DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-2, 5-7, 9-12, and 14-23 are pending and under examination in the instant application.
Specification
The disclosure is objected to because of the following informalities: The specification is written in a font that is too small (approximately size 9) and therefore makes both the spacing and text size makes it difficult to read.
The use of the term Fortebio®, 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. See e.g. p. 9, p. 24, p. 29.
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.
Appropriate correction is required.
Drawings
The drawings are objected to because:
Fig. 2, Fig. 3, Fig. 4A, Fig. 4B, Fig. 5B, Fig. 8, Fig. 9 are objected to because the conversion from color to greyscale means that the positive and negative control points are not easily discernable from the experimental groups, and therefore the legends are unclear. The examiner suggest using more distinct shades or shapes for the groups to help the conversion to greyscale.
Fig. 13C is objected to because the CD31 and DAPI signals cannot be distinguished from each other in greyscale. The Examiner suggests using separate panels for each stain rather than the merge of the fluorescent images.
Fig. 14 is objected to because the labels across the row at the top are too small and blurry to be readable.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
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:
Fig. 19 shows enumerated sequences that are not identified by SEQ ID NO in the Figure or in the specification brief description of drawings.
Claim Objections
Claims 2, 7, 9, 11, and 15 are objected to because of the following informalities:
Claim 2 is objected to for “[…], 98%, 99%, or more identity […] to the amino acid sequence of (i)” because the phrase “or more identity” in line 6 is a term of degree that obscures the meaning of the claim. It is uncertain what amount “or more” than at least 99% would refer to. The Examiner suggests amending the claim to recite e.g. “at least 80% identity to an amino acid sequence selected from SEQ ID NOs: 24, 20, 16, 12, 8, and 4”.
Claims 2, 7, 9, 11, and 15 are objected to for the recitation of e.g. “at least 80%, 90%, 91%, […] or 99%”. The language is informal because the recitation of multiple minimums in the alternate results in broader and narrower ranges of sequence identity recited in the same claim and obscures the minimum identity limitation. 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.
Claim 1-2, 5-7, 9-12, and 14-23 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.
Regarding claim 1, the recitation of “comprising or consisting of an amino acid sequence set forth in” is indefinite because it recites both a narrow (consisting) and a broad (comprising) range (See MPEP § 2173.05(c)). This further renders the claim indefinite because, even though the limitations are recited in the alternate, a person of ordinary skill in the art would not be able to determine which antibodies have a CDR “consisting of” the claimed sequence, because no definition of the CDR numbering system is provided, and therefore it is not clear what the boundaries of the CDRs for any given VHH would be to have no additional amino acids in the CDR.
The term “preferably” or “more preferably” in claims 2, 7, 9, 11, 12, 15, 22, and 23 are exemplary terms which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant revise the claims to remove the terms “preferably” and “more preferably” and the limitations following it.
Claim 2 is indefinite for the recitation of “[…], 98%, 99%, or more identity […] to the amino acid sequence of (i)” because the “preferably” in (i) renders the antecedent basis for “the amino acid sequence of (i)” unclear.
Claim 2 is indefinite for the recitation of “comprises an amino acid sequence having at least 1-30, 1-20, 1-15, 1-10, or 1-5 amino acid changes” because the recitation of “at least” followed by a range makes it unclear whether the number at the top of the range is a minimum number of changes or a maximum number of changes. A person of ordinary skill in the art would not be able to determine whether a polypeptide having 31 amino acid changes reads on the claims because it is uncertain whether the meaning is “at least 30 amino acid changes” or “at least one, but less than 30 amino acid changes”.
Regarding claim 2, the parenthetical “(e.g., substitutions, deletions, and/or insertions, preferably substitutions, and more preferably conservative substitutions)” renders the claim indefinite because it is unclear whether the limitations following the parenthetical are part of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant amend the claim to remove the parenthetical and the limitations within.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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 21-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating a disease or disorder with neovascularization comprising administering to a subject in need thereof the bispecific binding protein according to claim 6 or a pharmaceutical composition comprising the bispecific binding protein
does not reasonably provide enablement for a method for treating any neovascularization-associated disease comprising administering to any generic subject the bispecific binding protein according to claim 6 or a pharmaceutical composition comprising the bispecific binding protein.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Scope of the claimed genus and nature of the invention
The instant claim is directed towards a method for treating a neovascularization-associated disease, comprising administering to a subject a bispecific binding protein comprising a first antigen-binding component specifically binding to human VEGF C, wherein the first antigen-binding component comprises a single-domain antibody polypeptide comprising a VHH domain of the formula consisting of 3 CDRs and 4 FRs FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein the VHH domain comprises (i) CDR1 comprising or consisting of an amino acid sequence set forth in SEQ ID NO:21, CDR2 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 22, and CDR3 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 23:(ii) CDR1 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17, CDR2 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, and CDR3 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19:(iii) CDR1 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 9, CDR2 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 10, and CDR3 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 11: or (iv) CDR1 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, CDR2 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and CDR3 comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and a second antigen-binding component specifically binding to human VEGF A; wherein the bispecific binding protein inhibits the binding of VEGF A to its VEGF receptor and inhibits the binding of VEGF C to its VEGF receptor. Regarding the meaning of “neovascularization-associated disease” the instant specification states “Herein, the term "neovascularization-associated disease" refers to a disease, disorder, and/or condition in which the onset, development, and/or progression of the disease involves neovascularization (including neovascularization, neolymphangiogenesis, and/or both). Such diseases, disorders, or conditions would benefit from the blocking of the biological activity of VEGF-C or VEGF-A or both”. Thus, the broadest reasonable interpretation of the claim is that it reads on a method of treating any disease that may involve neovascularization at any point in the etiology of the disease, but does not require the disease have neovascularization involvement at the point of treatment; and further, the body of the method is not linked to the preamble, and therefore the claim reads on administering the bispecific binding molecule to any generic subject regardless of the presence of the neovascularization-associated disease.
State of the relevant art; level of ordinary skill; and level of predictability in the art
VEGF-C and VEGF-A are endothelial growth factors known to be involved in the development of blood vessels via angiogenesis or lymphangiogenesis through the signals to endothelial cells via VEGF receptors 1-3 (Reviewed in: Apte, Rajendra S., Daniel S. Chen, and Napoleone Ferrara. "VEGF in signaling and disease: beyond discovery and development." Cell 176.6 (2019): 1248-1264; see e.g. Fig. 2). Apte et. al. teaches that “VEGF (now referred to as VEGF-A) is a member of a family of proteins including VEGF-B, VEGF-C, VEGF-D, VEGF-E (virally encoded), and PlGF (reviewed in Ferrara and Adamis, 2016). VEGF-C and VEGF-D are primarily implicated in regulation of lymphangiogenesis (Alitalo et al., 2005)” (“Insights into the Complexity of VEGF Signaling” section, ¶1).
Regarding methods of treating neovascularization-associated diseases, there has been clinical use of anti-VEGF-A neutralizing antibodies or VEGF-Trap molecules against VEGF-A, VEGF-B, and PIGF, as well as VEGF gene expression inhibitors; the receptors have also been targeted using anti-VEGFR immunotherapy, neutralizing antibodies, and VEGFR TK inhibitors such as sunitinib, sorafenib, etc.) (Shibuya M. VEGF-VEGFR Signals in Health and Disease. Biomol Ther (Seoul). 2014 Jan;22(1):1-9. doi: 10.4062/biomolther.2013.113; See Fig. 2).
However, the scope of these diseases that are associated at stages with neovascularization is not predictable, and it is not clear that all subjects at any stage with any version or etiology of the entire scope of the diseases claimed may be treated with the bispecific binding protein as claimed. For example, Costa, Paulo Zoé, and Raquel Soares. "Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox." Life sciences 92.22 (2013): 1037-1045 teaches that diabetes mellitus is a chronic metabolic condition with complications such as nephropathy, retinopathy, neuropathy, impaired wound healing and accelerated atherosclerosis, are implicated with a large number of cellular and subcellular changes on vessels. In agreement, evidence indicates that in retinopathy, nephropathy and atherosclerotic plaque, there is excessive angiogenesis, whereas in wound healing and myocardial perfusion, blood vessel growth is impaired” (Abstract). Costa et. al. teach that microvascular disease is not present in early stages (p. 1038 left column ¶2) and that “Angiogenesis plays an ambiguous role when it comes to the pathogenesis of vascular disease in diabetes mellitus. Exacerbated angiogenesis occurs in diabetic retinopathy, nephropathy and diabetic atherosclerosis. This excess leads to the increased risk of cardiovascular events — the growth of vasa vasorum inside vascular wall is stimulated, leading to bleeding, plaque instability and consequent rupture. On the other hand, in diabetic foot disease there is a clear deficit in angiogenesis” (p. 1038, right column ¶3). Costa et. al. also teach that some diabetes-associated conditions have decreases in neovascularization (Table 1). Therefore, it would not have been predictable whether diabetes, a neovascularization-associated disease could be treated with the breadth claimed because not all diabetes (such as early stages, or those with diabetic foot disease) have a clearly delineated condition that could benefit from inhibition of VEGF C/VEGF A.
In regards to solid tumors, studies have shown that some tumors are non-angiogenic (Donnem, Tom, et al. "Non-angiogenic tumours and their influence on cancer biology." Nature Reviews Cancer 18.5 (2018): 323-336; Abstract, entire document). Donnem teaches that many research articles have described tumors with a non-angiogenic blood supply (Supplementary Table 1) and that tumors may co-opt existing blood vessels rather than grow their own. Donnem teaches that the clinical implications of non-angiogenic tumor growth are a matter of debate because “Even within NSCLC, non-angiogenic tumour growth was reported to be both a positive and a negative prognostic factor for survival in separate studies90,91” (). Donnem further teaches “Furthermore, in a cohort of patients with metastatic colorectal cancer receiving preoperative bevacizumab (an anti-VEGF monoclonal antibody) in combination with chemotherapy, those with a non-angiogenic replacement HGP responded poorly compared with those with the angiogenic desmoplastic HGP15. In addition, the majority of breast cancer liver metastases showed a non-angiogenic HGP, which is important because the combination of bevacizumab and chemotherapy has thus far failed to provide a survival benefit in metastatic breast cancer15”. It, therefore, would not have been predictable that any neovascular-associated disease, such as a solid tumor, may be treated in any patient using the instant bispecific antibody because it would not have been predictable a priori which subsets of the genus, even among patients only with solid tumors, may be treated with the anti-VEGF C antibody.
In regard to ocular diseases, some ocular diseases such as glaucoma are neovascularization-associated but have different causative mechanisms and therefore would not clearly be treated by the instant anti-VEGF C/VEGF A bispecific. For example, neovascular glaucoma is a secondary glaucoma where the primary disease is commonly proliferative diabetic retinopathy or central vein retinal occlusion (Rodrigues, Gustavo B., et al. "Neovascular glaucoma: a review." International journal of retina and vitreous 2.1 (2016): 26), and this type of glaucoma would be enabled because it is neovascularized. However, the broader disease of glaucoma is an ocular disease causing vision loss characterization by degeneration of retinal ganglion cells (Weinreb, Robert N., Tin Aung, and Felipe A. Medeiros. "The pathophysiology and treatment of glaucoma: a review." Jama 311.18 (2014): 1901-1911). Therefore, although glaucoma is a “neovascularization-associated disease”, a person of ordinary skill in the art would not expect that someone with primary glaucoma would be treated by the instant bispecific.
Summary of species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and the quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification teaches 6 species of anti-VEGF C VHH binding domains that bind to VEGF C (Example 3, Table 1) which block the binding of VEGF C to VEGFR2 and VEGFR 3 (Examples 4 and 5). The instant specification teaches 9 species of bispecific antibodies using the anti-VEGF C VHHs and the anti-VEGF antibodies Aflibercept or Lucentis Fab (Table 3). Two of the bispecific antibodies, IEX04-56 and IEX04-57, block VEGFR2 signaling in HEK293 cells (Example 10) and BaF3-FLT4 cells (Example 11). Blocking of VEGF A/VEGF C signaling was also observed on human umbilical vein endothelial cells (HUVECs) (Example 12). For a working example of a method of treating, the instant specification teaches that administering the anti-VEGFC/VEGFA antibody IEX04-056 to a nude mouse model of melanoma (A375 cells) showed up to a 77% reduction in tumor growth by day 21 (Table 5, Example 14) and that IEX04-056 and IEX04-057 in a cynomolgus monkey laser-induced choroidal neovascularization model showed similar improved retinal pathology compared to positive controls (Example 15). There are no methods of treating neovascularization-associated diseases in the absences of neovascularization, or treatment of diseases prior to a secondary condition of neovascularization (e.g. treatment of glaucoma or diabetes) with the instant bispecific shown.
Conclusion
Applicant does not have enablement for a method of treating any generic neovascular-associated disease comprising administering the instant bispecific antibodies. It would take undue experimentation to determine the method of treating any subject, and any neovascular-associated disease regardless of the etiology of the subject with the disease with the instant bispecific antibodies.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 5-7, 9-11, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19154503 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '503 anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1, 2, 5, the claims of ‘503 teach a pharmaceutical composition comprising a bispecific binding protein wherein the bispecific binding protein comprises an anti-VEGFC single-domain antibody comprising CDR1 SEQ ID NO: 1, CDR2 SEQ ID NO: 2, and CDR3 SEQ ID NO: 3 (identical to instant SEQ ID NOs: 17, 18, and 19) and comprising a VHH domain of SEQ ID NO: 4 (identical to instant SEQ ID NO: 20).
Regarding claims 6 and 20, the bispecific binding protein comprises a second antigen binding domain specifically binding to human VEGFA, for example SEQ ID NO: 6. The specification was consulted regarding the definition and scope of this anti-VEGFA binding domain (MPEP 804. ), and evidences that this is a domain that inhibits binding of VEGFA to its receptor (e.g. Example 9) and claim 3 teaches the pharmaceutical protein in a buffering system (reads on pharmaceutically acceptable carrier).
Regarding claim 7, claim 13 teaches that the first antigen binding component is fused to the second antigen binding component via a linker, preferably a (G4S)n or G(G4S)n linker.
Regarding claim 9, claim 10 teaches the VEGFA binding domain comprises SEQ ID NO: 6, which is identical to instant SEQ ID NO: 26.
Regarding claims 10 and 11, claim 14 teaches the composition where the first and second polypeptide chain comprise SEQ ID NO: 8, which is identical to instant SEQ ID NO: 47 and comprises the single-domain polypeptide binding to VEGF C linked to the C-terminus of the Fc fusion polypeptide.
Claims 16-19 and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19154503 (reference application) in view of U.S. 20110143428 to Bagri et. al. published 16 June 2011 (Of Record, IDS dated 9/3/2025).
This is a provisional non-statutory double patenting rejection.
The teachings of the ‘503 claims are in the NSDP rejection above.
Regarding claims 16-19, The claims of ‘503 do not explicitly teach a polynucleotide encoding the bispecific binding protein according to claim 6, an expression vector comprising the polynucleotide, a host cell transfected with the vector, or a method for producing the bispecific binding protein comprising culturing the host cell and recovering the produced bispecific binding protein.
This deficiency is resolved by Bagri.
Bagri teaches anti-VEGF-C antagonist antibodies (Abstract). Bagri teaches that some embodiments of the anti-VEGF-C antibodies are bispecific antibodies [0149]. Bagri teaches polynucleotides encoding the antibodies, vectors comprising the polynucleotides, and host cells comprising the vectors; as well as methods of making the antibodies wherein the method comprises culturing the host cell under conditions suitable for expression of the polynucleotide encoding the antibody and isolating the antibody [0153].
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to make a polynucleotide encoding the antibody, a vector comprising the polynucleotides, and host cells comprising the vectors and use them in a method of making as taught by Bagri in order to make the bispecific antibody of ‘503. This would have a predictable effect because a person of ordinary skill in the art would understand that vectors and polynucleotides encoding the various antibodies and methods of making them are conventional and are obvious variants of the protein sequences taught by the ‘503 claims, as taught by Bagri.
Regarding claims 21-23, The claims of ‘503 do not explicitly teach a method comprising administering to a subject the bispecific binding protein according to claim 6, or a pharmaceutical composition comprising the bispecific binding protein thereof; wherein the disease is a solid tumor or wherein the disease is an ocular disease.
This deficiency is resolved by Bagri.
Bagri teaches that anti-VEGFC and anti-VEGFA antibodies are used for a method of inhibiting angiogenesis comprising administering the anti-VEGFC antibodies [0157]. Bagri teaches that the methods are for treating a tumor, cancer, or proliferative disorder [0158]. In some embodiments the cancer is non-small cell lung cancer [0161] (reads on solid tumor, claim 22). In some embodiments the antibody is used for a method of treating a pathological condition associated with angiogenesis, wherein the pathological condition is an intraocular neovascular disease [0164] (reads on ocular disease). Bagri et. al. teaches the VEGF-C antibody may be bispecific [0149] and that anti-VEGF-C antibodies in combination with anti-VEGF-A antibodies reduced the tumor growth of 66c14 tumors (e.g. [0196], Fig. 16) and H460 tumors ([0197], Fig. 17, Fig. 43).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to perform the method of treating as taught by Bagri et. al. using the bispecific of ‘503 in order to benefit from the improved method of treating solid tumors and intraocular neovascularization with a combination of VEGF-A and VEGF-C inhibitors as taught by Bagri. This would have a reasonable expectation of success because ‘503 teaches a bispecific with VEGF A and VEGF C inhibitory domains, and Bagri teaches methods of treating with VEGF C and VEGF A inhibitors, and that their VEGF C antibodies may be bispecific.
Claims 1-2 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 19133948 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '948 anticipate the instant claims.
This is a provisional NSDP rejection.
The claims of ‘948 teach a trispecific fusion protein comprising a polypeptide chain comprising a VEGFC binding domain, wherein the VEGF C binding domain comprises or consists of a VHH domain that specifically binds VEGF C, wherein the VEGF C comprises a CDR1-3 sequence contained SEQ ID NO: 4 (identical to instant SEQ ID NO: 20 and comprising instant CDRs 1-3 SEQ ID NO: 17, 18, and 19, respectively; instant claims 1 and 3); preferably wherein the anti-VEGF C VHH comprise SEQ ID NO: 4 (identical to instant SEQ ID NO: 20; instant claim 2).
Claims 6-7, 9-11, and 16-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 19133948 (reference application) in view of U.S. 20110143428 to Bagri et. al. published 16 June 2011 (Of Record, IDS dated 9/3/2025).
This is a provisional NSDP rejection.
The teachings of ‘948 in regard to claim 1, 2, and 5 are in the NSDP rejection above.
The claims of ‘948 do not teach a bispecific binding protein comprising the VEGF C VHH binding domain and a second antigen-binding component to VEGF A, wherein the VEGF A inhibits the binding of VEGF A to its receptor.
‘948 teaches a trispecific binding protein where one of the domains binds to VEGF C (as above), and a second domain binds to VEGFA comprising a ligand capture domain that specifically binds to VEGFA (claim 1) (reads on inhibiting binding to VEGF A to its receptor). ‘948 teaches wherein the trispecific binding protein comprises the VEGF A binding protein linked to the VEGF C binding protein via a linker (e.g. claims 5, 7, reads on instant claim 7).
Regarding claim 9, claim 1 teaches wherein the ligand capture domain is an extracellular domain from a VEGFR and wherein the VEGFA binding domain comprises the Ig-like domain of VEGFR-1 and the Ig-like domain of VEGFR-2, preferably SEQ ID NO: 9 (identical to instant SEQ ID NO: 26).
Regarding claim 11, the claims of ‘948 teach a trispecific wherein the VEGF C and VEGF A portions of the trispecific with the linker is 97.2% identical to instant SEQ ID NO: 47 as shown below, which the difference being a (GGGGS) linker vs. a GRPGS linker as shown below:
RESULT 1
US-18-681-904-47
Query Match 77.8%; Score 2886.5; DB 1; Length 564;
Best Local Similarity 97.2%;
Matches 548; Conservative 2; Mismatches 9; Indels 5; Gaps 1;
Qy 139 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 198
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 60
Qy 199 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 258
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 120
Qy 259 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 318
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 180
Qy 319 GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 378
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 240
Qy 379 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 438
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 300
Qy 439 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS 498
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS 360
Qy 499 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH 558
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH 420
Qy 559 YTQKSLSLSPG-----GRPGSGRPGSEVQLVESGGGLVQPGGSLRLSCAASGSSFSPYAM 613
||||||||||| | ||| ||||||||||||||||||||||||||||||||||||
Db 421 YTQKSLSLSPGGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGSSFSPYAM 480
Qy 614 GWYRQAPGKQRELVSATSEGGFTLYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYY 673
|||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||
Db 481 GWYRQAPGKQRELVSATSSGGFTLYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYY 540
Qy 674 CYMHWRGSDPENYWGQGTQVTVSS 697
|| ::| ||| ||||||||||||
Db 541 CYTYYREYDPEMYWGQGTQVTVSS 564
Regarding claim 16, claim 11 teaches a polynucleotide encoding the protein.
Regarding claims 17-19, claims 12-14 teach a vector encoding the protein, a host cell transfected with the vector, and a method of producing the polypeptide comprising culturing the host cell and recovering the fusion protein.
Regarding claim 20, claim 15 teaches a pharmaceutical composition comprising the protein.
Regarding claims 21-23, the claims teach a method of treating a neovascularization-related disease comprising administering the fusion protein, wherein the disease is a solid tumor or an ocular disease (reference claims 15-17).
Thus, the difference between the claims of ‘948 and the instant claims is that the claims of ‘948 claim a trispecific further comprising an anti-Ang2 binding domain, and the instant claims are directed towards a bispecific with only the VEGF C and VEGF A binding domains.
This deficiency is resolved by Bagri.
Bagri teaches that anti-VEGFC and anti-VEGFA antibodies are used for a method of inhibiting angiogenesis comprising administering the anti-VEGFC antibodies [0157]. Bagri teaches that the methods are for treating a tumor, cancer, or proliferative disorder [0158]. In some embodiments the cancer is non-small cell lung cancer [0161] (reads on solid tumor, claim 22). In some embodiments the antibody is used for a method of treating a pathological condition associated with angiogenesis, wherein the pathological condition is an intraocular neovascular disease [0164] (reads on ocular disease). Bagri et. al. teaches the VEGF-C antibody may be bispecific [0149] and that anti-VEGF-C antibodies in combination with anti-VEGF-A antibodies reduced the tumor growth of 66c14 tumors (e.g. [0196], Fig. 16) and H460 tumors ([0197], Fig. 17, Fig. 43).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to make a bispecific antibody comprising anti-VEFC antagonist antibodies by modifying the trispecific antibody of ‘948 down to only the anti-VEGF C and anti-VEGF A binding domains in order to benefit from combining the anti-VEGF C and anti- VEGF A binding domains as taught by ‘948. This would have a reasonable expectation of success because Bagri teaches methods of treating with the combined effects of VEGF C and VEGF A, so a person of ordinary skill in the art would consider the bispecific VEGF C antagonist as taught by Bagri comprising the VEGF A and VEGF C domains as taught by ‘948 to have a reasonable chance of having the combined anti-VEGF C and anti-VEGF A inhibitory effects as taught by Bagri, and therefore to be an obvious variant of the trispecific of ‘948.
Allowable Subject Matter
The single domain antibodies of claim 1 comprising the sets of CDRs, wherein the CDRs comprise the SEQ ID NOs as recited in parts (i)-(iv), are free of the prior art.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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