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 .
Priority
The instant application, filed 10/14/2022, claims domestic benefit to US provisional applications 63/370,895 and 63/256,410, filed 08/09/2022 and 10/15/2021, respectively.
Claim Status
The amendment, filed on 06/07/2023, in which claims 6-7, 10, 12-14, 18, 20, 23-24, 26, 30-33, 36-41, 44, 47-50, 52-55, 57, 60-61, and 63 are amended; and claims 15-17, 21-22, 34-35, 42-43, 45-46, 51, and 63-65 are canceled, is acknowledged.
Claims 1-14, 18-20, 23-33, 36-41, 44, 47-50, and 52-63 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed 06/30/2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. References EP-0463131-A1 (FP58), EP-0546073-A1 (FP59), and NPL79 (ISR corresponding to PCT/EP2016/068319) have been placed in the application file, but the references have been lined through and the information referred to therein has not been considered.
The information disclosure statement filed 06/30/2023 also fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. References EP-0058481-B1 (FP48), JP-3068180-B2 (FP63), JP-3068506-B2 (FP64), and JP-3068507-B2 (FP65) have been placed in the application file, but the references have been lined through and information referred to therein has not been considered.
Applicant is notified that references have been uploaded which are not cited in the IDS filed (EP-0133988-A2 and WO-199110741-A1). Unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Applicant is further notified of references that have duplicate citations: NPL30 is duplicated as NPL33 [WIKSTRAND et al., Cancer Res., 55(14): 3140-3148 (1995)]; NPL35 is duplicated as NPL41 [URLAUB et al., Proc. Natl. Acad. Sci. USA. 77: 4216-20 (1980)]; and NPL36 is duplicated as NPL77 [TOMLINSON et al., EMBO J. 14: 4628-4638 (1995)]. References, where duplicated, have been lined through on the IDS.
All other references, where not lined through, have been considered by the examiner.
Specification
The use of the term “Alexa Fluor” (¶ [0216] and [0235]), “Graphpad Prism” (¶ [0217], [0218], and [0235]), “Glutamax” (¶ [0222], [0224], and [0239]), “MACSQuant” (¶ [0235]), “U-PLEX” (¶ [0238]), “WinNonlin” (¶ [0240]), which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 39 is objected to because the claim recites “selected from the group of proteases as shown in Table 2” where Table 2 instead lists “Cleavable Moieties” (page 32). Applicant is also notified that incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (See MPEP § 2173.05(s). Appropriate correction is required.
For examination purposes, examiner has assumed that “group of proteases shown in Table 2” should read “group of cleavable moieties shown in Table 2.”
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, 6-10, 12-14 18-20, 23, 26-28, 30-33, 36-41, 44, and 47-49 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/075405 A1 (herein Boustany; published 04/18/2019) in view of WO 2018/045110 A1 (herein Bernett) and Xenaki (Front Immunol. 2017;8:1287), and as evidenced by US 11,046,759 B2 (herein Moore).
Regarding claim 1, Boustany teaches an activatable anti-EGFR, anti-CD3 heteromultimeric bispecific polypeptide complex (HBPC) (FIG. 17 (shown below); FIG. 18 ‘CI107’, and FIG. 19 ‘CI106’) an anti-EGFR IgG antibody (divalent double-armed) that binds to first target (AB1; c225v5 - details in Table 6) with each light chain linked to masking moiety (MM) and cleavable moiety (CM) (CM1-MM1) and each heavy chain linked respectively to C-terminus of anti-CD3 scFv that bind second target (AB2; v16 - details in Table 1) with N-terminal MM-CM construct (CM2-MM2).
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Boustany does not teach a one-arm scFv-mAb.
Bernett teaches a one armed scFv-mAb (Figure 2D - shown below) wherein one monomer comprises just an Fc domain, another monomer comprises uses an scFv attached to N-terminus of the heavy chain such that the format from N- to C-terminus is as follows: VH1-scFv linker-VL1-[optional linker]-VH2-CH1-hinge-CH2-CH3 or (in the opposite orientation) VL1-scFv-linker-VH1-[optional linker]-VH2-CH1-hinge-CH2-CH3 (i.e. instant first polypeptide), and third monomer encodes an additional variable light chain and constant light domain that associates with the heavy chain to form a Fab (i.e. instant second polypeptide) (¶ [00443]).
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Xenaki teaches engineering smaller antibody fragments has been shown to improve the rate of tumor uptake and intratumoral distribution (abstract), but smaller antibody fragments (i.e. scFvs) exhibit shorter plasma half-lives because of their inability to bind FcRn (i.e. through intact IgG Fc domain) (page 4, column 2, ¶ 1).
One of ordinary skill in the art would recognize bispecific antibodies can be constructed in various formats depending on binding requirements and tumor characteristics. Therefore, one of ordinary skill in the art would recognize that the symmetrical anti-EGFR, anti-CD3 heteromultimeric bispecific polypeptide complex (HBPC) as taught by Boustany can be substituted for a non-symmetric single arm format as taught by Bernett and would be motivated to do so because Xenaki teaches that smaller constructs with intact IgG Fc domain would likely have better intratumoral penetration while maintaining longer circulatory half-life.
Regarding claim 2, the combined teachings of Boustany, Bernett, and Xenaki teach claim 1. Boustany further teaches antibodies or antigen binding fragments specific for CD3 epsilon (¶ [0063]).
Regarding claims 6-10, 12-14, 18-20, 23, 26, 31-33, 41, 44, 47-49, the combined teachings of Boustany, Bernett, and Xenaki teach claim 1. Boustany teaches amino acid and nucleic acid sequences for HBPC CI106 (CF41-2008-C225v5Fcmt4-h20GG-0011-v16sc-H-N) composed of (i) heavy chain vector pLW289 and (ii) light chain vector pLW246.
(i) Heavy chain vector pLW289 comprises structural arrangement analogous to instant claims first polypeptide: MM1-CM1-scFv-VH2-CH1-hinge region-Fc1, wherein MM1 domain, identical to instant SEQ ID NO:72, is linked via GS linker (i.e. “L1” identical to instant SEQ ID NO:12) to CM1, identical to SEQ ID NO:2 (annotated pLW289 amino acid sequence shown below). This vector further comprises an Fc1 domain that is 96% identical to instant SEQ ID NO:23 (see pairwise comparison below).
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pLW289 (Query) pairwise comparison with Instant SEQ ID NO:23 (Sbjct)
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(ii) Light chain vector pLW246 (annotated below; identical to instant SEQ ID NO:31) comprises structural arrangement of MM2-CM2-VL2, wherein sequences for MM2 and CM2 separated by GS linker (i.e. L2 identical to SEQ ID NO:127) are identical to instant SEQ ID NO: 13 and 14, respectively. Within this vector the CM2 domain is a substrate for at least one MMP and at least one serine protease as evidenced by Moore (column 186, lines 29-32; SEQ ID NO:485)
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Together, the heavy and light chain vectors shown above, form an EGFR binding domain (C225v5) with VH/VL identical with instant SEQ ID NO:21 and 22 (Table 6; SEQ ID NO:64 and 63 respectively) with CDRs identical to instant SEQ ID NOs: 15-20 (Table 5; SEQ ID NOs: 57-62, respectively).
Regarding claims 27-28 and 30, the combined teachings of Boustany, Bernett, and Xenaki teach claim 1. Bernett further teaches that for single-arm embodiments that comprise an Fc-only chain, this sequence comprises a format of hinge-CH2-CH3 (i.e. hinge-Fc2) (“Fc-only” fragments; Figure 68) and matching Fab-Fc HC fragment encode the same hinge amino acid sequence (identical to SEQ ID NO: 34).
Regarding claim 36-40, the combined teachings of Boustany, Bernett, and Xenaki teach claim 1. Within HBPC CI106 as taught by Boustany described above, CM1 (identical to instant SEQ ID NO:2) contains serine protease (e.g. u-PA and/or matriptase) substrate “LSGRSDDH” and CM2 (identical to instant SEQ ID NO:14) contains a substrate “ISSGLLSGRSDQH” that can be cleaved by both the same serine protease and different protease (e.g. MMP14) as evidenced by Moore (column 4, ¶ 3, SEQ ID NO:547; column 179, ¶ 1 (substrate proteolysis assay); column 186, example 5, SEQ ID NO:485). Such proteases are disclosed within the instant specification to be elevated within the tumor microenvironment (¶ [0137]).
Regarding claims 55-63, the combined teachings of Boustany, Bernett, and Xenaki teach claim 1. Boustany further teaches nucleic acid sequences, vector construction, and expression within mammalian cells for antibody production via recovery from supernatant (Example 1). Boustany also teaches that the bispecific antibody can be incorporated into pharmaceutical compositions which comprise a pharmaceutically acceptable carrier (¶ [0216]-[0217]), utilized within kits (¶ [0240]-[0245]). Boustany teaches the HBPC reduces human xenograft tumor growth in mouse models (Figures 4-5), suggesting HBPC effectiveness of treating cancer in humans.
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Boustany, Bernett, and Xenaki as applied to claim 1 above, and further in view of WO 2008/119567 A2 (herein Ebert).
The combined teachings of Boustany, Bernett, and Xenaki teach claim 1 as discussed above. However, none of these references teach a CD3 scFv with the amino acid sequences (CDRs/VH/VL) as claimed.
Ebert teaches a CD3 scFv (SEQ ID NO:185 [Db]) with identical CDRs and VH/VL domains identical to instant SEQ ID NOs: 3-10, respectively (see alignment with instant CD3 scFv SEQ ID NO:11 [Qy]; CDRs highlighted).
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One of ordinary skill in the art would recognize that the modular nature of bispecific antibodies and would recognize that domains can be swapped depending on targeting requirements. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the CD3 scFv as taught by Boustany can be substituted with a known CD3 scFv as taught by Ebert with a reasonable expectation of success.
Claims 11 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Boustany, Bernett, and Xenaki as applied to claim 1 above, and further in view of Yang (Front Immunol. 2018;8:1860).
The combined teachings of Boustany, Bernett, and Xenaki teach claim 10 as discussed above.
Boustany further teaches variant Fc domains can also be selected for use with the HBPC as disclosed above to reduce effector function (¶ [0098]). Boustany teaches variant with residues L234, L235, P331, and variable residue (X) at N297 (e.g. SEQ ID NO:154 - aligned with SEQ ID NO:23 and ) (¶ [0100]-[0101], Table 4-2). Boustany teaches that X could be any naturally occurring amino acid including glycine (¶ [0101]) as disclosed in instant Fc1 (SEQ ID NO:23).
Bernett further teaches the Fc domains of mAb-scFv format generally comprise heterodimeric skew variant (¶ [00317]). These variants are generally sets of paired amino acid residues, wherein one set is incorporated into the first monomer (i.e. Fc1) and the other set of the pair is incorporated into the second monomer (i.e. Fc2) and the interface formed between these sets (i.e. where one monomer binds to the other) encourages heterodimer formation and discourages homodimer formation (¶ [00231]). Bernett teaches am Fc variant set with one Fc monomer with K392D/K409D and the second monomer with E356K/D399K (Figure 4C, first row), which are identical to the mutations utilized in instant Fc domains from the third polypeptide (SEQ ID NO:28) and first polypeptide (SEQ ID NO:23) in comparison with homodimer Fc domain as described by Boustany (SEQ ID NO: 154) (see alignments below; skew variants indicated with arrowheads).
However, neither Boustany, Bernett, nor Xenaki explicitly disclose R292C, N297G, and R302C (highlighted in alignments below) mutations in the Fc domain as disclosed in instant Fc domain sequences (SEQ ID NOs:23 and 28).
Yang teaches R292C, N297G, and R302C mutations in IgG1 Fc improves stability, decreases rate of clearance, and increases molecular half-life in in vivo models (page 6, column 1, ¶ 1).
Instant Fc1 (SEQ ID NO:23) aligned with Boustany Fc variant (SEQ ID NO:154)
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Instant Fc2 (SEQ ID NO:28) aligned with Boustany Fc variant (SEQ ID NO:154)
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One of ordinary skill in the art would recognize the Fc domains can be changed/mutated to facilitate proper formation of heterodimeric constructs with increased stability. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that effector function mutations as taught by Boustany in constructs described above can be substituted for known native residues (e.g. L234, L235, P331). Furthermore, it would be obvious to one of ordinary skill that incorporating Fc domain skew variants as taught by Bernett would ensure proper heterodimer formation of single-armed scFv-mab and addition of mutations as taught by Yang would predictably improve construct stability.
Claim 29 are rejected under 35 U.S.C. 103 as being unpatentable over Boustany, Bernett, and Xenaki as applied to claim 27 above, and further in view of Rayner (J Biol Chem. 2015;290(13):8420-8438).
The combined teachings of Boustany, Bernett, and Xenaki teach claim 27 (first and third polypeptide comprise and immunoglobin hinge region) as discussed above.
However, none of the references discuss different amino acid sequences for respective hinge domains (i.e. hinge sequence for Fc1 is different from hinge sequence for Fc2).
Rayner teaches the hinge domain as a three-part structure: (1) the upper hinge, which determines arrangement of the two Fab regions and mediates flexibility and reorientations of each Fab arm, (2) the middle hinge (or core) wherein two cysteine residues (Cys226 and Cys229) form interchain disulfide bonds between respective Fc pair, and (3) the lower hinge responsible for the flexibility and positioning of the Fc region and interactions with Fc receptors.
One of ordinary skill in the art would recognize that in a polypeptide of Fc only domain (i.e. third polypeptide of the instant HBPC), that an upper hinge domain would likely be superfluous, and that so long as the hinge core and lower hinge remain intact proper interactions with partner hinge would be possible. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that Fc domains on a single arm activatable scFv-mAb as taught by the combined teachings of Boustany, Bernett, and Xenaki could be designed such that the Fc only domain comprises a different hinge sequence (i.e. without an upper domain) since it does not comprise an immunoglobin variable domain because Rayner teaches the core and lower hinge domains are responsible for Fc domain interactions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 18/046,860
Claims 1-2, 12-14, 26, 30-33, 36-37, 40-41, 44, 47, and 55-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-11, 14-20, 22, 24-26, 29-31, 35, 38-39, and 43-48 of copending Application No. 18/046,860 (herein US860). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1-2, claim 1 of US860 claims an HBPC with identical format to the instant HBPC (i.e. polypeptides (a)-(c)). Dependent claim 2 of US860 claims the first target is a T-cell antigen (scFv) and the second target is a cancer cell surface polypeptide (defined to include EGFR; ¶ [0097]). Dependent claim 4 of US860 claims the T-cell antigen is CD3ε.
Regarding claim 12 (dependent on claim 1), claim 5 of US860 claims CH1 domain between the VH2 and Fc1 domain.
Regarding claim 13 (dependent on claim 1), claim 6 of US860 claims a hinge between CH1 and the Fc domain, which by broadest reasonable interpretation would also be between the VH2 and Fc1
Regarding claim 14 (dependent on claim 1), claim 7 of US860 claims an identical N- to C-terminal format: MM1-CM1-scFv-VH2-CHl-hinge region-Fc1.
Regarding claims 26 and 30 (dependent on claim 1), claim 10 of US860 claims the third polypeptide comprises a immunoglobin hinge (HR2) and claim 11 of US860 claims N- to C-terminal arrangement HR2-Fc2.
Regarding claim 31 (dependent on claim 1), claim 14 of US860 claims one or more linkers in the first, second, and/or third polypeptide.
Regarding claims 32-33 (dependent on claim 1), claim 15 of US860 claims a linker in one or more locations including (a) between MM1 and CM1 and (b) between MM2 and CM2. Claim 17 of US860 claims linker (L1) linking MM1 to CM1. Claim 18 of US860 claims linker (L2) linking MM2 to CM2.
Regarding claim 36 (dependent on claim 1), claim 25 of US860 claims CM1 and CM2 each comprise a substrate for a protease present in a tumor microenvironment.
Regarding claim 37 (dependent on claim 1), claim 26 of US860 claims CM1 and CM2 comprise substrates for the same protease.
Regarding claim 40 (dependent on claim 1), claim 29 of US860 claims CM1 and CM2 comprise substrates for a protease selected from group consisting of serine protease or an MMP.
Regarding claims 41 and 44 (dependent on claim 1), claim 30 of US860 claims CM1 and/or CM2 comprise sequences identical to those in the instant claims (SEQ ID NO: 2, 14, and 73).
Regarding claim 47 (dependent on claim 1), claim 31 of US860 claims the MM1 and/or MM2 comprises between 5-40 amino acids.
Regarding claim 55 (dependent on claim 1), claim 35 of US860 claims a pharmaceutical composition of the activatable bispecific polypeptide complex and a pharmaceutically acceptable carrier.
Regarding claim 56 (dependent on claim 55), claim 38 of US860 claims a kit comprising the composition of US860 claim 35.
Regarding claim 57 (dependent on claim 1), claim 39 of US860 claims nucleic acids encoding the polypeptides of the activatable bispecific polypeptide complex.
Regarding claim 58 (dependent on claim 57), claim 43 of US860 claims a vector comprising the nucleic acid of US860 claim 39.
Regarding claim 59 (dependent on claim 58), claim 44 of US860 claims a host cell comprising the vector of US860 claim 43.
Regarding claim 60 (dependent on claim 59), claim 45 of US860 claims an identical method of making the HBPC using host cells from US860 claim 44.
Regarding claim 61 (dependent on claim 55), claim 46 of US860 claims a method of treating disease by administering the HBPC of US860 claim 1.
Regarding claim 62 (dependent on 61), claim 47 of US860 claims the subject of treatment from US860 claim 46 is human.
Regarding claim 63 (dependent on 62), claim 48 of US860 claims the disease from US860 claim 46 is cancer.
US 18/701,356
Claims 1-3, 6-7, and 55-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-15 of copending Application No. 18/701,356 (herein US356) in view of WO 2018/045110 A1 (herein Bernett) and Xenaki (Front Immunol. 2017;8:1287). This is a provisional nonstatutory double patenting rejection.
Regarding claims 1-3 and 6-7, claim 1 of US356 claims an bivalent version of the instant anti-EGFR, anti-CD3 HBPC with identical formats for first and second polypeptides with identical CDRs for respective CD3 and EGFR binding.
US356 does not specifically claim the monovalent version (i.e. one arm construct, wherein the third polypeptide is an Fc domain without an immunoglobin variable domain and without a fourth polypeptide).
Bernett teaches different formats for bispecific antibodies that include variations with single arm scFv-mAb (Figure 2D) and bivalent DVD-Ig (Figure 2L).
Xenaki teaches engineering smaller antibody fragments has been shown to improve the rate of tumor uptake and intratumoral distribution (abstract)
One of ordinary skill in the art would recognize that a monovalent antibody can be generated from an existing bivalent antibody as taught by Bernett and a skilled artisan would be motivated to do so because Xenaki teaches that smaller antibody fragments have been shown to increase tumor penetration. Therefore, the claims are patentably indistinct.
Regarding claim 55 (dependent on claim 1), claim 6 of US356 claims a pharmaceutical composition of the activatable bispecific polypeptide complex and a pharmaceutically acceptable carrier.
Regarding claim 56 (dependent on claim 55), claim 7 of US356 claims a kit comprising the composition of US356 claim 6.
Regarding claim 57 (dependent on claim 1), claim 8 of US356 claims nucleic acids encoding the polypeptides of the activatable bispecific polypeptide complex.
Regarding claim 58 (dependent on claim 57), claim 9 of US356 claims a vector comprising the nucleic acid of US356 claim 8.
Regarding claim 59 (dependent on claim 58), claim 10 of US356 claims a host cell comprising the vector of US356 claim 9.
Regarding claim 60 (dependent on claim 59), claim 11 of US356 claims an identical method of making the HBPC using host cells from US356 claim 10.
Regarding claim 61 (dependent on claim 55), claim 12 of US356 claims a method of treating disease by administering the HBPC of US356 claim 1.
Regarding claim 62 (dependent on 61), claim 13 of US356 claims the subject of treatment from US356 claim 12 is human.
Regarding claim 63 (dependent on 62), claim 14 of US356 claims the disease from US356 claim 12 is cancer.
Allowable Subject Matter
An MM1 domain comprising amino acid sequence of SEQ ID NO:1 is free from prior art. Therefore, claim 50 and 52-54 (polypeptides comprising said MM) are also free from prior art.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647