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 .
DETAILED ACTION
Applicant’s election without traverse of Group I, claims 1-3, 5-7, 9, 10, 15, 17, 20-23, 25, 35, 41, 42 and 47 in the reply filed on May 29, 2026 is acknowledged.
Applicant’s election without traverse of species: 1) a specific antibody fusion protein comprising HCDRs 1-3 of SEQ ID NOs: 4-7-12 and LCDRs 1-3 of SEQ ID NOs: 17-19-24, corresponding heavy chain of SEQ ID NO: 38 and light chain of SEQ ID NO: 42; 2) a specific VEGFR configuration: 2 VEGFR components, each comprising an Ig-like domain 2 of Flt1 (Flt1d2) and an Ig-like domain 3 (Flk1d3), wherein the first VEGFR component is fused to the C-terminus of a first heavy chain of the anti-Ang2 full length antibody via an optional first linker, and wherein the second VEGFR component is fused to the C-terminus of a second heavy chain of the anti-Ang2 full length antibody via an optional second linker; is acknowledged.
Claims 1-3, 5-7, 9, 10, 15, 17, 20-23, 25, 35, 41, 42, 47, 48, 52 and 57 are pending.
Claims 15, 17, 25, 35, 48, 52, and 57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1-3, 5-7, 9, 10, 20-23, 41, 42 and 47 are pending and under consideration.
It is noted that prior art does not teach or suggest the elected antibody fusion protein comprising HCDRs 1-3 of SEQ ID NOs: 4-7-12 and LCDRs 1-3 of SEQ ID NOs: 17-19-24. Thus, the search is extended to other species encompassed by claim 9, such as claim 9 (6).
Priority
It is acknowledged that this application is a 371 of Internation Patent Application No. PCT/CN2022/082448 filed March 23, 2022, and claims priority benefits of foreign Patent Application No. PCT/CN2021/083093, filed March 25, 2021.
Certified copies of foreign priority applications have been received as required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed on 09/13/2023 has been considered and entered by examiner.
Claim Objections
Claim 3 is objected to because of the following informalities: there is an extra space in “claim 1 ,”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7 and 23 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 7, which depends on claim 1, recites “wherein the VEGFR component is fused to the multivalent anti-Ang2 antibody or antigen-binding fragment thereof via an optional linker” which renders the claim indefinite. A wherein clause is to recite a specific structure (linker) to further limit claim 1. Consequently, the use of the term “wherein” implies that this structure is there. However, adding the word “optional” implies a total absence of the specific structure (linker), thus the claim is indefinite.
Claim 23, which depends on claim 1 indirectly, recites “wherein the antibody fusion protein comprises a first VEGFR component and a second VEGFR component”. Claim 1 recites an antibody fusion protein comprises: i) …, and ii) a VEGFR component. It is unclear whether “a first VEGFR component and a second VEGFR component” are additional VEGFR components for the antibody fusion protein or refer to the VEGFR component recited by claim 1.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-7, 9, 10, 20-23, 41, 42 and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is drawn to an antibody fusion protein which encompasses a broad genus of multivalent Ang2 antibodies and a broad genus of VEGFR components. For the encompassed antibodies, the claim defines the antibody by function only: the multivalent anti-Ang2 antibody or antigen-binding fragment thereof does not inhibit the binding between Ang2 and TEK receptor tyrosine kinase (TIE2). Given Broadest Reasonable Interpretation (BRI), the claim encompasses any part of any VEGFR (not only Ig-like domain). As evidenced by paragraph [0133] of the instant publication US 2024/0182553, “a VEGFR component” also encompasses variants derived from VEGFR (with mutations, substitutions).
Taken together, claim 1 encompasses a broad genus of antibody fusion proteins which vary significantly; have different structures and/or different physical and chemical properties. However, the specification lacks written description support for the broadly claimed genera.
Regarding the multivalent anti-Ang2 antibodies, MPEP 2163 II A 3(a) states: Disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Wong (Wong et al., MABS, 2021, Vol. 13, No. 1, e1873478, Publication Year: 2021) teaches that sequence-distant antibodies can target the same epitope (Abstract). Thus, one ordinary skill in the art would not be able to visualize other antibody encompassed by the claims, which binds to a specific epitope (Ang2), based on a few antibodies disclosed in the specification.
In the instant case, the specification and prior art (see 103 rejection below, reference Park, in particular) discloses a few anti-Ang2 antibodies which can target Ang2, but do not inhibit Ang2 binding to TIE2 (Examples 1 of Specification, Table 1 in particular). However, the disclosed antibodies would not tell the structure of other antibodies, variants or antibody fragments encompassed by the claims.
In addition, the specification and prior art have not established the relationship between the claimed functions and the structure of the antibody. One of ordinary skilled in the art would not be able to readily recognize/visualize an antibody with required properties. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of anti-Ang2 antibodies with required functions.
Regarding the broadly claimed VEGFR components, as evidenced by paragraph [0023] of the instant publication US 2024/0182553 A1, the function of the fusion protein requires that the fusion protein retains high binding affinity to both VEGF and Ang2. Shaik (Shaik et al., Biomolecules 2020, 10, 1673; Publication Date: 12/15/2020) teaches that different VEGFR binds to different VEGF and have different functions (Fig. 1 A). Shaik further teaches that VEGFR proteins have different domains (Table 1) and only Ig-like domain 2 and Ig-like domain 3 are critical for VEGF binding (the bottom paragraph on page 6). Consistent with this, the Example of the specification uses only one VEGFR component comprising both Ig-like domain 2 of VEGFR1 and Ig-like domain 3 of VEGFR2. However, the claims encompass a broad genus of VEGFR components, including different domains of VEGFR and variants of known domains. The specification and prior art have not established the relationship between the required functions and the structure of the VEGFR domains. One of ordinary skilled in the art would not be able to readily recognize/visualize a VEGFR component can be used in the fusion protein. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of VEGFR components used in the fusion protein.
In addition, claim 6 recites “wherein the VEGFR component comprises an amino acid of SEQ ID NO: 32”. As such by the recitation of “an” that is underlined and italicized above, the VEGFR component encompass components that comprise partial sequences of SEQ ID NO: 32 (i.e., “an amino acid sequence of” rather than “the amino acid sequence of” SEQ ID NO: 32). The instant specification only disclose an antibody fusion protein which comprises complete sequences of SEQ ID NO: 32. See [0236], Examples 1. One of ordinary skill in the art would not be able to readily visualize or recognize partial sequences of SEQ ID NO: 32 which have the same VEGF binding properties as full length SEQ ID NO: 32. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such VEGFR components at the time the instant application was filed.
Claims 2-3, 5, 7, 9, 10, 20-23, 41, 42 and 47 also encompass a broad genus of multivalent Ang2 antibodies and/or a broad genus of VEGFR components of claim 1. Thus, these claims lack the written description support as set forth above.
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.
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.
Claims 1-3, 5-7, 41, 42, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (Wu et al, WO 2019/075270 A1, Publication Date: 04/18/2019, cited in IDS of 09/13/2023) and Park (Park et al, WO2009/155015 A1, Publication Date: 12/23/2009, cited in IDS of 09/13/2023).
Wu teaches that VEGF plays an important role in angiogenesis. Tumor tissues tend to have higher expression of VEGF which stimulates tumor angiogenesis ([0004]).
Wu teaches that fusion protein comprising VEGFR component has been developed to treat diseases associated with VEGF expression, such as cancer. The VEGFR fragments will bind to and inactivate VEGF, thereby providing a means for reducing or inhibiting VEGF activity and, in turn, reducing or inhibiting endothelial cell proliferation and angiogenesis ([0006]).
Wu discloses an antibody fusion protein comprising 1) an antibody comprising a light chain, and 2) a VEGFR component, wherein the VEGFR component is fused to the C-terminus of the antibody light chain (such as C-terminus of antibody VL-CL domain), the antibody specifically recognizes Angiopoietin-2 (Ang2) ([0009], [0019], and Fig. 1), the antibody is a multivalent antibody, such as a divalent antibody or a tetravalent antibody ([0169]). In some embodiments, the antibody is a bispecific antibody ([0026], Fig. 2). In some embodiments, the antibody is a multispecific antibody ([0104]). The antibody can be a full-length antibody ([0171]). A full-length anti-Ang2 antibody (2 heavy chains and 2 light chains) would be a multivalent anti-Ang2 antibody.
However, Wu does not disclose the multivalent anti-Ang2 antibody or antigen-binding fragment thereof does not inhibit the binding between Ang2 and TIE2.
Park teaches ABTAA (Ang2-binding and TIE2 activating antibody (see Abstract), which has a dual function.
Park teaches that anti-angiogenic approaches often cause extreme hypoxia in tumors resulting from vascular regression and rarefaction, and eventually lead to increased drug resistance (page 954, col. 1, para. 2).
Park teaches that ABTAA has stronger anti-tumor activity than ABA (Ang2-blocking antibody) (Fig. 1B); ABTAA profoundly reduced vascular leakage and edema formation in glioma (Fig. 1C-1I).
Park teaches that ABTAA leads to a polarization of tumor-associated macrophage (TAM) toward anti-tumor phenotype, while ABA exacerbates pro-tumor polarization in glioma (Fig. 1G-1I, and page 956, col. 1, para. 2).
Park teaches that ABTAA reduces tumor hypoxia through tumor vessel normalization (page 956, col. 2; and Fig. 3). In LLC model, ABTAA favorably alters immune cell infiltration to tumor and effectively depletes circulating Ang2 (Fig. 5).
Park teaches that ABTAA also shows anti-tumor activity in lung carcinoma tumor model (Fig. 4A). In this model, ABTAA dramatically obliterated the hypoxic area by 66% compared with Fc while ABA had no effect (Fig. 4H).
Park teaches that ABTAA anti-tumor activity depends on TIE2 activation (the bridging paragraph of pages 959-960).
Park teaches that ABTAA suppresses Tumor growth and metastasis in breast tumor (Fig. 7).
Park teaches that ABTAA shows better efficacy in various combination treatments (e.g. Fig. 3F, Fig. 6B, and Fig. 8C)
Park teaches that ABTAA can form ABTAA/Ang2/Tie2 tripartite. This feature could be a key advantage of ABTAA, so that ABTAA can selectively act one tumor vessels that express high levels of Ang2 unlike normal blood vessels (page 965, col. 1, para. 2). Thus, ABTAA does not inhibit the binding between Ang2 and TIE2.
Park teaches that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment (Abstract).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine the teachings of Wu and Park, to substitutes the anti-Ang2 antibody in VEGFR-Ang2 antibody with ABTAA antibody with better therapeutic properties taught by Park. One of ordinary skill in the art would have had a reasonable expectation of success because ABTAA antibody has stronger anti-tumor activities; has better therapeutic activity in various combination treatments; has better specificity; elicits a favorable tumor microenvironment. Given that each components and methods are known in the art, as evidenced by the references, one of ordinary skill in the art would have a reasonable expectation of success to reach the claimed invention. The motivation would have been to develop an antibody-fusion protein with better therapeutic properties.
Regarding claims 2, 3, and 5, Wu teaches that VEGF component comprises an immunoglobulin-like (Ig-like) domain 2 of a VEGFR Flt1 (Flt1d2), may further comprise an Ig-like domain 3 of VEGFR Flk1 (Flk1d3) ([0010]).
Regarding claim 6, by reciting “an amino acid sequence of SEQ ID NO: 32” (not the amino acid sequence of SEQ ID NO: 32), given Broadest Reasonable Interpretation (BRI), claim 6 would encompass VEGFR component comprising partial sequence of SEQ ID NO: 32. Wu teaches a VEGFR component of SEQ ID NO: 8 ([0104]). As shown below, SEQ ID NO: 8 is 98.9% identical to instant SEQ ID NO: 32:
PCT-US18-55512-8
Query Match 98.9%; Score 1057; DB 1; Length 211;
Best Local Similarity 98.1%;
Matches 205; Conservative 0; Mismatches 0; Indels 4; Gaps 1;
Qy 1 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 62
Qy 61 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 63 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 122
Qy 121 VLNCTARTELNVGIDFNWEYPSSKHQHKKL----VNRDLKTQSGSEMKKFLSTLTIDGVT 176
|||||||||||||||||||||||||||||| ||||||||||||||||||||||||||
Db 123 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVLSPVNRDLKTQSGSEMKKFLSTLTIDGVT 182
Qy 177 RSDQGLYTCAASSGLMTKKNSTFVRVHEK 205
|||||||||||||||||||||||||||||
Db 183 RSDQGLYTCAASSGLMTKKNSTFVRVHEK 211
Thus, the VEGFR component would read on the VEGFR component of instant claim 6.
Regarding claim 7, Wu teaches that a linker may be used to connect the VEGFR component and the C-terminus of the antibody light chain ([0175]).
Regarding claims 41, 42 and 47, Wu teaches an isolated nucleic acid encoding the antibody fusion protein and a vector comprising the isolated nucleic acid ([0023]).
Wu teaches pharmaceutical compositions comprising the antibody fusion protein and a pharmaceutically acceptable carrier ([0258]).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Wu (Wu et al, WO 2019/075270 A1, Publication Date: 04/18/2019, cited in IDS of 09/13/2023) and Park (Park et al, WO2009/155015 A1, Publication Date: 12/23/2009, cited in IDS of 09/13/2023), as applied to claims 1-3, 5-7, 41, 42, and 47 above, and further in view of Kim (Kim et al., US 2015/0337033 A1, Publication Date: 11/26/2015).
Wu and Park teach the antibody fusion protein of claim 1 as set forth above. However, Wu and Park do not teach the anti-Ang2 antibody has the CDRs recited by claim 9.
Kim teaches anti-Ang2 antibody which does not inhibit binding between Ang2 and TIE2 ([0026], [0030], [0037], and 10D6 of Fig. 1, Example 1).
Kim teaches that the antibody has dual functions: lowering circulating Ang2 (inhibition of angiogenesis) and inducing TIE2 downstream signaling (normalization of blood vessels) ([0037] and [0038]).
Kim teaches humanized 10D6 with improved affinities, such as h10D6-OPTI-1 (Example 8, Table 12). h10D6-OPTI-1 comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 57. As shown below, h10D6-OPT1-1 reads on the antibody of claim 9 (6).
US-14-721-591-52
Query Match 85.7%; Score 147.4; Length 118;
Best Local Similarity 40.3%;
Matches 31; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 SDYAWN--------------KISYSGKTDYNPSLKS------------------------ 22
|||||| ||||||||||||||||
Db 31 SDYAWNWIRQPPGKGLEWMGKISYSGKTDYNPSLKSRSTISRDTSKNQFSLKLSSVTAAD 90
Qy 23 --------GNFEGAMDY 31
|||||||||
Db 91 TAVYYCARGNFEGAMDY 107
US-14-721-591-57
Query Match 82.8%; Score 119.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQSVSNDVA---------------YASNRYP--------------------------- 18
||||||||||| |||||||
Db 24 KASQSVSNDVAWYQQKPGKAPKLLIYYASNRYPGVPSRFSGSGSGTDFTLTISSLQPEDF 83
Qy 19 -----QQDYSSPWT 27
|||||||||
Db 84 ATYYCQQDYSSPWT 97
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine the teachings of Wu and Park, to make an VEGFR-ABTAA antibody fusion protein, and to substitute ABTAA with a full-length antibody with binding domains of 10D6. One of ordinary skill in the art would have had a reasonable expectation of success because similar to ABTAA, 10D6 antibody has dual functions: lowering circulating Ang2 (inhibition of angiogenesis) and inducing TIE2 downstream signaling (normalization of blood vessels); has affinity to Ang2. Thus, one of ordinary skill in the art would have a reasonable expectation that VEGFR-10D6 fusion protein would have good therapeutic properties too. The motivation would have been to expand options for VEGFR-anti-Ang2 fusion proteins.
Note: Claims 10, 20-23 are free of the prior art. The prior art does not disclose anti-Ang2 antibodies, or antigen-binding portions thereof, that specifically bind to angiopoietin 2 and do not inhibit the binding between Ang2 and TIE2 having the sequences recited in the instant claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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