant Fc V282M which increases ADCC by 1.28 fold relative to control (Table 8). Stavenhagen teaches that the Fc may be any IgG subclass including IgG2 [0246].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify the anti-PSCA scFv-Fc IgG2 and method of imaging a cancer cell in vivo of modified Wu 2009 as described above with the H310A/H435Q mutations in order to improve the anti-PSCA scFv-Fc for imaging by improving the blood clearance and tumor to nontarget ratios as taught by Kenanova et. al. and with the V228M mutations in order to increase ADCC against the tumor target antigen PSCA as taught by Stavenhagen et. al. As shown below, making these mutations in the sequence of modified Wu 2009 as taught above would result in an scFv sequence 100% identical to the instant SEQ ID NO: 3:
RESULT 1
AASEQ2_06242026_132321
Query Match 100.0%; Score 2440; DB 1; Length 456;
Best Local Similarity 100.0%;
Matches 456; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
Qy 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
Qy 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
Qy 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKP 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKP 300
Qy 301 REEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 REEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
Qy 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
Qy 421 VDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
||||||||||||||||||||||||||||||||||||
Db 421 VDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
This would have a predictable effect because Stapleton et. al. teach that IgG1 and IgG2 Fc domains have conserved FcRn binding, and therefore an artisan would expect that modifying the IgG2 Fc domain of Wu et. al. in view of Li et. al. would have the same effect on pharmacokinetics as that of the IgG1 Fc domain of Kenanova et. al. and Stavenhagen teaches that the ADCC mutations may be in any desired IgG backbone.
Response to Arguments
The Remarks filed 4/30/2026 have been fully considered. Applicant argues that none of the six references (Wu, Kufer, Weatherill, Li, Kenanova, and Stapleton) cited in the Non-Final rejection disclose a peptide having an amino acid sequence comprising SEQ ID NO: 2 or 3 (p. 11-12). This argument is moot because of the new rejection including Wu 2009, Pfizenmaier, and Stavenhagen, as described above, which make obvious the missing limitations as described. The new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Double Patenting- New, necessitated by amendment
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.
U.S. Patent No. 9527919
Claims 31, and 35-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10-11, 13-17, 29, 31, 32 of U.S. Patent No. 9527919 (Of Record, cited in IDS dated 7/10/2023).
Claims of the ‘919 patent teach an antigen binding protein construct (ABPC) comprising an antigen binding domain comprising the heavy chain CDRs of SEQ ID NO: 6 and the light chain CDRs of SEQ ID NO: 6, or a light chain and a heavy chain variable domain of SEQ ID NO: 6, wherein SEQ ID NO: 6 comprises anti-PSCA CDRs identical to those of the instant VL and the instant VH of SEQ ID NO: 3 (claims 1-3). Claims 10 and 11 teach the antibody conjugated to a therapeutic agent, wherein the therapeutic agent is cytotoxic. Claims 13 and 14 teach wherein the therapeutic agent of claim 10 is a radioactive isotope. Claim 15 teaches wherein the construct is linked to an enzyme. Claims 16 and 17 recite wherein the anti-PSCA ABPC is labeled with a detectable marker, wherein the marker is a radioisotope, fluorescent compound, among others. Claim 29 teaches a method for imaging cancer cells expressing PSCA in a patient, said method comprising administering to said patient an ABPC according to claim 1 wherein said ABPC is conjugated to a detectable moiety, and detecting the presence and location of the ABPC within the patient’s body. Claim 32 teaches an antibody that binds to human PSCA comprising an antigen binding domain comprising the heavy or light chain CDRs or SEQ ID NO: 6. Claim 33 teaches the antibody of claim 32, wherein the antibody is a minibody, a diabody, or a scFv-Fc. Therefore, although the claims do not explicitly recite the scFv-Fc comprising the complete VH and VL of SEQ ID NO: 6, the claims make obvious this embodiment because a person would understand that one embodiment of the genus of scFv-Fc antibodies comprising the CDRs of SEQ ID NO: 6 is a an scFv-Fc protein comprising the entire VH and VL of SEQ ID NO: 6.
Claims 1, 8-11, 38-39, and 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10-11, 13-17, 29, 31, 32 of U.S. Patent No. 9527919 (Of Record, cited in IDS dated 7/10/2023) in view of US 20120034228 to Kufer et. al. published 9 February 2012 (PTO-892 12/1/2025); Weatherill, Eve E., et al. "Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL–vH orientation." Protein Engineering, Design & Selection 25.7 (2012): 321-329 (PTO-892 12/1/2025); U.S. 20130244341 to Pfizenmaier et. al. published 19 September 2013 (IDS 7/101/2023); CN104177496 to Li et. al. published 3 December 2014 (citations refer to the Patentscope machine translation) (PTO-892 12/1/2025); Kenanova, Vania, et al. "Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti–carcinoembryonic antigen single-chain Fv-Fc antibody fragments." Cancer research 65.2 (2005): 622-631 (IDS dated 7/10/2023); Stapleton, Nigel M., et al. "Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge." Scientific reports 9.1 (2019): 7363 (PTO-892 12/1/2025); and U.S. 20060134709 to Stavenhagen et. al. published 22 June 2006.
Claims of the ‘919 patent teach an antigen binding protein construct (ABPC) comprising an antigen binding domain comprising the heavy chain CDRs of SEQ ID NO: 6 and the light chain CDRs of SEQ ID NO: 6, or a light chain and a heavy chain variable domain of SEQ ID NO: 6, wherein SEQ ID NO: 6 comprises anti-PSCA CDRs identical to those of the instant VL and the instant VH of SEQ ID NO: 3 (claims 1-3). Claims 4-6 teach wherein the protein binding construct is a minibody, which definitionally includes the VH and VL in scFv form. SEQ ID NO: 6 teaches that the scFv is in VL-VH order from N to C terminus. Claims 10 and 11 teach the antibody conjugated to a therapeutic agent, wherein the therapeutic agent is cytotoxic. Claims 13 and 14 teach wherein the therapeutic agent of claim 10 is a radioactive isotope. Claim 15 teaches wherein the construct is linked to an enzyme. Claims 16 and 17 recite wherein the anti-PSCA ABPC is labeled with a detectable marker, wherein the marker is a radioisotope, fluorescent compound, among others. Claim 29 teaches a method for imaging cancer cells expressing PSCA in a patient, said method comprising administering to said patient an ABPC according to claim 1 wherein said ABPC is conjugated to a detectable moiety, and detecting the presence and location of the ABPC within the patient’s body. Claim 32 teaches an antibody that binds to human PSCA comprising an antigen binding domain comprising the heavy or light chain CDRs or SEQ ID NO: 7. Claim 33 teaches the antibody of claim 31, wherein the antibody is a minibody, a diabody, or a scFv-Fc.
The ‘919 does not explicitly teach the variable domains are arranged in the order of VH-VL in the scFv-Fc of claim 33.
Weatherill et. al. teaches engineering of scFv fragments for antigen binding and stability to determine where disulfide bonds might most improve scFv biophysical characteristics (Discussion, p 328 left column bottom- right column ¶1). Weatherill et. al. teaches “ scFv are comprised of a vH and vL, where the C-terminus of a first variable region domain is connected to the N-terminus of the second by means of a flexible peptide linker. scFv have been described in both vL–vH (LH) and vH–vL (HL) orientations. Some studies have shown no difference in binding activity and expression between the two orientations (Rajagopal et al., 1997) whereas others have shown the LH orientation to be both superior (Desplancq et al., 1994; Luo et al., 1995) and inferior (Albrecht et al., 2006) to HL for expression or antigen binding” (p. 321 right column ¶1). Weatherill et. al. demonstrates that out of six scFvs tested “[m]ost scFv showed little or no preference with regard to variable region orientation in terms of both yield and propensity to form monomer” (p. 322 left column ¶3). Weatherill teaches “Most of the scFv expressed appear to be equally functional in either orientation, but scFv 3 produced substantially more monomer and scFv 2 was ∼4°C more stable in the LH orientation while scFv 1 appeared to be slightly less capable of forming monomer in the LH orientation.” (p. 329 left column, ¶2).
Kufer et. al. teaches an anti-PSCA scFv as part of a PSCAxCD3 bispecific antibody (SEQ ID NOs: 385 and 389) wherein the scFv is oriented in the VH-VL orientation, and wherein the VH and VL of the scFv are 96.7% and 98.9% identical to the anti-PSCA VH and VL of Wu 2009:
Query Match 96.7%; Score 582; Length 233;
Best Local Similarity 96.4%;
Matches 108; Conservative 3; Mismatches 1; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
|||||||||||||||||||||||||||||||||||||||||||||||||||||| ||:||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSS 112
|||||||||:|||||||||||||||||||||||||||||||||:||||||||
Db 61 VPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS 112
Query Match 98.9%; Score 546; Length 233;
Best Local Similarity 99.1%;
Matches 105; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 128 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 187
Qy 61 FSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIK 106
|||||||||||||||||||||||||||||| |||||||||||||||
Db 188 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIK 233
It would have been obvious to make an scFv-Fc as taught by ‘919 using an scFv in VH-VL format because the VH-VL and VL-VH formats are obvious variants of one another and as taught by Weatherill and Kufer a person of ordinary skill in the art would reasonably believe that the particular VH and VL of ‘919 would work in this format because a highly similar antibody maintains PSCA binding.
Wu et. al. in view of Weatherill and Kufer does not teach the anti-PSCA scFv-Fc protein with the peptide linker GGGGSGGGGSGGSAQ as in instant SEQ ID NOs: 2 and 3 residues 113-127.
This deficiency is resolved by U.S. 20130244341 to Pfizenmaier et. al.
Pfizenmaier et. al. teaches a 15 residue scFv linker of SEQ ID NO: 13 which comprises GGGGSGGGGSGGSAQ identical to SEQ ID NOs: 2 or 3 residues 113-127.
It would have been obvious, at the instant time of filing, to use SEQ ID NO: 13 of Pfizenmaier in order to benefit from a known variant of a glycine/serine rich linker as taught by Wu 2009. This would have a reasonable expectation of success because ‘919 teaches that a person of ordinary skill in the art can vary linkers of the VH and VL and SEQ ID NO: 13 is a known variant of a GS linker for use in an scFv.
‘919 in view of Weatherill, Kufer, and Pfizenmaier does not teach the sequence of the Fc domain of the scFv-Fc protein. This deficiency is partially resolved by Li et. al.
Li et. al. teaches an improved IgG2 antibody hinge wherein the “hinge region lacks Glu216Arg217Lys218 amino acids and the Cys219 and/or Cys220 contains amino acid substitution and/or deletion” (Abstract). Li et. al. teaches that, although IgG2 is less susceptible to protease digestion than other isotypes such as IgG1, the upstream hinge region sequence “ERK” comprises protease target cut sites and can result in degradation of the antibody (p. 1, last ¶). Li et. al. teaches that deleting the protease restriction sites of Glu 216 Arg 217 Lys 218 (EU index) and simultaneously replacing or deleting the two amino acids in the upstream hinge to “obtain a uniform and stable IgG2 antibody product” (p. 2, first ¶). Li et. al. teaches the full-length antibody comprising SEQ ID NO: 5 comprising the mutant Fc sequence.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to combine the anti-PSCA scFv-Fc of ‘919 with the protease resistant IgG2 hinge of Li et. al. in order to benefit from the protease-resistant hinge and IgG2 Fc domain as taught by Li et. al., resulting in an anti-PSCA scFv-Fc with a truncated hinge and Fc domain and a method of imaging a cancer cell in vivo comprising the anti-PSCA scFv-Fc with the truncated hinge. The scFv-Fc sequence of ‘919 in view of Weatherill, Kufer, and Pfizenmaier, comprising the Fc hinge of Li comprises the following sequence:
RESULT 1
AASEQ2_06242026_121713
Query Match 99.4%; Score 2425; DB 1; Length 456;
Best Local Similarity 99.3%;
Matches 453; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
Qy 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
Qy 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
Qy 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKP 300
||||||||||||||||||||||||||||||||||||||||||||||||||:|||||||||
Db 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKP 300
Qy 301 REEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
|||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||
Db 301 REEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
Qy 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
Qy 421 VDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
||||||||||||||||||||||| ||||||||||||
Db 421 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 456
This would have a predictable effect because an artisan would expect that the protease-resistance would improve any Fc-containing protein to prevent severing the antigen-binding portion from the Fc portion (comprising the effector domain or labeling moiety for effective labeling or therapeutic effect).
‘919 in view of Weatherill, Kufer, Pfizenmaier, and Li does not teach the scFv-Fc domain comprising SEQ ID NO: 3. As shown in the alignment above, the difference between the modified ‘919 scFv-Fc and instant SEQ ID NO: 3 is 3 point mutations in the IgG2 Fc domain: H310A, H435Q, and V282M.
This deficiency is resolved by Kenanova et. al., Stapleton et. al., and Stavenghagen et. al.
Kenanova et. al. teaches anti-CEA scFv-Fc fusion proteins with the human IgG1 isotype comprising mutations in order to alter the binding to FcRn in order to modulate the half-life of the receptors (Abstract). Kenanova et. al. teaches that compared to other scFv-Fc mutations, 125I and 131I-labeled scFv-Fc fragment comprising the H310A and H435Q mutations was cleared the fastest from the blood (Fig. 4, Table 2). This increased turnover in the blood resulted in better distinction between tumor-to-nontarget ratios in microPET scans of mice when administered a 124I-labeled scFv-Fc of 11.7:1 as compared to 0.6:1 for wildtype (Fig. 6, p. 628 left column) and that “Among the scFv-Fc proteins used in the imaging studies, the H310A/H435Q mutant showed a superior ability to quickly localize to the tumor site and clear from the circulation (p. 630 left column, ¶1). Kenanova et. al. teaches that “instead of producing one fragment with one distinct pharmokinetic profile, we can produce several fragments with the same format exhibiting broadly different pharmacokinetic characteristics. Thus, one can choose a format that would best suit a specific in vivo application” and that the scFv-Fc format can be tailored to clear from the serum as quickly as a minibody (p. 628 right column, ¶2).
Stapleton et. al. teaches that both IgG1 and IgG2 are reported to have similar fractional catabolic rates and half-lives of 21-28 days, “indicating that FcRn is able to rescue IgG1 and IgG2 equally efficiently from lysosomal degradation” (p. 2 ¶1). Additionally, “IgG1 and IgG2 are not known to differ in their affinities for FcRn or known IgG-FcRn contact residues” (p. 2 ¶2). Stapleton et. al. report “Recently, we also found no evidence for any preference for either light chain isotype or IgG2 hinge isomer (formed by different disulphide-bridge formations between cysteines in the upper IgG2-hinge and the light chains), indicating that the difference in hinge flexibility reported by Dillon et al.34 does not affect FcRn function26. We have also recently generated a IgG variant lacking Fc-receptor effector functions by engrafting IgG2- and IgG4-derived amino acids onto IgG1 (Δnab35), which still binds FcRn” (p. 2 ¶2).
Stavenhagen et. al. teaches Fc variant regions that stimulate increased effector cell function by increased FcR interaction, including the variant Fc V282M which increases ADCC by 1.28 fold relative to control (Table 8). Stavenhagen teaches that the Fc may be any IgG subclass including IgG2 [0246].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify the anti-PSCA scFv-Fc IgG2 and method of imaging a cancer cell in vivo of modified ‘919 as described above with the H310A/H435Q mutations in order to improve the anti-PSCA scFv-Fc for imaging by improving the blood clearance and tumor to nontarget ratios as taught by Kenanova et. al. and with the V228M mutations in order to increase ADCC against the tumor target antigen PSCA as taught by Stavenhagen et. al. As shown below, making these mutations in the sequence of modified ‘919 as taught above would result in an scFv sequence 100% identical to the instant SEQ ID NO: 3:
RESULT 1
AASEQ2_06242026_132321
Query Match 100.0%; Score 2440; DB 1; Length 456;
Best Local Similarity 100.0%;
Matches 456; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSGGGGSGGG 120
Qy 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKL 180
Qy 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECPPCP 240
Qy 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKP 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKP 300
Qy 301 REEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 REEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL 360
Qy 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 420
Qy 421 VDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
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Db 421 VDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
This would have a predictable effect because Stapleton et. al. teach that IgG1 and IgG2 Fc domains have conserved FcRn binding, and therefore an artisan would expect that modifying the IgG2 Fc domain of Wu et. al. in view of Li et. al. would have the same effect on pharmacokinetics as that of the IgG1 Fc domain of Kenanova et. al. and Stavenhagen teaches that the ADCC mutations may be in any desired IgG backbone.
Double Patenting- Maintained, changes necessitated by amendment
Claim 1, 8-11, 35-39, and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 11-14, 24-26, 30-32 of copending Application No. 19154999 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '999 application anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 the ‘999 application teaches an engineered anti-PSCA scFv-Fc fusion protein comprising two peptides which form a homodimer, wherein each peptide comprises variable domains VH and VL of an anti-PSCA antibody and a truncated hinge and Fc region, wherein the variable domains are arranged in the order of VH-VL and wherein the FcRn binding region of the Fc region comprises one or more first point mutations. Claim 2 recites wherein the VH and VL are connected by a glycine-rich linker. Claim 4 recites wherein the linker has a sequence of SEQ ID NO: 1, which is identical to instant SEQ ID NO: 1. Claims 5 and 6 narrow the point mutations to those that reduce hematological toxicity and recites that the mutations may be H310A, H435Q, or both. Claim 9 recites wherein the truncated hinge is derived from IgG2. Claim 10 recites the fusion protein wherein the fusion protein has an amino acid sequence at least 80% identical to SEQ ID NO: 2, 3, or 5 (SEQ ID NO: 2 is 100% identical to instant SEQ ID NO: 2; the others are unclear because ‘999 application SEQ ID NOs: 3 and 5 are nucleic acid sequences). Claim 11 recites where the scFv-Fc fusion protein is conjugated to an effector moiety; claim 12 recites wherein the effector moiety includes a labeling moiety and/or a therapeutic moiety. Claim 13 recites wherein the labeling moiety comprises one or more radioactive or fluorescent labels. Claim 14 recites wherein the therapeutic moiety includes a cytotoxic agent, and anti-tumor drug, a toxin, a radioactive agent, a cytokine, a second protein, an antibody, a radionuclide, or an enzyme. Claim 24 recites a method of detecting cancer expressing PSCA in a subject, comprising administering one of more scFv-Fc fusion proteins, measuring the level of the scFv-Fc fusion protein in the subject, wherein an elevated level of the scFv-Fc fusion protein in the subject indicates the presence of cancer (reads on imaging a cancer cell in vivo). Claims 25 and 26 recite wherein the scFv-Fc fusion protein is conjugated with a labeling moiety, and wherein the labeling moiety comprises one or more radioactive isotopes. Claim 30 recites a method of imaging a cancer expressing PSCA in a subject comprising administering the scFv-Fc fusion proteins and imaging the subject. Claims 31 and 32 recite wherein a labeling moiety wherein the labeling moiety is one or more radioactive isotopes.
Response to Arguments
The Remarks filed 4/30/2026 have been fully considered. Applicant argues that none of the NSDP rejections the six references (Wu, Kufer, Weatherill, Li, Kenanova, and Stapleton) cited in the Non-Final rejection because none of them disclose a peptide having an amino acid sequence comprising SEQ ID NO: 2 or 3 (p. 11-12). This argument is moot because of the new rejection including Pfizenmaier, and Stavenhagen, as described above, which make obvious the missing limitations as described. The new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Regarding co-pending application ‘999, the Examiner notes that the NSDP rejection was an anticipatory-style NSDP rejection and did not rely on any of the references cited; therefore, this rejection is maintained.
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 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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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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