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 .
Claim Status
Claims 1, 2, 4, 6-11, and 31-41 are pending and under examination in the instant office action.
Drawings
The drawings are objected to because the brief description of the drawings contains references to color for . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The examiner suggests obviating the objection by either filing a petition for color drawings (as described in the Drawings section) or by amending the specification to remove the references to color in the drawings (as described in the Specification section, below). In the Brief Description of the Drawings see: [0012] “blue dots”.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because of the following informalities: the brief description of the drawings contains references to color for Fig. .
The examiner suggests obviating the objection by either filing a petition for color drawings (as described in the Drawings section, above) or by amending the specification to remove the references to color in the drawings. In the Brief Description of the Drawings see: [0012] “blue dots”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1, 2, 4, 6-11, and 31-41 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.
Claims 1, 31, and 38 are indefinite for the recitation of “position 310” and “position 435” without additional identifying sequence or numbering features. It is unclear whether these positions refer to the SEQ ID NOs: 2 and 3 recited in the dependent claims or an art-known antibody numbering system. For the purposes of expedited prosecution, the histidine at position 310 and the histidine at position 435 will be interpreted as according to EU numbering of the Fc domain.
Claims 1, 31, and 38 are indefinite for the parenthetical “(H435Q)” because the claim recites “replacing a second histidine residue at position 435” but does not recite replacement with glutamine (Q), and therefore it is unclear whether the scope of the parenthetical is required by the claim. The examiner suggests amending the claims to recite “replacing a second histidine residue with glutamine at position 435 (H435Q)”.
Claims 1, 31, and 38 are indefinite for the recitation of “wherein the variable domains are arranged in the order of VH-VL”. The claim is indefinite because neither the claim nor the specification defines the order in reference to what. Is it N-terminus to C-terminus? C-terminus to N-terminus? It is unclear.
Claim 6 is indefinite for the recitation of “derived from human IgG2”. The term “derived from” is not one, which has a universally accepted meaning in the art nor is it one which has been adequately described in the specification. The primary deficiency in the use of this phrase is the absence of an ascertainable meaning for said term. Two species of derivatives in SEQ ID NO: 2 and SEQ ID NO: 3 are disclosed [0005], but this is not defined as a closed group. Since it is unclear how IgG2 is to be derivatized to yield the class of molecules referred to in the claims, a person of skill in the art cannot describe the metes and bounds of a discrete and identifiable class of molecules to these claims.
Regarding claim 39, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 39, the recitation of “the detectable marker comprises […] haptens or proteins which can be made detectable” is indefinite because it is unclear how the hapten or protein “which can be made detectable” is a detectable marker if it must be made detectable in the future or it is not already a detectable marker. An artisan would not be apprised of the metes and bounds because claims 38 and 39 already require the marker to be detectable; how then does “can be made detectable” further limit the claim?
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 1, 31, and 38, the claims recite an “anti-PSCA” scFv-Fc fusion protein with no additional structure disclosed for the antigen-binding determinant region, but the art and genus of known species does not allow for predictable binding to PSCA. Additionally, the claims recite a “truncated hinge” with no additional structure of what is to be truncated.
Claims 7, 33, 34, 40, and 41 recites either 90% identity SEQ ID NO: 2 or 3, or for comprising one or more CDR regions selected from those in SEQ ID NO: 2 or 3, which allow for changes to the CDR within the VH and VL of the antibody which is the binding determinant region, and therefore do not sufficiently narrow claims 1, 31, and 38.
Claims 2, 4, 6, 8-11, 32, 35-37, and 39 are ultimately dependent on claims 1, 31, and 38 without narrowing the binding determinant region.
Scope of the claimed genus
Claims 1 and 31 are directed at an anti-PSCA scFv-Fc protein comprising any VH and VL arranged in the order of VH-VL, any truncated hinge, and any Fc region comprising two point mutations replacing a first histidine residue with alanine at position 310 and a second histidine at position 435. Claim 1 requires that the fusion protein comprising two peptide which form a homodimer. Claim 31 requires the VH-VL are connected by a glycine rich linker and that the Fc region is an IgG2 Fc region.
Claim 38 recites a method of imaging a cancer cell in vivo comprising administering an anti-PSCA scFv-Fc protein comprising any VH and VL arranged in the order of VH-VL, any truncated hinge, and any Fc region comprising two point mutations replacing a first histidine residue with alanine at position 310 and a second histidine at position 435, wherein the VH-VL are connected by a glycine rich linker and the Fc region is an IgG2 Fc region; and imaging the recombinant anti-PSCA scFv-Fc fusion protein in vivo.
Dependent claims 7, 34, and 41 narrow the claims to anti-PSCA fusion proteins having an amino acid sequence at least 80% identical to SEQ ID NO: 2 or SEQ ID NO: 3.
Dependent claims 33 and 40 narrow the claims to fusion proteins comprising one or more CDR regions selected from those found in SEQ ID NO: 2 or SEQ ID NO: 3.
However, none of the claims narrow sufficiently to claim 6 particular VH and VL CDRs that would recite an anti-PSCA binding determinant region or a particular truncated hinge.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “at least 80% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 80% identity to the anti-PSCA fusion proteins of SEQ ID NO: 2 or SEQ ID NO: 3 would allow 91 amino acid changes, which allows for complete exchange of all 6 heavy and light chain CDRs. For example, U.S. Patent No. 10793632 teaches an anti-PD-L1 scFv-Fc heavy chain of SEQ ID NO: 27561 which is 85.7% identical to instant SEQ ID NO: 2:
OTHER INFORMATION: XENP021832 GSK_314.8[ICOS]_H0L0
_Fab-YW243.55.S70[PD-L1]_H0L0_scFv scFv-Fc Heavy Chain
Query Match 85.7%; Score 2096.5; Length 471;
Best Local Similarity 84.9%;
Matches 400; Conservative 16; Mismatches 40; Indels 15; Gaps 4;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
||||||||||||||||||||||||||| | :|||||||||||||||||| | | : :
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCK----TGGF--WGRGTLVTVSSGG 114
:|| |:|||||||||||||||||||||||||| ||| ||:||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSGG 120
Qy 115 GGSGGGGSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSV-RFIHWYQQKPGKAPKRL 173
|||||||||| |||:||||||||||||||||||| || | : ||||||||||| |
Db 121 GGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLL 180
Qy 174 IYDTSKLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIK 233
|| | | |||||||||||||||||||||||||||||||||||: | |||||||||||
Db 181 IYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIK 240
Qy 234 V--------ECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFN 285
|||||||||||||||||||||||||||||||||||||||| ||||||:||
Db 241 EPKSSDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFN 300
Qy 286 WYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTI 345
|||||:|||||||||||||:|||:||||||||:||||||||||||||||| |||||||||
Db 301 WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI 360
Qy 346 SKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 405
|| |||||||||||||||||:|||||| ||||||||||||||||||||||||||||||||
Db 361 SKAKGQPREPQVYTLPPSREQMTKNQVKLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 420
Qy 406 MLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 456
:||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 471
In regards to anti-PSCA antibodies, other anti-PSCA antigen binding sites are known in the art. For example, U.S. 20140134155 to Bachmann teaches an anti-PSCA VH and VL of SEQ ID NO: 24 and SEQ ID NO: 26, which comprise structurally distinct CDRs forming the antigen binding site from the instant anti-PSCA antibody:
Variable heavy chain CDRs compared between instant CDRs and SEQ ID NO: 26
RESULT 1
AASEQ2_11242025_114343
Query Match 62.0%; Score 373; DB 1; Length 122;
Best Local Similarity 59.8%;
Matches 73; Conservative 15; Mismatches 24; Indels 10; Gaps 1;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
:|||||||||||:|||||||||||||| | : |:|||||||||||::|: | : :
Db 1 QVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMSWIRQAPGKGLEWVSYINDSGGSTFY 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGF----------WGRGTLVTV 110
:|| |:| | :||: ||||||||||||||||| : ||:|| |||
Db 61 PDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRMYYGNSHWHFDVWGQGTTVTV 120
Qy 111 SS 112
||
Db 121 SS 122
Variable light chain CDRs compared between instant CDRs and SEQ ID NO: 24
RESULT 1
AASEQ2_11242025_114957
Query Match 73.8%; Score 407.5; DB 1; Length 107;
Best Local Similarity 74.5%;
Matches 79; Conservative 11; Mismatches 15; Indels 1; Gaps 1;
Qy 1 DIQLTQSPSSLSASVGDRVTITCSASSSV-RFIHWYQQKPGKAPKRLIYDTSKLASGVPS 59
|||:||||||||||||||||||| | : :::|||||||| || ||| ||:| |||||
Db 1 DIQMTQSPSSLSASVGDRVTITCGTSQDINNYLNWYQQKPGKVPKLLIYYTSRLHSGVPS 60
Qy 60 RFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEI 105
|||||||||||||||||||||| ||||||| : |:||| ||:: :
Db 61 RFSGSGSGTDFTLTISSLQPEDVATYYCQQSKTLPWTFGGGTQLTV 106
Thus, the state of the art would not allow an artisan to envision at once from the claims all CDRs that would bind to PSCA, or bind to PSCA with only one of the VH and VL CDRs and any other CDR, or all anti-PSCA antibodies with 80% identity to the scFv-Fc of SEQ ID NOs: 2 or 3 with complete exchange of the anti-PSCA binding determinant CDRs.
Summary of Species disclosed in the original specification
The instant specification discloses two species of homodimeric anti-PSCA scFv-Fc fusion proteins, each comprising identical scFvs of the anti-PSCA antibody “A2”; the only difference between the species is the presence or absence of the H310A and H435Q mutations by EU numbering in the Fc domain (referred to as “double mutant” or “DM”) and the same truncated hinge of residues 6-20 of SEQ ID NO: 5. There are no alternate anti-PSCA binding domains, truncated hinges, or Fc domains.
Regarding methods of imaging a cancer cell in vivo, the instant specification administers both of the anti-scFv-Fc species and demonstrates that they can be detected in PSCA-specific tumors (Examples 7 and 8).
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants of all generic, unspecified anti-PSCA scFv-fusion with any binding determinant region or any unspecified truncated hinge.
Are the disclosed species representative of the claimed genus?
MPEP 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The instant specification discloses one species of anti-PSCA antigen binding domain and two species of scFv-Fc anti-PSCA fusion proteins and one truncated hinge comprising residues 6-20 of SEQ ID NO: 5. Given the breadth of the genus potentially encompassing millions of generic anti-PSCA antibodies or thousands with mix-and-match CDRs with by or more CDRs of the described species, an artisan would not understand the applicant to be in possession of the entire genus from the instant examples.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by the disclosure of relevant, identifying characteristics (i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or discloses correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet the requirement in the instant case, the specification must describe structural features that the skill artisan, as of the effective filing date, would have expected to convey the claimed activity.
As noted above, the art identifies the CDRs as determining the binding of an antibody. The specification only discloses a single species of an anti-PSCA binding determinant regions comprising 6 CDRs. The art teaches that the binding of the anti-PSCA antibody would be unpredictable. There are no alternate CDRs or CDR residues disclosed. Therefore, there is insufficient structure/function correlation to define a genus of anti-PSCA scFv-Fc fusion proteins.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein PSCA. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; and iii) disrupt protein target binding; additionally, there is a lack of an appropriate number of alternate hinges or alternate truncations to demonstrate which residues are key to truncate in any hinge. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1, 31, and 38 at the time of filing. Regarding claims 2, 4, 6-11, 32-37, and 39-41 the claims are ultimately dependent on the rejected claims 1, 31, and 38 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
Claims 38-41 are rejected 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. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application.
Scope of the claims and the nature of the invention
Claim 38 is directed towards a method of imaging any generic, singular, cancer cell in vivo comprising administering a recombinant anti-PSCA scFv-Fc fusion protein to a subject and imaging the recombinant anti-PSCA scFv-Fc fusion protein in vivo. As described in the written description rejection above, the anti-PSCA scFv-Fc fusion proteins encompass an entire genus of potentially millions of anti-PSCA binding regions which have not been described. Dependent claims do not further limit the scope of the method beyond any singular, generic cancer cell.
State of the relevant art; level of one of ordinary skill; and the level of predictability in the art
Methods of in vivo imaging of tumors that express tumor-specific antigen using antibodies are well described in the art. Warram, J.M., de Boer, E., Sorace, A.G. et al. Antibody-based imaging strategies for cancer. Cancer Metastasis Rev 33, 809–822 (2014). https://doi.org/10.1007/s10555-014-9505-5 teaches that repurposing of therapeutic antibodies for antibody-based imaging is advantageous because of the known pharmacokinetic, biodistribution, and side effect profile (p 809 right column). Warram et. al. teaches that “almost any kind of imaging probe can be linked to antibodies” (p. 810 left column, Fig. 2). Warram et. al. teaches that strategies for imaging the tumor include using antibodies directed to ligands that are overexpressed by the tumor or antibodies to molecular targets that are resident within the tumor (p. 811 right column). Thus, an artisan would understand that a particular expression level of the target antigen in the tumor is required.
Methods of in vivo imaging of cancer using anti-PSCA antibodies is also known in the art. Tove, Olafsen et. al. Targeting, Imaging, and Therapy Using a Humanized Antiprostate Stem Cell Antigen (PSCA) Antibody. Journal of Immunotherapy 30(4):p 396-405, May 2007 teaches that a prostate specific marker highly suitable for antibody-based therapy is PSCA because it is expressed in most prostate cancer patients and PSCA expression is correlated with tumor stage, grade and progression to androgen independence (p. 397, left column, ¶2). Tove et. al. teaches a humanized version of a murine 1G8 anti-PSCA antibody conjugated to a radiolabel, which were imaging by microPET in mice with palpable tumors expressing PSCA. The tumors with PSCA+ expression were able to be seen in the microPET scans and were treated by the administration of the antibody (Fig. 3, p. 401-403). WO2007108321 to Wu et. al. published 27 September 2007 (Of record, IDS dated 7/10/2023) teaches methods of imaging cancer with anti-PSCA antibodies that are scFv-Fc fusions or minibodies (scFv-CH3 fusions) for prostate, bladder, and pancreatic cancer (Abstract, [0008]). Wu et. al. also teaches administering the antibody to diagnose whether or not PSCA protein is overexpressed [0010].
Thus, although the state of the art, predictability, and level of ordinary skill in the art allow a wide breadth of imaging techniques and detectable markers coupled with antibodies for in vivo imaging, there is no evidence in the art of imaging non-PSCA expressing tumors or of imaging a singular cancer cell.
Summary of species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification discloses a method of administering to mice in vivo two species of anti-PSCA scFv-Fc fusion proteins with the same antigen-binding domain, homodimers of SEQ ID NO: 2 and 3 (Example 7 and 8). The species are both conjugated with 89Zr radionuclide and administered to nude mice with PSCA-expressing xenografts using PET scan (Example 7 and 8). Example 8 describes that the mice bore bilateral RM9 and RM9-PSCA tumors and that the scFv-Fc were specific for the PSCA tumors [0092]. There is no evidence of record of imaging a single cancer cell, or imaging a cancer that does not express the same target antigen (PSCA) as that bound by the antibody.
Conclusion
The applicant does not have enablement for the complete scope of the method for imaging cancer in vivo comprising imaging a single cancer cell or any generic cancer that does not express PSCA.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 2, 6-11, 31, 33-34 and 35-41 are rejected 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.
Regarding claims 1, 31, and 38, Wu et. al. teaches “In a first embodiment, the invention provides a humanized antibody fragment which specifically binds to PSCA on the surface of cancer cells. Examples of antibody fragments of this invention include a scFv, a scFv dimer (diabody), a sc-Fv-CH3 dimer (minibody), and a scFv-Fc, in which the antibody fragment comprises sequences of the variable light chain (VL) and variable heavy chain (VH) regions as shown in Figure 1. In aspects of this embodiment, the scFv dimer can include two scFv monomers joined by a linker” ([0009], Fig. 7a, Fig. 11); the two monomers are joined to form a dimer ([0065], reads on two peptides form a homodimer). The scFv comprises a VH and VL ([0009-0011], [0065], Example 1, [0098]). Wu et. al. teaches that the fusion protein is preferably with an immunoglobulin heavy chain constant domain comprising at least part of the hinge, CH2, and CH3 regions [0075].
Regarding claims 2, 31, and 38, Wu et. al. teaches the anti-PSCA scFv comprises the VH and VL connected by a (GGGS)2 linker or “a 10 residue Gly-Ser peptide linker” (reads on glycine-rich, [0009], [0061], [0072], Example 1, [0098]).
Regarding claims 8, 9, 10, 35, 36, and 39 Wu et. al. teaches that the antibodies of the invention are compositions comprising anti-PSCA fragments and a radionuclide coupled together useful for therapeutic, imaging, diagnostic, or prognostic purposes ([0048-0049] (reads on conjugated to an effector moiety, claim 8; labeling moiety or therapeutic moiety, claims 9 and 35; and radionuclide read on radioactive label, claims 10, 36, and 39).
Regarding claims 38 and 39, Wu et. al. teaches a method of diagnosing a cancer that overexpresses cell surface PSCA comprising administering to a subject a humanized antibody fragment which specifically binds to PSCA on the surface of cancer cells, in which the antibody fragment can be an scFv-Fc and determining whether or not PSCA protein is overexpressed in the subject using molecule in vivo imaging [0010] (reads on imaging a cancer cell in vivo, and a detectable marker, imaging the recombinant anti-PSCA scFv-Fc fusion protein in vivo). The anti-PSCA fragment is linked to a detectable moiety including a radionuclide, a nanoparticle, a fluorescent dye, a fluorescent marker, or an enzyme [0011] (emphasis is the examiner’s).
Wu et. al. does not explicitly teach the variable domain are arranged in the order of VH-VL.
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 SEQ ID NO: are 100% identical to the anti-PSCA VH and VL of Wu et. al. Fig. 1:
scFv of Kufer et. al. compared to VH of Wu Fig. 1
RESULT 1
AASEQ2_11262025_122839
Query Match 48.7%; Score 601; DB 1; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEF 60
Qy 61 VPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS 112
scFv of Kufer et. al. compared to VL of Wu Fig. 1
RESULT 1
AASEQ2_11262025_123356
Query Match 44.5%; Score 550; DB 1; Length 106;
Best Local Similarity 100.0%;
Matches 106; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 128 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 187
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 60
Qy 188 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIK 233
||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIK 106
Kufer et. al. teaches “In the bispecific single chain antibody molecule of the invention the binding domains are arranged in the order VL-VH-VH-VL, VL-VH-VL-VH, VH-VL-VH-VL or VH-VL-VL-VH, as exemplified in the appended examples. Preferably, the binding domains are arranged in the order VH PSCA-VL PSCA-VH CD3-VL CD3 or VL PSCA-VH PSCA-VH CD3-VL CD3” ([0175], emphasis is the examiner’s). Kufer et. al. teaches that the anti-PSCA scFv binds to human-PSCA transfected CHO cells (e.g. Fig. 46A) and was effective for stimulating anti-PSCA activity of human PBMCs (e.g. Fig. 47A).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to arrange the order of the variable domains VH-VL in order to benefit the anti-PSCA VH-VL scFv of Wu et. al. binding to PSCA effectively in the VH-VL orientation as taught by Kufer et. al. This would have a predictable effect because an artisan would expect the pairing of the VH and VL to be determinant of binding to the PSCA target and stability, rather than orientation, for a known anti-PSCA antibody, as taught by Weatherill for the majority of tested scFvs and because Kufer et. al. demonstrates that this orientation is effective for binding.
Wu et. al. does not explicitly teach that the hinge is truncated.
This deficiency is 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 ¶).
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. 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 et. al. in view of Li et. al. does not teach that the anti-PSCA scFv-Fc fragment comprising the protease resistant truncated IgG2 hinge and Fc domain comprises H310A and H435Q mutations (as numbered by EU numbering, see 112(b) above).
This deficiency is resolved by Kenanova et. al. and Stapleton 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).
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 Wu et. al. in view of Li et. al. 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. 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.
Regarding claims 6, 31, and 38, the truncated hinge and Fc region of Li et. al. and therefore modified Wu et. al. is modified from human IgG2 (Abstract), see above.
Additionally, as described above, Kenanova et. al. teaches 125I and 131I-labeled scFv-Fc fragment comprising the H310A and H435Q mutations.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to conjugate the modified Wu et. al. with an effector moiety such as a radionuclide for imaging, diagnostic, or prognostic purposes as taught by Wu et. al. and Kenanova et. al. This would have a predictable effect because modified Wu et. al. and Kenanova et. al. both teach the use of scFv-Fc fragments for imaging tumors expressing and target tumor antigen.
Regarding claim 11 and 37, Wu et. al. teaches the anti-PSCA fragments conjugated to therapeutic effectors used in therapeutic applications such as drug carriers to deliver chemotherapeutic agents, radiotherapeutics agents, or any other cytotoxic or anti-cancer agent ([0050], [0066], [0076]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to conjugate an effector moiety comprising a cytotoxic agent to the anti-PSCA of modified Wu et. al. in view of Li et. al., Kenanova et. al., and Stapleton et. al. in order to benefit from the delivery of a cytotoxic drug to a PSCA-positive tumor as taught by Wu et. al.
Regarding claims 7, 33, 34, 40, and 41 Wu et. al. teaches a particular embodiment of a minibody comprising an anti-PSCA scFv with the particular VH and VL sequence with the linker GGGSGGGSGGGGSS (Fig. 1). As described above, it would have been obvious to create an anti-PSCA scFv-Fc comprising the scFv in VH-VL order of Wu et. al. fused to the IgG2 region of Li et. al. This would result in a sequence, shown below, fusing a VH-VL scFv as made obvious by Wu et. al. with the hinge-CH2-CH3 region sequences of Li et. al. The CDRs of the VH and VL of Wu et. al. are identical to instant CDRH-1, CDRH-3, CDRL-1 and CDRL-2 as shown below, underlined (reads on claims 33 and 40). This resulting scFv-Fc fusion is 96.9% identical to instant SEQ ID NO: 2 and 97.4% identical to SEQ ID NO: 3 once the H310A and H435Q mutations, made obvious by Kenanova et. al., are made in the Fc sequence as described above.
RESULT 1
AASEQ2_11242025_154408
Query Match 97.4%; Score 2376.5; DB 1; Length 459;
Best Local Similarity 96.9%;
Matches 445; Conservative 5; Mismatches 6; Indels 3; Gaps 1;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEF 60
|||||||||||||||||||||||||||||||||||||||||||||||||||||| ||:||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEF 60
Qy 61 VPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSSG---GGGS 117
|||||||||:|||||||||||||||||||||||||||||||||:||||||||| ||||
Db 61 VPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSGSTSGGGS 120
Qy 118 GGGGSGGSAQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDT 177
||| || : ||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGGSGGGGSSDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDT 180
Qy 178 SKLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKVECP 237
|||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||
Db 181 SKLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIKVECP 240
Qy 238 PCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAK 297
|||||||||||||||||||||||||||||||||||||||||||||||||||||:||||||
Db 241 PCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAK 300
Qy 298 TKPREEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQV 357
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TKPREEQFNSTFRVVSVLTVVAQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQV 360
Qy 358 YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYS 417
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYS 420
Qy 418 KLTVDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 456
|||||||||||||||||||||||||||||||||||||||
Db 421 KLTVDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK 459
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the sequence of the VH and VL of an anti-PSCA antibody as taught by Wu et. al. linked by a particular glycine-rich linker sequence as taught by Wu et. al. fused to a hinge-CH2-CH3 Fc region encoded by the particular Fc sequence as taught by Li et. al. in order to make a particular embodiment of the anti-PSCA scFv-Fc fusion protein and the method of imaging cancer comprising the anti-PSCA scFv-Fc fusion protein of Wu et. al., Li et. al., Kenanova et. al., and Stapleton et. al. as taught above. This would have a predictable effect because as artisan would use the particular protein sequences taught by the prior art in order to make the particular embodiments and to obtain the benefits of the anti-PSCA scFv-Fc fusion described above.
Claim(s) 4 and 32 are rejected 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.
The teachings of Wu et. al., Li et. al., Kenanova et. al., and Stapleton et. al. in regards to claims 1 and 31 are in the 103 rejection above.
In regards to VH-VL linkers, Wu et. al. teaches “In aspects of this embodiment, the scFv dimer can include two scFv monomers joined by a linker. Suitable linkers include peptide sequences, of which, the sequence [(GGGS).sub.2] is an advantageous example” [0009]. Wu et. al. teaches that the linker joining the VH and VL allows for proper binding and creation of an active binding site [0061]. Wu et. al. teaches that the VH and VL linkers can be preferably no more than 20 amino acids in length, and is in some embodiments a concatemer of GGGS in which amino acid substitutions can be made [0072].
Kenanova et. al. teaches the anti-CEA scFv fragment comprises a glycine-rich linker “GSTGGGSGGGSGGGGSS” (Fig. 1).
Wu et. al., Li et. al., Kenanova et. al., and Stapleton et. al. do not teach the anti-PSCA scFv-Fc with a truncated hinge and H310A/H435Q mutations wherein the glycine-rich linker has the sequence of SEQ ID NO: 1. Regarding claims 4 and