DETAILED ACTION
Claims 1-20 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
the name of the XML file
the date of creation; and
the size of the XML file in bytes; or
In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
the name of the XML file;
the date of creation; and
the size of the XML file in bytes.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See page 22, paragraph [00128], line 2.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
“RPIM medium” should read “RPMI medium” (page 30, paragraph [00181]).
“RIPM1640” should read “RPMI1640” (page 31, paragraph [00184])
The use of the terms Lipofectamine and NanoDrop, which is a trade name or a mark 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. All trademarks referenced herein should be identified as such with the appropriate notation:
Lipofectamine (page 26, paragraph [00157])
NanoDrop (page 27, paragraph [00161])
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 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.
Claim 10 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.
Regarding instant claim 10, the exemplary languages “…SEQ ID NO: 19 (X1=S, X2=A, X3=V)” and “…SEQ ID NO: 19 (X1=W, X2=L, X3=Y)” renders the claim indefinite, because it is unclear whether the limitation following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “wherein” should be inserted before identifying the X residues, so that the claim recites “…SEQ ID NO: 19 (wherein X1=S, X2=A, X3=V)…SEQ ID NO: 19 (wherein X1=W, X2=L, X3=Y).”
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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 1-5 and 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over Mazor et al (US2024/0287183A1, priority to 4/30/2021; hereinafter Mazor), and further in view of Xia et al (US2025/0034253A1, priority to 2/14/2022; hereinafter Xia) and Brinkmann and Kontermann (mAbs, 2017, 9(2):182-212).
Regarding instant claims 1-5 and 12-18, Mazor teaches a bispecific antibody (page 16, paragraph [0006]; page 17, paragraph [0023]) comprising a first binding domain that binds PD-1 and a second binding domain that binds TIGIT (claims 1, 5, and 9; page 18, paragraph [0038]-page 19, paragraph [0038]), wherein the bispecific antibody is afucosylated, which is a known technique for stability and reduced effector function thereof (claim 34; page 21, paragraph [0069]), and features a knob and hole mutation in the heavy chain constant domains (page 21, paragraph [0076]). Mazor also teaches the manufacturing components, including a nucleic acid comprising a nucleotide sequence encoding the bispecific antibody (claim 37; page 19, paragraph [0052]), an expression vector comprising the nucleic acid (claim 42; page 18, paragraph [0030]; page 20, paragraph [0057]), and a host cell comprising the expression vector (claim 43; page 18, paragraph [0030]; page 20, paragraph [0057]). Furthermore, regarding claims 15-18, Mazor teaches a method of treating cancer comprised of administering a therapeutically effective amount of a pharmaceutical composition comprising the bispecific antibody that binds to PD-1 and TIGIT (claim 48; page 16, paragraph [0007]; page 22, paragraph [0083]; page 23, paragraphs [0090]-[0095]), wherein the cancer can be a solid tumor (page 22, paragraph [0087]) or one or more of ovarian cancer, colorectal cancer, melanoma, pancreatic cancer, renal cell carcinoma, and cervical cancer (claim 49; page 22, paragraph [0087-page 23, paragraph [0087]).
Mazor, however, does not directly teach a bispecific molecule comprising a TIGIT-binding domain and a VEGF-binding domain, with the structure of the bispecific molecule comprising:
a first polypeptide, containing, from N-terminus to C-terminus, an anti-TIGIT heavy chain variable region and a heavy chain constant region,
a second polypeptide, containing an anti-TIGIT light chain variable region,
a third polypeptide, containing, from N-terminus to C-terminus, an anti-VEGF heavy chain variable region, and a heavy chain constant region, and
a fourth polypeptide, containing an anti-VEGF light chain variable region,
wherein the anti-TIGIT heavy chain variable region in the first polypeptide and the anti-TIGIT light chain variable region in the second polypeptide associate to form the anti-TIGIT binding domain, the anti-VEGF heavy chain variable region in the third polypeptide and the anti-VEGF light chain variable region in the fourth polypeptide associate to form the anti-VEGF binding domain, and the heavy chain constant region in the first polypeptide and the heavy chain constant region in the third polypeptide are associated together. Furthermore, Mazor does not teach the bispecific antibody comprising a light chain constant region in the C-terminus in the second and/or fourth polypeptides.
This deficiency is resolved by Xia et al and Brinkmann and Kontermann.
Xia teaches an anti-TIGIT antibody used in combination with an anti-PD-1/anti-VEGFA bispecific antibody to prevent or treat tumors, because the combination of targeting immune checkpoint inhibitors (e.g. TIGIT and PD-1) and angiogenic factors, e.g. VEGF, exhibited synergistic anti-tumor effects by displaying effective tumor growth inhibition superior to that of monotherapies (page 18, paragraph [0021]; page 34, Example 11 and paragraph [0220]; and Figure 19), wherein the tumors were associated with diseases involving TIGIT signaling (page 17, paragraphs [0004] and [0005]), such as ovarian cancer, pancreatic cancer, cervical cancer, and melanoma (page 18, paragraph [0022]). Xia also teaches the manufacturing components as well, including a nucleic acid molecule comprising a nucleotide sequence encoding the bispecific antibody (page 19, paragraph [0045]), a vector comprising the nucleic acid molecule (page 19, paragraph [0046]), and a host cell comprising the vector (page 19, paragraph [0047]). Xia further teaches a pharmaceutical composition comprising the anti-TIGIT antibody with the anti-PD-1/anti-VEGFA bispecific antibody used with an acceptable carrier (claim 1; page 20, paragraphs [0053]-[0055]) for a method of treating or preventing cancer by administering a therapeutically effective amount of the bispecific antibody (page 20, paragraph [0065]).
Brinkmann and Kontermann teach different structures of bispecific antibodies, some of which comprise a first and second polypeptide binding to a target protein and a third and fourth polypeptide binding to a different target protein wherein:
the first polypeptide comprises a heavy chain variable region and a heavy chain constant region
the second polypeptide comprises a light chain variable region
the third polypeptide comprises a heavy chain variable and constant region, and
the fourth polypeptide comprises a light chain variable region
wherein the first and third polypeptides of the bispecific antibody are associated together (page 182, paragraph 3 – page 183, paragraph 2; Figure 2). Additionally, Brinkmann and Kontermann teach that the light chains may also comprise a constant domain in the c-terminus (Figure 2). Brinkmann and Kontermann further teach that knob and hole mutations are introduced in the two heavy chain CH3 domains (page 189, paragraph 4; Figure 3) of the bispecific antibody to generate heteromeric heavy chains to produce functional bispecific antibodies, which have been widely adopted and now forms a versatile basis of producing bispecific antibodies (page 190, paragraphs 1-2).
Regarding instant claims 1-5, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the afucosylated bispecific antibody comprising PD-1 and TIGIT binding domains as taught by Mazor and modify the bispecific antibody to comprise a four-polypeptide structure wherein knob and hole mutations are introduced in the heavy chain constant regions of the first and third polypeptides as taught by Brinkmann and Kontermann, and substitute PD-1 with VEGF as taught by Xia. This is obvious, because Mazor teaches an afucosylated PD-1/TIGIT bispecific antibody that contains knob and hole mutations in the heavy chain constant domains, Xia teaches an anti-TIGIT antibody used in combination with an anti-PD-1/anti-VEGF bispecific antibody to prevent or treat tumors to achieve synergistic anti-tumor effects, and Brinkmann and Kontermann teach bispecific antibodies as four-polypeptide structures where the heavy chains associate with light chains to bind to two different target proteins wherein knob and hole mutations are introduced in the heavy chain CH3 domains to generate functional heteromeric heavy chains. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the afucosylated bispecific antibody comprising PD-1 and TIGIT binding domains as taught by Mazor which comprises a four polypeptide structure and knob and hole mutations in the heavy chain constant domains of the first and third polypeptides as taught by Brinkmann and Kontermann and substitute PD-1 with VEGF taught by Xia in the bispecific antibody to form the instant afucosylated bispecific molecule comprising TIGIT and VEGF binding domains, wherein the instant bispecific antibody comprises a four polypeptide structure wherein:
the anti-TIGIT heavy chain variable region in the instant first polypeptide and the anti-TIGIT light chain variable region in the instant second polypeptide associate to form the instant anti-TIGIT binding domain,
the anti-VEGF heavy chain variable region in the instant third polypeptide and the anti-VEGF light chain variable region in the instant fourth polypeptide associate to form the anti-VEGF binding domain,
the heavy chain constant regions in the instant first polypeptide and the instant third polypeptide are associated together,
the instant second and/or fourth polypeptides comprise a light chain constant region, and
the instant bispecific antibody contains a knob and hole mutation in the heavy chain constant domains of the instant first and third polypeptides.
Regarding instant claims 12-14, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the nucleic acid molecule (wherein the nucleic acid molecule encodes the bispecific antibody comprising PD-1 and TIGIT binding domains), expression vector, and host cell as taught by Mazor and substitute PD-1 with VEGF as taught by Xia. This is obvious, because Mazor teaches the nucleic acid molecule, expression vector, and host cell for production of the bispecific antibody comprising PD-1 and TIGIT binding domains, and Xia teaches the nucleic acid molecule that encodes the bispecific antibody comprising a VEGF binding domain. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the nucleic acid molecule that encodes the bispecific antibody comprising PD-1 and TIGIT binding domains, the expression vector, and the host cell as taught by Mazor and substitute PD-1 with VEGF as taught by Xia to form the instant nucleic acid molecule encoding the instant bispecific antibody comprising anti-TIGIT and anti-VEGF binding domains, the instant expression vector comprising the instant nucleic acid molecule encoding the instant bispecific antibody, and the instant host cell comprising the instant expression vector.
Regarding instant claims 15-18, it would have been obvious for a person having ordinary skill in the art at the time of filing to administer the pharmaceutical composition comprising the bispecific antibody comprising PD-1 and TIGIT binding domains as taught by Mazor and substitute PD-1 with VEGF as taught by Xia. This is obvious, because Mazor teaches a pharmaceutical composition for treating solid tumors of various cancers, including ovarian and pancreatic cancers, wherein the pharmaceutical composition comprises the bispecific antibody comprising PD-1 and TIGIT binding domains, and Xia teaches a pharmaceutical composition of combining immune checkpoint inhibition (TIGIT and PD-1) with anti-angiogenic activity (VEGF) using an anti-TIGIT antibody with an anti-PD-1/anti-VEGFA bispecific antibody to treat or prevent cancers such as ovarian cancer, pancreatic cancer, cervical cancer and melanoma. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical composition comprising the bispecific antibody comprising PD-1 and TIGIT binding domains as taught by Mazor and substitute PD-1 with VEGF as taught by Xia to form the instant pharmaceutical composition and instant method for treating or alleviating a tumor associated with TIGIT or VEGF signaling, wherein the tumor can be a solid tumor or (but not limited to) ovarian cancer or pancreatic cancer with the instant pharmaceutical composition comprising the instant bispecific molecule comprising a TIGIT binding domain and a VEGF binding domain.
Additionally, regarding claim 17, it is widely known in the art that a solid tumor cancer is an abnormal mass of tissue that forms in solid organs, unlike liquid cancers (e.g. leukemia), with common types including e.g. breast, lung, prostate, and colon cancers.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Mazor et al (US2024/0287183A1, priority to 4/30/2021; hereinafter Mazor), Xia et al (US2025/0034253A1, priority to 2/14/2022; hereinafter Xia) and Brinkmann and Kontermann (mAbs, 2017, 9(2):182-212) as applied to claim 1 above, and further in view of Baca et al (US Patent No. 6,884,879 B1; hereinafter Baca).
The teachings of Mazor, Xia, and Brinkmann and Kontermann are
discussed above.
However, Mazor, Xia, and Brinkmann and Kontermann do not teach the bispecific molecule wherein the anti-VEGF heavy chain variable region comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequences of instant SEQ ID NOs:7, 8, and 9, respectively, and the anti-VEGF light chain variable region comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising the amino acid sequences of instant SEQ ID NOs:10, 11, and 12, respectively. Furthermore, Mazor, Xia, and Brinkmann and Kontermann do not teach the anti-VEGF heavy chain variable region and the anti-VEGF light chain variable region of the bispecific antibody comprising amino acid sequences having 100% sequence identity to instant SEQ ID NOs:15 and 16, respectively.
The deficiency is resolved by Baca et al.
Baca teaches humanized anti-VEGF antibodies, including sequences for the variable heavy chain, SEQ ID NO:7 (FIG. 1A, 9B, 10B; page 48-49, Sequence Listing for SEQ ID NO:7), and variable light chain, SEQ ID NO:8 (FIG. 1B, 9A, 10A; page 49, Sequence Listing for SEQ ID NO:8), wherein the sequences are 100% identical to instant SEQ ID NOs :15 and 16, respectively. Additionally, Baca describes CDRH1, CDRH2, and CDRH3 sequences that comprise the heavy chain of the VEGF domain as SEQ ID NOs:1, 2, and 3, respectively (page 20, column 2, paragraph 4), which are identical to instant SEQ ID NOs:7, 8, and 9, respectively, and CDRL1, CDRL2, and CDRL3 sequences that comprise the light chain of the VEGF domain as SEQ ID NOs:4, 5, and 6, respectively (page 21, column 3, paragraph 1), which are identical to instant SEQ ID NOs:10, 11, and 12, respectively.
Regarding instant claims 6 and 7, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the four-polypeptide bispecific antibody comprising VEGF and TIGIT binding domains as taught by the combined teachings of Mazor, Xia, and Brinkmann and Kontermann to include the amino acid sequences SEQ ID NO:7 for the VEGF heavy chain variable region comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and SEQ ID NO:8 for the VEGF light chain variable region comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6) as taught by Baca. This is obvious, because the combined teachings of Mazor, Xia and Brinkmann and Kontermann teach a four-polypeptide TIGIT/VEGF bispecific antibody for use in achieving synergistic anti-tumor effects and Baca teaches anti-VEGF antibodies, providing the amino acid sequences for the heavy chain variable region, SEQ ID NO:7 comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3), and the light chain variable region, SEQ ID NO:8 comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the four-polypeptide bispecific antibody comprising VEGF and TIGIT binding domains as taught by the combined teachings of Mazor, Xia, and Brinkmann and Kontermann wherein the VEGF heavy chain variable region comprises SEQ ID NO:7 with CDRH1-3 comprising SEQ ID NOs:1-3 and the VEGF light chain variable domain comprises SEQ ID NO:8 with CDRL1-3 comprising SEQ ID NOs:4-6 as taught by Baca to form the instant bispecific molecule comprising TIGIT and VEGF binding domains, wherein the instant bispecific antibody comprises a four polypeptide structure wherein:
the anti-TIGIT heavy chain variable region in the instant first polypeptide and the anti-TIGIT light chain variable region in the instant second polypeptide associate to form the instant anti-TIGIT binding domain,
the anti-VEGF heavy chain variable region in the instant third polypeptide and the anti-VEGF light chain variable region in the instant fourth polypeptide associate to form the instant anti-VEGF binding domain, wherein the instant anti-VEGF heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:15 comprising VH-CDR1-3 (instant SEQ ID NOs:7, 8, and 9) and the instant anti-VEGF light chain variable region has at least 85% sequence identity to instant SEQ ID NO:16 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12), and
the heavy chain constant regions in the instant first polypeptide and the instant third polypeptide are associated together.
Claims 8-9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Mazor et al (US2024/0287183A1, priority to 4/30/2021; hereinafter Mazor), Xia et al (US2025/0034253A1, priority to 2/14/2022; hereinafter Xia), Brinkmann and Kontermann (mAbs, 2017, 9(2):182-212), and Baca et al (US Patent No. 6,884,879 B1; hereinafter Baca) as applied to claim 1 above, and further in view of Li et al (US2022/0396617A1, priority to 6/10/2021; hereinafter Li ‘617).
The teachings of Mazor, Xia, Brinkmann and Kontermann, and Baca are discussed above.
However, Mazor, Xia, Brinkmann and Kontermann, and Baca do not teach a bispecific antibody, wherein the anti-TIGIT heavy chain variable region comprises a VH-CDR1, a VH-CDR2 and a VH-CDR3 comprising the amino acid sequences of instant SEQ ID NOs:1, 2 and 3, respectively, and the anti-TIGIT light chain variable region comprises a VL-CDR1, a VL-CDR2 and a VL-CDR3 comprising the amino acid sequences of instant SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-TIGIT heavy chain and light chain variable regions comprise amino acid sequences having at least 100% sequence identity to instant SEQ ID NOs:13 and 14, respectively. Furthermore, Mazor, Xia, Brinkmann and Kontermann, and Baca do not teach a bispecific antibody wherein the first, second, third, and fourth polypeptides comprise the amino acid sequences of i) instant SEQ ID NOs: 21, 14, 23 and 16, respectively; ii) instant SEQ ID NOs: 21, 22, 23 and 24, respectively; iii) instant SEQ ID NOs: 25, 16, 25 and 16, respectively; or iv) instant SEQ ID NOs: 25, 24, 25 and 24, respectively.
The deficiency is resolved by Li ‘617.
Li ‘617 teaches an isolated monoclonal antibody, or an antigen-binding portion thereof, that specifically binds human TIGIT (page 1, abstract; page 10, paragraph [0015]), and comprises a VH-CDR1, a VH-CDR2 and a VH-CDR3 comprising the amino acid sequences of SEQ ID NOs:1, 2 and 3 (wherein SEQ ID NOs:1, 2, and 3 are identical to instant SEQ ID NOs:1, 2, and 3), respectively, and the anti-TIGIT light chain variable region comprises a VL-CDR1, a VL-CDR2 and a VL-CDR3 comprising the amino acid sequences of SEQ ID NOs:4, 5 and 6 (wherein SEQ ID NOs:4, 5, and 6 are identical to instant SEQ ID NOs:4, 5, and 6), respectively (page 10, paragraph [0015] and [0016]), wherein the anti-TIGIT heavy chain variable region and the anti-TIGIT light chain variable region comprise amino acid sequences having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to instant SEQ ID NOs:13-23 (wherein SEQ ID NO:15 is identical to instant SEQ ID NO:13) and SEQ ID NOs:24-32(wherein SEQ ID NO:28 is identical to instant SEQ ID NO:14), respectively (page 10, paragraph [0017] and [0018]). Furthermore, Li ‘617 teaches an amino acid sequence, SEQ ID NO:25, which comprises the polypeptides of the anti-TIGIT antibody, wherein SEQ ID NO:25 is identical to instant SEQ ID NO:25 (page 14, paragraph [0073]; Table 1).
Regarding instant claims 8-9, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the four-polypeptide bispecific antibody comprising a VEGF binding domain comprising SEQ ID NO:7 for the heavy chain variable region comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and SEQ ID NO:8 for the light chain variable region comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6), and a TIGIT binding domain as taught by the combined teachings of Mazor, Xia, Brinkmann and Kontermann, and Baca to include amino acid sequences SEQ ID NO:15 for the TIGIT heavy chain variable region comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and SEQ ID NO: 28 for the TIGIT light chain variable region comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6) as taught by Li ‘617. This is obvious, because the combined teachings of Mazor, Xia, Brinkmann and Kontermann, and Baca teach a four-polypeptide TIGIT/VEGF bispecific antibody for use in achieving synergistic anti-tumor effects wherein the VEGF heavy chain variable region comprises SEQ ID NO:7, comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and the light chain variable region comprises SEQ ID NO:8, comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6), and Li ‘617 teaches an isolated monoclonal antibody or antigen binding portion that binds human TIGIT wherein the heavy chain variable region comprises SEQ ID NO:15 comprising VH-CDR1-3 sequences comprising SEQ ID NOs:1, 2, and 3, respectively, and the light chain variable region comprises SEQ ID NO:28 comprising VL-CDR1-3 sequences comprising SEQ ID NOs: 4, 5, and 6, respectively. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the four-polypeptide bispecific antibody comprising VEGF and TIGIT binding domains wherein the VEGF heavy chain variable region comprises SEQ ID NO:7 with CDRH1-3 comprising SEQ ID NOs:1-3 and the VEGF light chain variable domain comprises SEQ ID NO:8 with CDRL1-3 comprising SEQ ID NOs:4-6 as taught by the combined teachings of Mazor, Xia, Brinkmann and Kontermann, and Baca, and the heavy chain variable region of TIGIT comprises SEQ ID NO:15 with VH-CDR1-3 comprising SEQ ID NOs:1, 2, and 3 and the light chain variable region of TIGIT comprises SEQ ID NO:28 with VL-CDR1-3 comprising SEQ ID NOs:4, 5, and 6 as taught by Li ‘617 to form the instant bispecific molecule comprising TIGIT and VEGF binding domains, wherein the instant bispecific antibody comprises a four polypeptide structure wherein:
the anti-TIGIT heavy chain variable region in the instant first polypeptide and the anti-TIGIT light chain variable region in the instant second polypeptide associate to form the instant anti-TIGIT binding domain, wherein the instant anti-TIGIT heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:13 comprising VH-CDR1-3 (instant SEQ ID NOs:1, 2, and 3) and the instant anti-TIGIT light chain variable region has at least 85% sequence identity to instant SEQ ID NO:14 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12),
the anti-VEGF heavy chain variable region in the instant third polypeptide and the anti-VEGF light chain variable region in the instant fourth polypeptide associate to form the instant anti-VEGF binding domain, wherein the instant anti-VEGF heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:15 comprising VH-CDR1-3 (instant SEQ ID NOs:7, 8, and 9) and the instant anti-VEGF light chain variable region has at least 85% sequence identity to instant SEQ ID NO:16 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12), and
the heavy chain constant regions in the instant first polypeptide and the instant third polypeptide are associated together.
Regarding instant claim 11, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the four-polypeptide bispecific antibody comprising VEGF and TIGIT binding domains comprising SEQ ID NO:8 for the light chain of the second and fourth polypeptide as taught by the combined teachings of Mazor, Xia, Brinkmann and Kontermann, and Baca to include amino acid sequence SEQ ID NO:25 in the first and third polypeptide as taught by Li ‘617. This is obvious, because the combined teachings of Mazor, Xia, Brinkmann and Kontermann, and Baca teach a four-polypeptide TIGIT/VEGF bispecific antibody for use in achieving synergistic anti-tumor effects wherein the VEGF heavy chain variable region comprises SEQ ID NO:7 and the light chain variable region comprises SEQ ID NO:8, and Li ‘617 teaches an isolated monoclonal antibody or antigen binding portion that binds human TIGIT wherein SEQ ID NO:25 comprises the polypeptides of the anti-TIGIT antibody for the TIGIT binding domain. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the four-polypeptide bispecific antibody comprising VEGF and TIGIT binding domains as taught by the combined teachings of Mazor, Xia, and Brinkmann and Kontermann, wherein the first, second, third, and fourth polypeptides comprise amino acid sequences SEQ ID NOs: 25, 8, 25, and 8, wherein SEQ ID NO:8 is taught by Baca and SEQ ID NO:25 is taught by Li ‘617 to form the instant bispecific antibody comprising TIGIT and VEGF binding domains, wherein the instant bispecific antibody comprises a four polypeptide structure wherein:
the anti-TIGIT heavy chain variable region in the instant first polypeptide and the anti-TIGIT light chain variable region in the instant second polypeptide associate to form the instant anti-TIGIT binding domain, wherein the instant anti-TIGIT heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:13 comprising VH-CDR1-3 (instant SEQ ID NOs:1, 2, and 3) and the instant anti-TIGIT light chain variable region has at least 85% sequence identity to instant SEQ ID NO:14 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12),
the anti-VEGF heavy chain variable region in the instant third polypeptide and the anti-VEGF light chain variable region in the instant fourth polypeptide associate to form the instant anti-VEGF binding domain, wherein the instant anti-VEGF heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:15 comprising VH-CDR1-3 (instant SEQ ID NOs:7, 8, and 9) and the instant anti-VEGF light chain variable region has at least 85% sequence identity to instant SEQ ID NO:16 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12),
the heavy chain constant regions in the instant first polypeptide and the instant third polypeptide are associated together, and
the instant first, second, third, and fourth polypeptides comprise amino acid sequences of instant SEQ ID NOs: 25, 16, 25, and 16.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Mazor et al (US2024/0287183A1, priority to 4/30/2021; hereinafter Mazor), Xia et al (US2025/0034253A1, priority to 2/14/2022; hereinafter Xia), Brinkmann and Kontermann (mAbs, 2017, 9(2):182-212), Baca et al (US Patent No. 6,884,879 B1; hereinafter Baca), and Li et al (US2022/0396617A1, priority to 6/10/2021; hereinafter Li ‘617) as applied to claim 1 above, and further in view of Li et al (US Patent No. 9,745,382 B1; hereinafter Li ‘382).
The teachings of Mazor, Xia, Brinkmann and Kontermann, Baca, and Li ‘617 are discussed above.
However, Mazor, Xia, Brinkmann and Kontermann, Baca, and Li ‘617 do not teach a bispecific antibody wherein the heavy chain constant region in the first polypeptide which comprises, from N-terminus to C-terminus, the anti-TIGIT heavy chain variable and constant regions, comprising the amino acid sequence of instant SEQ ID NO: 19 (wherein X1=S, X2=A, X3=V), and the heavy chain constant region in the third polypeptide which comprises, from N-terminus to C-terminus, the anti-VEGF heavy chain variable and constant regions, comprising the amino acid sequence of SEQ ID NO: 19 (wherein X1=W, X2=L, X3=Y).
The deficiency is resolved by Li ‘382.
Li ‘382 teaches humanized bispecific anti-HER2 antibodies that comprise one antigen binding site containing variable regions of heavy and light chain of trastuzumab and another antigen binding site containing variable regions of heavy and light chain of pertuzumab, comprising an amino acid sequence, SEQ ID NO:7 (which is identical to instant SEQ ID NO:19 wherein X1=S, X2=A, X3=V) for the constant region of the first heavy chain, and an amino acid sequence, SEQ ID NO:8 (which is identical to instant SEQ ID NO:19 wherein X1=W, X2=L, X3=Y) for the constant region of the second heavy chain (page 19, column 6, line 21-page 20, column 7, line 6).
Regarding instant claim 10, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the four-polypeptide bispecific antibody comprising a VEGF binding domain comprising SEQ ID NO:7 for the heavy chain variable region comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and SEQ ID NO:8 for the light chain variable region comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6), and a TIGIT binding domain comprising SEQ ID NO:15 for the heavy chain variable region comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and SEQ ID NO:28 for the light chain variable region comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6) as taught by the combined teachings of Mazor, Xia, Brinkmann and Kontermann, Baca, and Li’617 to include amino acid sequences SEQ ID NO:7 for the heavy chain constant region in the first polypeptide comprising the anti-TIGIT domain, and SEQ ID NO:8 for the heavy chain constant region in the third polypeptide comprising the anti-VEGF domain as taught by Li ‘382. This is obvious, because the combined teachings of Mazor, Xia, Brinkmann and Kontermann, Baca, and Li ‘617 teach a four-polypeptide TIGIT/VEGF bispecific antibody for use in achieving synergistic anti-tumor effects, wherein:
the VEGF heavy chain variable region comprises SEQ ID NO:7, comprising CDRH1-3 (SEQ ID NOs:1, 2, and 3) and the VEGF light chain variable region comprises SEQ ID NO:8, comprising CDRL1-3 (SEQ ID NOs:4, 5, and 6), and
the TIGIT heavy chain variable region comprises SEQ ID NO:15 comprising VH-CDR1-3 sequences comprising SEQ ID NOs:1, 2, and 3, and the TIGIT light chain variable region comprising SEQ ID NO:28 comprising VL-CDR1-3 sequences comprising SEQ ID NOs: 4, 5, and 6, respectively,
and Li ‘382 teaches humanized bispecific anti-HER2 antibodies that comprise an amino acid sequence, SEQ ID NO:7 for the constant region of the first heavy chain and an amino acid sequence, SEQ ID NO:8 for the constant region of the second heavy chain. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the four-polypeptide bispecific antibody comprising VEGF and TIGIT binding domains wherein the heavy chain variable region of TIGIT comprises SEQ ID NO:15 with VH-CDR1-3 comprising SEQ ID NOs:1, 2, and 3 and the light chain variable region of TIGIT comprises SEQ ID NO:28 with VL-CDR1-3 comprising SEQ ID NOs:4, 5, and 6 wherein the VEGF heavy chain variable region comprises SEQ ID NO:7 with CDRH1-3 comprising SEQ ID NOs:1-3 and the VEGF light chain variable domain comprises SEQ ID NO:8 with CDRL1-3 comprising SEQ ID NOs:4-6 as taught by the combined teachings of Mazor, Xia, Brinkmann and Kontermann, Baca, and Li ‘617 wherein the TIGIT heavy chain constant region comprises SEQ ID NO:7 and the VEGF heavy chain constant region comprises SEQ ID NO:8 as taught by Li ‘382 to form the instant bispecific antibody comprising TIGIT and VEGF binding domains, wherein the instant bispecific antibody comprises a four polypeptide structure wherein:
the anti-TIGIT heavy chain variable region in the instant first polypeptide and the anti-TIGIT light chain variable region in the instant second polypeptide associate to form the instant anti-TIGIT binding domain, wherein:
the instant anti-TIGIT heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:13 comprising VH-CDR1-3 (instant SEQ ID NOs:1, 2, and 3)
the instant anti-TIGIT light chain variable region has at least 85% sequence identity to instant SEQ ID NO:14 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12), and
the instant anti-TIGIT heavy chain constant domain comprises amino acid sequence instant SEQ ID NO:19 (wherein X1=S, X2=A, X3=V)
the anti-VEGF heavy chain variable region in the instant third polypeptide and the anti-VEGF light chain variable region in the instant fourth polypeptide associate to form the instant anti-VEGF binding domain, wherein:
the instant anti-VEGF heavy chain variable region has at least 85% sequence identity to instant SEQ ID NO:15 comprising VH-CDR1-3 (instant SEQ ID NOs:7, 8, and 9)
the instant anti-VEGF light chain variable region has at least 85% sequence identity to instant SEQ ID NO:16 comprising VL-CDR1-3 (instant SEQ ID NOs:10, 11, and 12), and
the instant anti-VEGF heavy chain constant domain comprises amino acid sequence instant SEQ ID NO:19 (wherein X1=W, X2=L, X3=Y), and
the heavy chain constant regions in the first polypeptide and the third polypeptide are associated together.
Claims 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Mazor et al (US2024/0287183A1, priority to 4/30/2021; hereinafter Mazor) and Xia et al (US2025/0034253A1, priority to 2/14/2022; hereinafter Xia), as applied to claim 1 above, and further in view of Lin et al (US2022/0162296A1, priority to 8/6/2019; hereinafter Lin), Lee et al (Invest Ophthalmol Vis Sci, 2014, 55(5): 2885-2892; hereinafter Lee), and Ge et al (Front. Immunol., 2021, 12:1-13; hereinafter Ge).
The teachings of Mazor and Xia are discussed above.
However, Mazor and Xia do not teach a method for treating or alleviating a neovascular eye disease associated with TIGIT signaling and/or VEGF signaling (e.g. diabetic macular edema, diabetic retinopathy, retinal vein occlusion, choroidal neovascularization, or age-related macular degeneration), in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition comprising a bispecific antibody comprising TIGIT and VEGF binding domains.
The deficiency is resolved by Lin et al, Lee et al, and Ge et al.
Lin teaches the method of administering to the patient a therapeutically effective amount of a bispecific antibody comprising a VEGF binding domain and an ANG-2 binding domain for the treatment of patients suffering from neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), a complication of diabetic retinopathy (page 11, paragraphs [0014]-[0015]). Furthermore, Lin teaches that this method is optimal to treat patients ensuring improvement and/or maintenance of their visual acuity as well as reducing unnecessary treatment burden (page 11, paragraph [0015]), because both VEGF and Ang-2 are recognized as key factors mediating diabetic eye disease pathogenesis, and new treatments that target additional pathways are needed (page 11, [0013]) since anti-VEGF monotherapies do not cover other pathways that contribute to the pathogenesis of the diabetic eye disease (page 10, paragraph [0009] – page 11, paragraph [0009]; page 11, paragraph [0012]).
Lee teaches a study exploring the function of natural killer (NK) cells in inflammatory angiogenesis in choroidal neovascularization (CNV) mouse models wherein in vivo depletion of IFN-γ secreting NK cells led to a significant reduction of corneal angiogenesis and CNV by reducing macrophage infiltration into the cornea in addition to reduced mRNA expression levels of VEGF (page 2885, Results; page 2890, paragraph 2; Figures 1, 2, and 4).
Ge teaches that TIGIT is a co-inhibitory molecule that is exclusively expressed on lymphocytes, including CD8+ T cells, memory and regulatory CD4+ T cells, follicular CD4+ T cells, and Natural Killer (NK) cells (page 2, paragraph 5), wherein the mechanism of TIGIT co-inhibition involves both direct and indirect mechanisms, e.g. TIGIT can inhibit CD8+ T cell proliferation and activation by directly acting on TCR expression, or TIGIT can suppress NK-cell mediated cytotoxicity and IFN-γ production by binding on to the NK cells via the ligand CD155 (page 3, paragraph 2; Figure 1). Ge further teaches that inhibition of TIGIT in lymphocytes exhibits a multitude of anti-tumor effects (Figures 2-4), which is a unique property of TIGIT among inhibitory immune checkpoints since its blockade augments not only anti-tumor effector CD8+ T-cell responses but also anti-tumor NK cell responses and reduces the suppressive capacity of regulatory T cells (page 9, paragraph 2). Finally, Ge teaches that TIGIT-blockade synergizes with PD-1/PDL-1 blockade to enhance anti-tumor CD8+ T-cell immunity and to treat patients with anti-PD-1 resistant tumors (page 9, paragraph 2).
Regarding instant claims 19-20, it would have been obvious for a person having ordinary skill in the art at the time of filing to use the pharmaceutical composition comprising the bispecific antibody comprising VEGF and TIGIT binding domains as taught in the combined teachings of Mazor and Xia in a method for treating neovascular eye disease associated with TIGIT and/or VEGF signaling, wherein the neovascular eye disease is e.g. choroidal neovascularization, diabetic retinopathy, or age-related macular degeneration as taught by Lin, Lee, and Ge. This is obvious, because the combined teachings of Mazor and Xia teach a pharmaceutical composition for treating various cancers, including ovarian and pancreatic cancers, wherein the pharmaceutical composition comprises the bispecific antibody comprising VEGF and TIGIT binding domains to target both immune checkpoint (TIGIT) and angiogenic activity (VEGF) to achieve synergistic anti-tumor effects, Lin teaches a method for treating neovascular eye disease by utilizing a bispecific antibody engineered to bind to VEGF and ANG-2, Lee teaches that in CNV mouse models, in vivo depletion of IFN-γ secreting NK cells significantly reduced corneal angiogenesis and CNV, and Ge teaches that TIGIT, which is expressed on lymphocytes, displays a unique property among inhibitory immune checkpoints since it not only augments anti-tumor CD8+ T cells but also anti-tumor NK-cell responses while reducing the suppressive capacity of regulatory T cells. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to create a method to treat TIGIT or VEGF-associated neovascular eye diseases e.g. nAMD or choroidal neovascularization by inhibiting an immune checkpoint that regulates not