Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-22 are pending and under consideration.
Specification
The specification is objected to for the following reasons:
a) The specification filed 08/17/2023 is objected on page 19, line 4 for recitation of amino acid sequences in the absence of a sequence identifier. See 37 CFR 1.821(c). 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.
b) The disclosure is objected to because it contains several embedded hyperlinks and/or other forms of browser-executable codes. See pages 13 and 28. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
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 1-4, 9-17, and 19-22 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 (and rejected dependents thereto) are broadly drawn to bispecific antibodies with an improved structural design, which prevents or attenuates the mispairing of heavy and light chains with different specificities. Specifically, claim 1 is drawn to a bispecific antibody comprising a first antigen-binding portion and a second antigen-binding portion that specifically bind to two different antigens or different epitopes of the same antigen, wherein the first antigen-binding portion comprises:
a first polypeptide comprising, from N-terminus to C-terminus, a first heavy chain variable domain and a first paired domain operably linked to the first heavy chain variable domain, and
a second polypeptide comprising, from N-terminus to C-terminus, a first light chain variable domain and a second paired domain operably linked to the first light chain variable domain,
wherein one of the first paired domain and the second paired domain comprises an amino acid sequence of engineered HLA-I α3, and the other paired domain comprises an amino acid sequence of engineered β2 microglobulin.
The rejected claims only describe the first and second paired domains as either any engineered HLA-I α3s and engineered β2 microglobulins or those with partial identity (at least 85%) to SEQ ID NO:1 (HLA-I α3s) and SEQ ID NO:2 (β2 microglobulin). Thus, the claims are broadly drawn to a genus of first and second paired domains that encompass thousands of structurally diverse amino acids that may or may not fulfill the structural role of HLA-I α3s and β2 microglobulins as applicants have presented in their disclosure.
To reiterate, the specification teaches [0008] that the disclosure provides a bispecific antibody with an improved structural design, which prevents or attenuates the mispairing of heavy and light chains with different specificities. The specification further teaches [0039] that the bispecific antibody of the present disclosure, the paired domains in the first antigen-binding portion can improve chain mispairing using the engineered HLA-I α3 and the engineered β2 microglobulin.
However, the specification does not provide guidance or direction on what it means to “engineer” these two proteins nor does it provide a representative number of species of HLA-I α3 (or β2 microglobulins) proteins that have been engineered and that would predictably improve chain mispairing. For example, according to the specification, the HLA-I allele is very divergent with over 20,000 HLA-I alleles (page 27). Applicants appear to have chosen a consensus sequence of the α chain constant region of the HLA-I-B molecule. However, the chosen species is not representative of the entire genus of potential HLA-I-B proteins which is in the range of 4800 different proteins. (See table 2, page 28). Applicant have only provided a written description of two HLA-I α3 proteins, SEQ ID NO:1 and SEQ ID NO:3 and three β2 microglobulins (SEQ ID NOs: 2, 4, and 5) that are paired within the structure of the bispecific or trispecific (Claim 11) antibodies. Moreover, all of the engineering was subsequent to identifying the chosen HLA-I α3 consensus sequence(s) and the β2 microglobulin sequences. For example, to improve the pairing stability of the constant regions of MHC-I and optimize its developability, cysteine (Cys) could be introduced at position R60, A62, or G63 for MHCICαori, and cysteine (Cys) could be introduced at position Y26, R12, or Y67 for MHCICβori, at the contact interface of the domains of MHCICα and MHCICβ [see 0027]. Or, specific mutations could be introduced to optimize the isoelectric points. For example, [0228] mutations D22R, E48K, and D53K at three sites were introduced in MHCICα, and a single-point mutation E69R was introduced in MHCICβ, thereby increasing the theoretical isoelectric point of the MHC-I element to 7.8.
Thus, the written description is not commensurate in scope with alternative or engineered HLA-I α3 proteins and β2 microglobulin proteins as broadly claimed. The specification does not demonstrate possession that other possible bispecific antibodies with the claimed structures would predictably improve chain mispairing. A "representative number of species" means that the species, which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
It has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure, one of skill in the art would not know which domains, amino acids, or three-dimensional structures are essential for improving chain mispairing. Mere idea or observation of function in the absence of technical structural details is insufficient for written description; isolation and characterization at a minimum are required.
In the absence of sufficient guidance, direction, and disclosure of the claimed engineered HLA-I α3 proteins and β2 microglobulin proteins, the specification as filed does not appear to provide sufficient written description for the genus as broadly claimed. For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species cannot be achieved by disclosing only one (or none) species within the genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of bispecific antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiefs v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v.Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4, 9-10, 13-14, 17, and 20-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2018237192 (Basi, Guriqbai; published December 2018, Applicant’s IDS)
As to claims 1, 9-10, Basi teaches [7] a heterodimeric bispecific antibody (HBA) comprising a first antigen recognizing moiety (A) and a second antigen recognizing moiety (B).” (binds to two different antigens (bivalent) or different epitopes [159]) wherein the first antigen recognizing moiety (A) contains a first light chain comprising a first light chain variable region (VL1) fused to a light chain constant region (CL), a first heavy chain comprising a first heavy chain variable region (VH1) fused to a first heavy chain constant domain (CHI) and the second antigen recognizing moiety (B) contains a second light chain comprising a second light chain variable region (VL2) fused to a first light chain pairing partner (m), which VL2 is different from VL1, and a second heavy chain comprising a second heavy chain variable region (VH2) fused to a second light chain pairing partner (n). Basi teaches [8] that m can be MHC I α3 (HLA-I α3) and n can be β2microglobulin as further exemplified by Basi’s Figure 4 below. Also, this shows that the second antigen binding portion comprises a Fab.
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Compare the above to the current specification’s Figure 4A below:
[AltContent: textbox (Equivalent to n)][AltContent: arrow]
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As to claim 2, the broadest reasonable interpretation of “wherein the first paired
domain and the second paired domain can form a dimer, at least one non-natural interchain bond
can be formed between the first paired domain and the second paired domain, and the non-
natural interchain bond can stabilize the dimer” is that the paired domains spontaneously create non-natural interchain bonds due to the juxtaposition of cysteine residues that create disulfide bonds between the first and second paired domains. Basi teaches [165] that the case of β2 microglobulin (β2m) as "light chain" component of a heterodimer pair with the α3 domain from MHC-I presents an opportunity for increased combinatorial diversity of MHC-I α3 like-domains, as β2m has been documented to assemble as a heterodimer with a number of MHC-I homologs.
As to claim 3, Basi teaches (Table 3) that the HLA-1 α3 and the β2 microglobulin can exist as first and second paired domains in that order or their orders can be switched.
As to claim 4, Basi teaches [028] that the protein sequence of an MHC-I HLA-A (A*68 allele) α3 domain is SEQ ID NO:8. This SEQ ID NO:8 was 88% identical to the claimed SEQ ID NO:1.
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Basi further teaches that SEQ ID NO:12 is the protein sequence of β2microglobulin. SEQ ID NO:12 is 100% identical to the claimed SEQ ID NO:2.
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As to claim 13, Basi teaches that the bispecific antibodies further comprise an Fc domain composed of two Fc polypeptides capable of stable association. Specifically, Fig. 3-5 of Basi shows several bispecific antibody structures with two heavy chain constant regions (CH2) connected to hinge domains and X and Y domains (components of the Ig superfamily) which may confer more efficient assembly of, or stability to the heterodimers. [see para 167-168].
As to claim 14, Basi teaches that first and second antigen binding portions are operably linked at the C terminus to Fc (CH2) domains (Figure 4). Figure 4 also shows an Fab2 bispecific antibody which also appears to encompass a first polypeptide of the first antigen-binding portion operably linked at its C-terminus to one of the Fc polypeptides, and the second antigen-binding portion comprises a Fab and a Fab heavy chain of the second antigen-binding portion operably linked at its C-terminus to the other Fc polypeptide.
As to claim 17 and 20-22, Basi teaches [200] methods of treating a disease with the bispecific antibodies including cancers such as skin cancer (e.g., melanoma), ovarian, endometrial, bladder, breast, rectum, colon, gastric, pancreatic, lung, thymus, kidney and brain. The bispecific antibodies can exist as pharmaceutical compositions [215] and contain one or more pharmaceutically acceptable carriers. Basi further teaches [199] that the bispecific antibodies can be conjugated or linked to a therapeutic agent.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2018237192 (Basi, Guriqbai; published December 2018) as set forth above in view of (Bönisch et al., Protein Engineering, Design, & Selection, Vol.30 (9), August 2017)
Basi teaches as set forth above and further teaches [6] that product purity of bi-specific antibodies is dependent on two factors, heterodimeric assembly of two different heavy-chains co- expressed in the cell, and appropriate pairing of two different light chains with the respective heavy chains (Fig. 2). Despite the progress in technologies for expressing bi-specific antibodies, there is a need in the art for improved product purity, as well as a scale-able manufacturing solution.
Basi does not teach incorporating the F118A (EU numbering) substitution into the CL domain of the Fab bispecific antibody.
Bönisch et al. teach that maintaining the native IgG structure of a bsAb is favourable due to its well-established properties as a therapeutic molecule, including the long in vivo half-life and the ability to elicit effector functions. However, the production of this type of bsAb remains technically challenging as light and heavy chain pairing can occur randomly. This results in the formation of several mispaired by-products and, ultimately, translates into a reduced yield.
However, in a rational design approach to identify candidate mutations that could promote cognate light chain pairing within heterodimeric bsABs, the authors identified four key mutations within the CL domain that promoted cognate light chain pairing. These were F7S, F7A, F7V, and T18R. Notably, F7A is F118A according to EU numbering as identified by Table I-S from Bönisch et al. (see supplementary materials document in PTO-892). Bönisch et al. further teach that their strategy employs residues within the constant domains and thus mitigates any potential impact to the variable domains and that the interface designs did not adversely affect antibody expression yields, thermal stability, antigen affinity, dual antigen binding capabilities and biological function.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to incorporate the substitutions of Bönisch et al. into the CL domain of the bispecific antibody of Basi because both authors recognized the inherent problems of producing bsABs including the random mispairings of heavy and light chains leading to low yields of cognate product. However, Bönisch et al’s narrow and specifically tailored amino acid substitutions provided a solution that promoted cognate light chain pairing with no impact to the variable domains. Given this success and a potential higher yield of bsABs, it would have been obvious to incorporate the teachings of Bönisch.
Allowable Subject Matter
Claims 5-8, and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643