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 .
1. Claims 1, 2, 4-9, 11-16, 18-23 are pending and being examined.
Claim Rejections - 35 USC § 112
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.
2. Claims 8, 9, and 23 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.
Claim 8 recites: A method of treating a disorder in which CD47 is overexpressed or upregulated in a subject, comprising: using an isolated anti-CD47 antibody or fragment thereof having the ability of binding CD47 and competing with the binding of SIRPα to CD47.
Claim 23 recites: A method for treating hepatocellular carcinoma (HCC) comprising the use of the bispecific antibody of claim 11.
Claims 8 and 23 recite methods using an antibody but do not set forth any methods steps for how the antibody is actually used to accomplish the method. It is unclear what method applicant is intending to encompass and unclear how the method is actually practiced.
3. Claims 1, 2, and 4-9 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.
(A)
Claim 1 recites the anti-CD47 antibody comprises “(6) HCDR1, HCDR2, HCD3 as shown in (1)-(5), but at least one of which includes one, two, three, four, or five amino acids addition, conservative amino acid substitution or the combinations thereof”;
and “(6) LCDR1, LCDR2, LCDR3 as shown in (1)-(5), but at least one of which includes one, two, three, four, or five amino acids addition, conservative amino acid substitution or the combinations thereof”.
Claim 4 recites the anti-CD47 antibody or fragment of claim 1 comprises “(6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 SEQ ID NOs as shown in (1)-(5) but at least one of which includes one, two, three, four, or five amino acids addition, deletion, conservative amino acid substitution or the combination thereof”.
Claims 1 and 4 are unclear with regard to what the “at least one of which” is that includes the amino acid additions, substitutions or combinations thereof. Is the claim referencing a single CDR, or all the CDR1-3, or something else? The claim is unclear with regard to what is being modified.
(B)
Claims 5 and 6 recite the limitation "the activity of epitope-binding". There is insufficient antecedent basis for this limitation in the claim.
(C)
Claim 6 recites: the isolated anti-CD47 antibody or fragment thereof of claim 1 wherein the heavy chain variable region and the light chain variable region have the amino acid sequences selected from the group consisting of: (1)-(5) and (6) two amino acid sequences having at least 95% sequence identity to any one of (1)-(5) respectively and retaining the activity of epitope-binding.
In part (6), claim 6 is grammatically unclear with regard to which sequences from (1)-(5) respectively the “two amino acid sequences” claimed have at least 95% sequence identity to.
4. Claim 21 is 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. Claim 21 is indefinite in the use of the expression in parenthesis “(HC1 chain)” and “(HC2 chain)” in that it is not clear whether these recitations are intended to be part of the claim or not.
5. Claim 22 is 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. Claim 22 recites the bispecific antibody of claim 11 comprises “a HC1 portion”, “a LC1 portion”, “HC2” and “a LC2 portion” with defined SEQ ID NOs. Claim 22 is unclear with regard to what HC1, HC2, LC1, and LC2 mean, what a “portion” is, and it is unclear what part of the bispecific antibody recited in claim 11 is the “a HC1 portion”, “a LC1 portion”, “HC2” and “a LC2 portion”. Clarification is required.
Examiner suggests changing the language of claim 22 reflect that of claim 11, by reciting that the first and second antigen binding moieties each comprise a heavy chain and light chain, and by defining the heavy chain and light chain sequences of the first and second antigen binding moieties.
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.
6. Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 9 recites: The method of claim 8, wherein the disorder is a cancer selected from the group consisting of: solid tumor cancers of the lung, prostate, breast, bladder, colon, ovarian, pancreas, kidney, liver, glioblastoma, medulloblastoma, leiomyosarcoma, head and neck squamous cell carcinomas, melanomas, liquid cancers, hematological cancers, leukemias, lymphomas, brain cancers, an infection, a chronic infection, an immunological disease, an immunological disorder, an inflammatory disease, multiple sclerosis, and arthritis.
The claim recites selecting cancers from a group that contains disorders that are not enabled to be cancer, including an infection, a chronic infection, an immunological disease, an immunological disorder, an inflammatory disease, multiple sclerosis, and arthritis.
Examiner suggests amending the claim to separate out the non-cancer disorders from the list of cancers.
7. Claims 1, 2, 4-9, 11-16, 18-21, and 23 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claims 1, 2, and 4-7:
Claims 1, 2, and 4-7 are drawn to an anti-CD47 antibody or fragment thereof that functions to:
Bind CD47 and compete with the binding of SIRPα to CD47.
Claim 1 further recites the antibody comprises: three heavy chain variable region CDR SEQ ID NOs (HCDRs1-3) listed in any of (1)-(5) “but at least one of which includes one, two, three, four, or five amino acids addition, conservative amino acid substitution or the combinations thereof”;
and three light chain variable region CDR SEQ ID NOs (LCDRs1-3) listed in any of (1)-(5), “but at least one of which includes one, two, three, four, or five amino acids addition, conservative amino acid substitution or the combinations thereof”.
Claim 4 recites the anti-CD47 antibody or fragment of claim 1 comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 SEQ ID NOs as shown in (1)-(5) but at least one of which includes one, two, three, four, or five amino acids addition, deletion, conservative amino acid substitution or the combination thereof”.
Claim 5 recites the heavy chain variable region of the anti-CD47 antibody or fragment thereof comprises an amino acid sequence having at least 95% sequence identity to any one of the amino acid sequences shown in SEQ ID NOs:37-41 and retaining the activity of epitope-binding and comprises the light chain variable region comprises an amino acid sequence having at least 95% sequence identity to any one of the amino acid sequences shown in SEQ ID NOs:42-46 and retaining the activity of epitope-binding.
Claim 6 recites the anti-CD47 antibody of claim 1 wherein the heavy chain variable region and the light chain variable region have the amino acid sequence selected from the group consisting of: (1)-(5) and (6) two amino acid sequences having at least 95% sequence identity to any one of (1)-(5) respectively and retaining the activity of epitope-binding.
Thus, claims 1, 2, and 4-7 encompass a vast genus of antibody sequence variants comprising any mutations anywhere in the CDR sequences and functioning to bind CD47 and compete with the binding of SIRPα to CD47, and retain the activity of epitope-binding.
Claims 8 and 9:
Claim 8 recites a method for treating a disorder in which CD47 is overexpressed or upregulated in a subject, comprising: using an isolated anti-CD47 antibody or fragment thereof having the ability of binding and competing with the binding of SIRPα to CD47.
Thus, the claimed method requires employing a vast genus of antibodies that have no identifiable sequence structure and function by:
binding and competing with the binding of SIRPα to CD47; and
treating a disorder in which CD47 is overexpressed or upregulated in a subject.
Claims 11-21 and 23:
Claim 11 recites a bispecific antibody comprising:
a first antigen binding moiety that binds to human GPC3 (hGPC3) and
a second antigen binding moiety that binds to human CD47 (hCD47).
Claim 23 recites the bispecific antibody functions to treat HCC.
Thus, claims 11, 16, 18-21 and 23 encompass a vast genus of bispecific antibodies having no identifiable sequence structure and required to function by:
binding to human GPC3 (hGPC3);
binding to human CD47 (hCD47); and
treating HCC.
Claims 12-13 recite the sequence structure of the first antigen binding moiety critical to the function of binding to hGPC3, but do not recite the identifiable sequence structure of the second antigen binding moiety critical to binding CD47.
Claims 14 and 15 recite the sequence structure of the second antigen binding moiety critical to the function of binding to CD47, but do not recite the identifiable sequence structure of the first antigen binding moiety critical to binding hGPC3.
Anti-CD47 antibodies:
The instant specification discloses five highly homologous anti-CD47 human antibodies (BC18m03, BC18, BC7m03, BC7m04, BC7) that all share the same heavy chain variable region HCDR1-3 sequences HCDR1 (YHYWS), HCDR2 (YIYYSGSTTYNPSLKS), and HCDR3 (QRGAYDY) comprised in variable heavy region SEQ ID NOs:37-41 (see Table 1). The five highly homologous anti-CD47 antibodies also each comprise highly homologous light chain variable domain SEQ ID NOs:42-46 that comprise LCDR1 (RASQDIGSRLV or RASQDIGSRLA), LCDR2 (AASSLQS or AASSLQ), and LCDR3 (QQSYSTPYS or QQYNSFSPIT) (see Table 1). At paragraphs [158-165] the specification demonstrates antibodies BC18 and BC7 bound to cancer cells expressing CD47 and induced macrophage-mediated phagocytosis of cancer cells. At paragraphs [158-165] the specification demonstrates antibody BC18 treated lymphoma and breast cancer tumor models in vivo.
Thus, the instant specification discloses five anti-CD47 antibodies that comprise identical HCDR1-3 sequences and nearly identical LCDR1-3 sequences that are critical to the cd47 binding function claimed. The specification fails to disclose any structural sequence required of any other anti-CD47 antibodies to possess the functions as claimed and listed above.
Anti-GPC3 antibodies:
The instant specification discloses a single anti-GPC3 antibody (GC33 Codrituzumab) comprising variable heavy and variable light domain SEQ ID NOs:47 and 48, respectively (see Table 1). These anti-GPC3 antibody sequences were used to construct a bispecific CD47xGPC3 antibody with the CD47 BC18 antibody ([208-209]; Example 2). The specification demonstrates the bispecific antibody had superior safety profile and extended serum half-life compared to anti-CD47 antibody ([212-215]) and the bispecific antibody successfully treated cancer expressing GPC3/CD47 better than either CD47 or GPC3 antibody alone ([217-222]).
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibodies that function to bind hCD47 and compete with the binding of SIRPα to CD47, bind hGPC3, and treat cancer, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies that bind CD47 or GPC3 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies or binding moieties yet to be discovered that may function as claimed. The CD47 or GPC3 antigen provides no information about the structure of an antibody that binds to it.
In this case, the only factor present in the claims is a recitation of the antibody function as listed above. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only five highly homologous anti-CD47 antibodies and one GPC3 antibody that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the disclosed five highly homologous anti-CD47 antibodies and one GPC3 antibody, the specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequences for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
The claims broadly encompass any anti-CD47 antibody, any CD47 binding moiety, any sequence variants of anti-CD47 antibody comprising any mutations anywhere in the CDR sequences critical performing the antibody functions, and any GPC3 binding moiety. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain CD47 or GPC3 binding function, compete with the binding of SIRPα to CD47, and treat cancer. The instant claims attempt to claim every CD47 or GPC3 antibody, or sequence variants of CD47 antibody, that would achieve a desired result, i.e., bind CD47 or GPC3, compete with the binding of SIRPα to CD47, and treat cancer, wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only five highly homologous anti-CD47 antibodies and one anti-GPC3 antibody. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of five highly homologous anti-CD47 antibodies and one anti-GPC3 antibody to the structure of any and all anti-CD47 antibodies and anti-GPC3 antibodies as broadly claimed and required to practice the claimed methods. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed antibodies required to make and practice claimed methods, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs that provide the claimed functions, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that bind CD47 or GPC3 and function as claimed that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion:
Amend claim 1 to delete the phrases: “and (6) HCDR1, HCDR2, HCD3 as shown in (1)-(5), but at least one of which includes one, two, three, four, or five amino acids addition, conservative amino acid substitution or the combinations thereof” and
“and (6) LCDR1, LCDR2, LCDR3 as shown in (1)-(5), but at least one of which includes one, two, three, four, or five amino acids addition, conservative amino acid substitution or the combinations thereof”.
Amend claim 4 to delete the phrase: “(6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 SEQ ID NOs as shown in (1)-(5) but at least one of which includes one, two, three, four, or five amino acids addition, deletion, conservative amino acid substitution or the combination thereof”.
Amend claim 5 to delete the phrases: “and an amino acid sequence having at least 95% sequence identity to any one of the amino acid sequences shown in SEQ ID NOs:37-41 and retaining the activity of epitope-binding” and
“and an amino acid sequence having at least 95% sequence identity to any one of the amino acid sequences shown in SEQ ID NOs:42-46, and retaining the activity of epitope-binding.”
Amend claim 6 to delete the phrase: “and (6) two amino acid sequences having at least 95% sequence identity to any one of (1)-(5) respectively and retaining the activity of epitope-binding.”
Amend claim 8 to recite and require, at minimum, the six CDR SEQ ID NOs of the CD47 antibody.
Amend claim 11 to recite and require, at minimum, the six CDR SEQ ID NOs of both the CD47 and GPC3 binding moieties.
Claim Rejections - 35 USC § 102
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.
8. Claim(s) 8 and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xiao et al (Cancer Letters, 2015, 360:302-309).
Xiao teaches a method for treating liver cancer (HCC) overexpressing CD47 in a subject, the method comprising administering to the subject an isolated anti-CD47 antibody that blocks CD47 binding to SIRPα (Introduction; abstract; Figure 4 and 5, p. 306).
9. Claim(s) 11, 16, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CA 3062479, Song et al, published November 11, 2018.
Song teaches a bispecific antibody comprising:
(i) a first low-affinity binding arm that binds to CD47 and blocks the interaction of CD47 with SIRPα; and
(ii) a second high affinity binding arm that is an antibody binding to GPC-3 (abstract; Figure 3; p. 3-5, 7, 9, 13-15, 24, 26-27; claims 1-8);
wherein the bispecific antibody is configured as a knobs into holes heterodimerized Fc protein comprising:
a) a single chain protein “right arm” comprising and extracellular truncated variant of SIRPa fused to an Fc region (hinge, CH2, CH3) comprising Fc knob mutation,
b) light chain of “left arm” of GPC-3 antibody (VL, CL); and
c) heavy chain of “left arm” of GPC-3 antibody (VH, CH1, hinge, CH2, CH3) comprising an Fc hole mutation (Figure 3; p. 24, 26-27); wherein the knobs into holes mutations comprise "knobs" formed by the T366W mutation, and a hollow "holes" formed by one amino acid mutation (Y407V) or three amino acid mutations (T366S, L368A and Y407V) (p. 6-7).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
10. Claim(s) 11, 16, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over CA 3062479, Song et al, published November 11, 2018; in view of Ha et al (Frontiers in Immunology, 2016, 7:394, internet pages 1-16).
Song teaches the CD47xGPC-3 bispecific antibody comprising knobs into holes mutations: knob mutation T366W, and a hole mutations T366S, L368A and Y407V, as set forth above.
Song does not teach the knobs into holes mutations further comprise knob mutation S354C with hole mutation Y349C (Claim 19).
Ha reviews the known technology for constructing therapeutic bispecific antibodies using knobs-into-holes Fc heterodimerization. Ha teaches the known Fc mutations T366W and S354C with mutations Y407V, L368A, T366S, and Y349C to form knobs and holes for heterodimerization (Table 1; Figures 1-2), wherein the S354C CH3A - Y349C CH3B mutation pairing improves purity and stability (p. 3, col. 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize all of the knob mutations T366W and S354C with holes mutations Y407V, L368A, T366S, and Y349C to heterodimerize the Fc region of the CD47xGPC3 bispecific antibody. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Song teaches utilizing knobs-into-holes mutation T366W with Y407V, L368A, T366S, and Y349C to heterodimerize the Fc region, and (2) Ha teaches the Fc heterodimerization of bispecific antibodies can be improved in stability and purity by adding the S354C and Y349C mutations.
11. Claim(s) 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over CA 3062479, Song et al, published November 11, 2018; in view of WO2015172341, Li et al (see English translation).
Song teaches a therapeutic bispecific CD47xGPC3 antibody, as set forth above.
Song does not teach the sequence of the GPC3 antibody VH and VL are instant SEQ ID NOs:47 and 48, respectively, comprising the CDR sequences recited in claim 12.
Li teaches GPC3 antibody SEQ ID NO:5 comprising instant VH and VL SEQ ID NOs:47 and 48 (see English translation p. 5) (see sequence alignment below). Li teaches making bispecific GPC3 antibodies targeting immune cells (English translation page 2), wherein the GPC3 bispecific antibody successfully killed HCC cells (Huh-7 cells) (Experiments; Fig. 5). Li teaches the VH and VL domains are known in the art and taken from the published GC33 antibody (English translation p. 7-8).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the known GPC3 antibody sequence of instant SEQ ID NOs:47 and 48 in the bispecific CD47-GPC3 antibody of Song. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Song teaches constructing a therapeutic CD47xGPC3 bispecific antibody, for the treatment of cancer including liver cancer; and (2) Li teaches known GPC3 antibody VH and VL sequences SEQ ID NOs:47 and 48 derived from an established GPC3 antibody; and demonstrates the GPC3 binding sequences successfully function in a bispecific antibody to kill liver cancer cells.
Instant SEQ ID NO:47 aligned with Li SEQ ID NO:5:
BCH32116
ID BCH32116 standard; protein; 243 AA.
XX
AC BCH32116;
XX
DT 31-DEC-2015 (first entry)
XX
DE Anti-GPC3 single chain antibody sequence, SEQ ID 5.
XX
KW DGSX protein; GPC3 protein; GTR2-2 protein; MXR7 protein; OCI-5 protein;
KW SDYS protein; SGB protein; SGBS protein; SGBS1 protein; antibody therapy;
KW cancer; cytostatic; glypican-3; phosphatidylinositol proteoglycan-3;
KW single chain antibody; therapeutic.
XX
OS Synthetic.
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 1..113
FT /note= "Light chain variable region (VL)"
FT Region 114..128
FT /label= Linker
FT Region 129..243
FT /note= "Heavy chain variable region (VH)"
XX
CC PN WO2015172341-A1.
XX
CC PD 19-NOV-2015.
XX
CC PF 14-MAY-2014; 2014WO-CN077521.
XX
PR 14-MAY-2014; 2014WO-CN077521.
XX
CC PA (SHAN-) SHANGHAI CANCER INST.
XX
CC PI Li Z, Wang H, Jiang H, Shi B, Yang S, Gu J;
XX
DR WPI; 2015-719027/82.
DR N-PSDB; BCH32117.
XX
CC PT New bispecific antibody useful for preparing medicine for treating tumor,
CC PT comprising first and second functional domains for specific recognition
CC PT of glypican-3, and human T cell antigen cluster of differentiation and
CC PT joint.
XX
CC PS Claim 5; SEQ ID NO 5; 31pp; Chinese.
XX
CC The present invention relates to a novel bispecific antibody, useful for
CC treating cancer. The bispecific antibody comprises: (a) a first
CC functional domain for specific recognition of phosphatidylinositol
CC proteoglycan-3 (glypican-3, GPC3, DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB,
CC SGBS, SGBS1), (b) a second functional domain for specific recognition of
CC CD3, and (c) a linker for connecting the functional domains. The
CC invention further relates to: (1) a nucleotide sequence encoding the
CC bispecific antibody; and (2) a vector comprising the nucleotide sequence.
CC The bispecific antibody of the invention can be used for treating cancer.
CC The present sequence is an anti-GPC3 single chain antibody (scFV)
CC sequence, whose encoding gene is used in the invention for constructing a
CC vector capable of expressing the bispecific antibody which is useful for
CC treating cancer.
XX
SQ Sequence 243 AA;
ALIGNMENT:
Query Match 100.0%; Score 607; Length 243;
Best Local Similarity 100.0%;
Matches 115; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGALDPKTGDTAY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 129 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGALDPKTGDTAY 188
Qy 61 SQKFKGRVTLTADESTSTAYMELSSLRSEDTAVYYCTRFYSYTYWGQGTLVTVSS 115
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 189 SQKFKGRVTLTADESTSTAYMELSSLRSEDTAVYYCTRFYSYTYWGQGTLVTVSS 243
Instant SEQ ID NO:48 aligned with Li SEQ ID NO:5:
BCH32116
ID BCH32116 standard; protein; 243 AA.
XX
AC BCH32116;
XX
DT 31-DEC-2015 (first entry)
XX
DE Anti-GPC3 single chain antibody sequence, SEQ ID 5.
XX
KW DGSX protein; GPC3 protein; GTR2-2 protein; MXR7 protein; OCI-5 protein;
KW SDYS protein; SGB protein; SGBS protein; SGBS1 protein; antibody therapy;
KW cancer; cytostatic; glypican-3; phosphatidylinositol proteoglycan-3;
KW single chain antibody; therapeutic.
XX
OS Synthetic.
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 1..113
FT /note= "Light chain variable region (VL)"
FT Region 114..128
FT /label= Linker
FT Region 129..243
FT /note= "Heavy chain variable region (VH)"
XX
CC PN WO2015172341-A1.
XX
CC PD 19-NOV-2015.
XX
CC PF 14-MAY-2014; 2014WO-CN077521.
XX
PR 14-MAY-2014; 2014WO-CN077521.
XX
CC PA (SHAN-) SHANGHAI CANCER INST.
XX
CC PI Li Z, Wang H, Jiang H, Shi B, Yang S, Gu J;
XX
DR WPI; 2015-719027/82.
DR N-PSDB; BCH32117.
XX
CC PT New bispecific antibody useful for preparing medicine for treating tumor,
CC PT comprising first and second functional domains for specific recognition
CC PT of glypican-3, and human T cell antigen cluster of differentiation and
CC PT joint.
XX
CC PS Claim 5; SEQ ID NO 5; 31pp; Chinese.
XX
CC The present invention relates to a novel bispecific antibody, useful for
CC treating cancer. The bispecific antibody comprises: (a) a first
CC functional domain for specific recognition of phosphatidylinositol
CC proteoglycan-3 (glypican-3, GPC3, DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB,
CC SGBS, SGBS1), (b) a second functional domain for specific recognition of
CC CD3, and (c) a linker for connecting the functional domains. The
CC invention further relates to: (1) a nucleotide sequence encoding the
CC bispecific antibody; and (2) a vector comprising the nucleotide sequence.
CC The bispecific antibody of the invention can be used for treating cancer.
CC The present sequence is an anti-GPC3 single chain antibody (scFV)
CC sequence, whose encoding gene is used in the invention for constructing a
CC vector capable of expressing the bispecific antibody which is useful for
CC treating cancer.
XX
SQ Sequence 243 AA;
12. Claim(s) 11 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over CA 3062479, Song et al, published November 11, 2018; in view of Ma et al (Advanced Materials, 2017, 29:1604253, internet pages 1-6), Xiao et al (Cancer Letters, 2015, 360:302-309), and Nishida et al (Cancers, 2019, 11:1339, internet pages 1-13).
Song teaches the CD47xGPC-3 bispecific antibody as set forth above. Song further teaches administering the bispecific antibody to treat liver cancer (p. 8, 18-19; claim 15). Song further teaches it is known CD47 releases a "don't eat me" signal, by binding to SIRPa on the surface of macrophages, phosphorylating its immune receptor tyrosine-based inhibitory motif (ITIM), subsequently recruiting SH2-containing protein tyrosine phosphatase 1 protein, and triggering a series of cascades to inhibit the phagocytosis of macrophages (p. 2). Song teaches (p. 2-3):
CD47 can be a target for treating various cancers because it is widely expressed on the surface of various cancer cells. The mouse allogeneic tumor transplantation model has demonstrated the effectiveness of CD47 blockade, so CD47 has become a novel target of immune checkpoint therapy for cancer (Vonderheide R H. CD47 blockade as another immune checkpoint therapy for cancer. Nature Medicine, 2015, 21(10):1122-1123). The anti-CD47 antibody, SIRPa-Fc fusion protein and the like can relieve the inhibitory effect of CD47 on immune cells by blocking the CD47-SIRPa signaling pathway, and exhibit certain anti-tumor activity.
Song does not teach the liver cancer treated is hepatocellular carcinoma (HCC) (claim 23).
Ma teaches CD47 and GPC3 are known tumor antigens expressed by hepatocellular carcinoma (HCC). Ma teaches GPC3 is a known therapeutic target of HCC in the prior art (p. 1, col. 1). Ma teaches it is known in the prior art that CD47 expressed on cancer cells interacts with SIRPα in macrophage, compromising macrophage-mediated phagocytosis against tumor cells. Blocking of CD47-SIRpα signaling axis with antibodies or recombinant proteins can retard tumor progression (p. 1, col. 2).
Xiao teaches and demonstrates successful treatment of HCC by administering an anti-CD47 antibody that blocks CD47 from binding SIRPα (abstract; Figure 5).
Nishida teaches an established anti-GPC3 antibody (GC33, codrituzumab) clinically administered to treat HCC patients (section 4; Table 1). Nishida teaches the effectiveness of anti-GPC3 antibody treatment of HCC can be enhanced by making bispecific antibodies targeting GPC3 and an immune checkpoint inhibitor (section 4.1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat HCC as the liver cancer in the method of Song. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Song teaches treating liver cancer with the bispecific CD47xGPC3 antibody wherein it is known CD47 is an immune checkpoint protein; (2) Ma and Xiao teach it is known HCC is treated with anti-GPC3 antibodies and anti-CD47 antibodies and that HCC expresses both GPC3 and CD47 for therapeutic targeting; and (3) Nishida teaches HCC patients are already clinically treated with an anti-GPC3 antibody, suggesting improving antibody function by making GPC3 bispecific antibodies targeting immune checkpoint proteins.
13. Claim(s) 11 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over CA 3062479, Song et al, published November 11, 2018; in view of WO 2018/045090, Miao et al, published March 2018; and Nishida et al (Cancers, 2019, 11:1339, internet pages 1-13).
Song teaches the CD47xGPC-3 bispecific antibody as set forth above. Song further teaches administering the bispecific antibody to treat liver cancer (p. 8, 18-19; claim 15). Song further teaches it is known CD47 releases a "don't eat me" signal, by binding to SIRPa on the surface of macrophages, phosphorylating its immune receptor tyrosine-based inhibitory motif (ITIM), subsequently recruiting SH2-containing protein tyrosine phosphatase 1 protein, and triggering a series of cascades to inhibit the phagocytosis of macrophages (p. 2). Song teaches (p. 2-3):
CD47 can be a target for treating various cancers because it is widely expressed on the surface of various cancer cells. The mouse allogeneic tumor transplantation model has demonstrated the effectiveness of CD47 blockade, so CD47 has become a novel target of immune checkpoint therapy for cancer (Vonderheide R H. CD47 blockade as another immune checkpoint therapy for cancer. Nature Medicine, 2015, 21(10):1122-1123). The anti-CD47 antibody, SIRPa-Fc fusion protein and the like can relieve the inhibitory effect of CD47 on immune cells by blocking the CD47-SIRPa signaling pathway, and exhibit certain anti-tumor activity.
Song does not teach the CD47 binding arm comprises an antibody containing antibody regions of CH1, and light chain comprising a VL and CL (claim 21).
Miao teaches making a CD47-GPC3 bispecific antibody ([48]; [182]; claim 56; Examples 2 and 12; Table 20).
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196
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Miao teaches the bispecific antibody has the structure of (claim 1):
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540
744
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wherein one binding arm A has a light chain VL+CL, and heavy chain VH, CH1, hinge, HC2 and HC3, and the other binding arm B has a light chain VL+CL, and heavy chain VH, CH1, hinge, HC2 and HC3 ([47-50]).
Nishida suggests making GPC3 bispecific antibodies comprising one antibody arm binding to GPC3 and a second antibody arm binding to an immune checkpoint molecule in order to improve the therapeutic effects of anti-GPC3 antibodies. Nishida teaches there are known GPC3 bispecific antibodies produced in the prior art targeting immune checkpoint proteins (section 4.1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce a bispecific CD47-GPC3 antibody comprising two antibody halves, each half binding one antigen and comprising a light chain VL+CL, and heavy chain comprising VH+CH1+hinge+CH2+CH3. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Nishida suggests making a bispecific antibody targeting GPC3 and immune checkpoint molecule, and teaches they have already been produced using two antibody halves; and (2) Miao teaches and exemplifies successfully making a CD47-GPC3 bispecific antibody comprising two antibody halves, each half binding one antigen and comprising a light chain VL+CL, and heavy chain comprising VH+CH1+hinge+CH2+CH3.
14. Claim(s) 20 is rejected under 35 U.S.C. 103 as being unpatentable over CA 3062479, Song et al, published November 11, 2018; WO 2018/045090, Miao et al, published March 2018; and Nishida et al (Cancers, 2019, 11:1339, internet pages 1-13). as applied to claims 11 and 21 above, and further in view of Klein et al (Methods, 2019, 154:21-32).
Song, Miao, Nishida (the combined references) teach a therapeutic bispecific CD47xGPC3 antibody comprising two antibody halves that each include CH1 and CL regions, as set forth above.
The combined references do not teach the CH1 portion and the CL portion are replaced by each other (CrossMab technology) (claim 20).
Klein review the known CrossMab technology swapping CH1 and CL portions in therapeutic bispecific antibodies to gain the advantage of enforcing correct light chain association based on the domain crossover of immunoglobulin domains in the Fab region of the bispecific antibody (abstract; Figure 1 and 2; section 1). Klein teaches this technology has been successfully applied to numerous therapeutic bispecific antibodies (Table 1). Klein teaches pairing this technology with knobs-into-holes Fc heterodimerization to enable correct heavy chain association for the generation of bi- and multispecific antibodies (abstract; section 1; Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce a bispecific CD47-GPC3 antibody of the combined references using CrossMab technology swapping the CH1 portion and the CL portion. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Song teaches making the bispecific construct with knobs-into-holes heterodimerization; (2) Klein teaches pairing CrossMab technology with knobs-into-holes construction to enable correct heavy chain association for the generation of bi- and multispecific antibodies; (3) Klein teaches utilizing CrossMab technology to make bispecific antibodies in order to gain the advantage of enforcing correct light chain association; and (4) Klein demonstrates the CrossMab technology has been successfully used to construct numerous therapeutic bispecific antibodies.
15. Conclusion: No claim is allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642