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 .
Application Status
The Response to the Election of Species Requirement filed on August 21, 2025 is entered. Applicant’s election of the anti-LOX-1 antibody of “6A10”, having the following combination of heavy chain and light chain complementarity determining regions (CDRs), is acknowledged:
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Because Applicant did not distinctly and specifically point out supposed errors in the restriction requirement, the election has been treated as an election without traverse. See MPEP § 818.01(a).
Claims 1-2, 17, 19-24, 26-27, 29-30, 33, 35, 37-40, and 46 are pending and under examination herein. No claims are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Rejoinder
The combination of heavy chain and light chain CDRs corresponding to Antibody 6A10, as elected by Applicant, appear to be free of the prior art. The search was expanded to the CDR sequences of the remaining antibody clones.
Upon additional search, all of the antibody species are hereby rejoined.
Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement among the species of antibodies or epitope-binding fragments thereof that specifically bind to LOX-1 and comprise a distinct HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, as set forth in the Office action mailed on May 21, 2025, is hereby withdrawn. In view of the withdrawal of the restriction requirement, Applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See, e.g., page 2, lines 30-31; page 11, line 16; page 14, lines 1-2; page 23, line 8; page 58, line 26. Applicant is required to delete the embedded hyperlinks and/or other forms 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.
Applicant may remedy this objection by removing “www.” from the beginning of the URLs or by replacing the periods (“.”) in the URLs with “(dot)”. Applicant’s cooperation in identifying and remedying all URLs in the specification is respectfully requested.
In addition, the use of at least the following terms, which are a trade name or a mark used in commerce, has been noted in this application:
DVD-Ig™ (e.g., pages 9 and 64),
NANOBODY® (e.g., pages 9 and 64),
AFFIBODY® (e.g., pages 9 and 64),
AFFILIN® (e.g., pages 9 and 64),
AFFIMER® (e.g., pages 9 and 64),
ANTICALIN® (e.g., pages 9 and 64),
AVIMER® (e.g., pages 9 and 64),
DARPin® (e.g., pages 9 and 64), and
TWEEN® (e.g., Examples).
The terms 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.
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 Objections
Claims 1-2, 17, 19-24, 26-27, 29-30, 33, 35, 37-40, and 46 are objected to because of the following informalities:
Claim 1 recites Table 1 in (a), Table 2 in (b), Table 3 in (c), and Table 4 in (d). MPEP § 2173.05(s) states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)” (citations omitted). In this case, the sequences that the tables refer to could easily be incorporated in to the claim to define the invention.
Claims 2, 17, 19-24, 26-27, 29-30, 33, 35, 37-40, and 46, which do not remedy this deficiency, are similarly objected to.
Claim 2 is further objected to for reciting a premature period (“.”) at the end of (b), between “thereto” and “;”, before the end of the claim. MPEP 608.01(m) states that claims begin with a capital letter and end with a period. A period should not appear before the end of the claim.
Claim 21 is further objected to because the recitation of a single domain antibody appears in duplicate, in line 5 (“a single-domain antibody (sdAb)”) and line 12 (“a single domain antibody”).
Claim 22 is further objected to because the preamble recites “The antibody or epitope binding fragment thereof according to any claim 1”. The word “any” should be removed.
Claim 23 is further objected to because the word “binding” is misspelled in the preamble (“epitope biding fragment” instead of “epitope binding fragment”).
Claim 40 is further objected to because the word “cells” appears in superscript (“LOX-1 positive cells”). It is unclear why the word “cells” is formatted in this manner in the claim, as this formatting is not used in the specification (e.g., page 10, line 28; page 66, lines 5-6; pages 67-68, bridging sentence).
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 21-22, 27, 29-30, 33, 35, 37-40, and 46 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 21, the claim recites the limitation that the antibody or epitope binding fragment thereof according to claim 1 is, inter alia, “a human antibody”. The claim is indefinite because it is unclear how the antibody of claim 1 can be a human antibody when the disclosure teaches that the instantly claimed antibody clones were generated in BALB/c mice injected with human LOX-1 recombinant protein. See Example 1 (pages 80-84). This limitation thus renders the claim unclear because a "human antibody" is derived from a human source and does not contain any murine sequences. See, e.g., Harding (2010) MAbs 2(3): 256-265 (page 258). Murine sequences are immunogenic to humans, and murine-derived CDRs can be engrafted into human sequence-derived framework regions to produce humanized antibodies (Harding, page 258).
Further regarding claim 21, the claim recites the limitation that the antibody or epitope-binding fragment according to claim 1 is “a single chain comprising complementary scFvs (tandem scFvs) or bispecific tandem scFvs”. Hornig (Chapter 40 in Antibody Engineering: Methods and Protocols, Second Edition, Methods in Molecular Biology (2012), Vol. 907; cited in IDS) teaches that the tandem single-chain variable fragment (tandem scFv or taFv) is one of the most commonly used recombinant bispecific antibody formats (e.g., Abstract). Hornig teaches that taFvs are composed off the variable domains of two different antibodies (e.g., page 715; Figure 1). Blanco (Clinical Cancer Research (2021) 27(20): 5457-5464) similarly teaches that tandem scFvs is a small Fc-free molecule composed of two scFvs connected by a flexible linker on a single polypeptide (page 5458; Figure 1B). Accordingly, the art appears to recognize that “tandem scFvs” as recited in parentheses in the claim are a bispecific antibody format. The recitation of “a single chain comprising complementary scFvs (tandem scFvs) or bispecific tandem scFvs” renders the claim scope unclear at least because it is unclear if or how “a single chain comprising complementary scFvs” differs from “bispecific tandem scFvs”, and furthermore whether “(tandem scFvs)” in parentheses is merely an example of “a single chain comprising complementary scFvs” which is narrower in scope or is meant to denote an alternative term for the same thing. The specification does not provide clarity on what is meant by “a single chain comprising complementary scFvs”, for example, how “complementary” is defined and/or whether “complementary” is synonymous with “bispecific”. If the terms are synonymous, then “bispecific tandem scFvs” would be redundant based on what is taught regarding tandem scFvs in the art.
Further regarding claim 21, the claim recites the limitation(s) that the antibody or epitope binding fragment thereof according to claim 1 is “a single-chain molecule containing one light chain variable region (VL), one heavy chain variable region (VH) antigen-binding domain, and one or two constant ‘effector’ domains optionally connected by linker domains”. Firstly, due to the grammatical structure of the claim, it is unclear whether this recitation is intended to encompass a single embodiment comprising all of these components (a VH, a VL, and one or two constant domains) or is listing the individual components separately. If it is the latter, the claim scope is further unclear because, as gleaned from Applicant’s disclosure, the antibodies of the invention are monoclonal antibodies having a combination of three heavy chain and three light chain CDRs which together associate to form a functional antigen-binding site for LOX-1. It is understood in the art that this association is necessary for antigen-binding, and that an individual VH or VL region derived from a monoclonal antibody, in isolation, will not bind successfully to the target antigen. See, e.g., Almagro (Frontiers in Immunology (2018) 8: 1751).
Further regarding claim 21, the claim recites the limitations that the antibody or epitope binding fragment thereof according to claim 1 is “an aptamer”, “an affibody”, “an affilin”, “an affitin”, “an alphabody”, “an anticalin”, “a DARPin”, “a Fynomer”, “a Kunitz domain peptide”, or “a monobody”. When considered in the context of the prior art, which articulates that these molecules are antibody mimetics, not antibodies, these recitations are indefinite. For example, Zhou (Nature Reviews Drug Discovery (2017) 16: 181-202) teaches that aptamers are short, single-stranded DNA or RNA molecules (20-100 nucleotides in length, 6-30 kDa) that specifically bind to a molecular target and are often termed “chemical antibodies”, whereas antibodies are proteins consisting of two heavy chains and two light chains, having a molecular weight of 150-180 kDa (e.g., Introduction; Table 1, page 183). One of ordinary skill in the art would recognize based on the teachings of Zhou that while aptamers and antibodies both bind to a target antigen, their chemical compositions and structures (including antigen-binding sites) are very different. By extension, Zhang (Biotechnology Journal (2024) 19(1): 2300532) teaches that antibody mimetics with diverse structures have emerged to overcome the limitations of natural antibodies and provide more adaptable solutions for diagnostics and therapeutics (e.g., page 2). Among these antibody mimetics include affibodies, anticalins, DARPins, fynomers, avimers, peptide aptamers, affimers, affitin, and others (e.g., page 2; Box 1). Zhang notes that while antibody mimetics act similarly to antibodies and bind specific antigens, they are artificial polypeptides and are not related to antibodies (Box 1, page 2). For example, affibodies comprise a protein scaffold derived from the B region of staphylococcal protein A (Box 1). Accordingly, the claim is further indefinite because it is unclear how the instantly claimed “antibody or epitope binding fragment thereof” can be an antibody mimetic when these are two different classes of molecules.
Further regarding claim 21, the claim contains at least the trademarks/trade names DVD-Ig™, NANOBODY®, APTAMER®, AFFIBODY®, AFFILIN®, AFFIMER®, ALPHABODY®, ANTICALIN®, DARPin®, and AVIMER®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case,
The trademark/trade name “DVD-Ig™” is used to identify/describe a dual variable domain immunoglobulin;
The trademark/trade name “NANOBODY®” is used to identify/describe a single-domain VHH antibody derived from camelids;
The trademark/trade name “APTAMER®” is used to identify/describe a single-stranded oligonucleotide that folds into defined architectures and binds to targets such as proteins;
The trademark/trade name “AFFIBODY®” is used to identify/describe a small antibody mimetic protein engineered to bind to a target protein with high affinity;
The trademark/trade name “AFFILIN®” is used to identify/describe an artificial protein structurally derived from human ubiquitin that is designed to selectively bind proteins;
The trademark/trade name “AFFIMER®” is used to identify/describe a small non-antibody protein that binds to target proteins with affinity in the nanomolar range;
The trademark/trade name “ALPHABODY®” is used to identify/describe a small 10 kDa antibody mimetic protein engineered to a variety of antigens;
The trademark/trade name “ANTICALIN®” is used to identify/describe an artificial antibody mimetic protein that is able to bind to proteins or to small molecules;
The trademark/trade name “DARPin®” is used to identify/describe designed ankyrin repeat proteins; and
The trademark/trade name “AVIMER®” is used to identify/describe an artificial protein that is able to specifically bind to certain antigens via multiple binding sites and is a shorthand for “avidity multimer.”
Accordingly, the claim is indefinite.
Regarding claim 22, the phrase “optionally” 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). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present case, it is unclear whether the metes and bounds of the claim are drawn broadly to any detectable label or more narrowly to the specific examples recited in the claim (“…selected from an enzyme, a fluorescent label, a radioisotope, or a chemiluminescent label”).
Regarding claim 27, the phrase “optionally” 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). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present case, it is unclear whether the metes and bounds of the claim are drawn broadly to any substrate or more narrowly to the specific examples recited in the claim (“…a plate, an enzyme linked immunosorbent assay (ELISA) plate, a slide, …”).
Regarding claim 29, the claim is indefinite because the claim recites “(for example, tumor size)” in parentheses in step (d). This renders the claim indefinite because it is unclear if the phrase in parentheses is limiting or merely exemplary of a way to determine cancer progression not set forth in the claim. Accordingly, the metes and bounds of the claims cannot be determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth in 35 U.S.C. § 112(b) so as permit the skilled artisan to know or determine infringing subject matter. Furthermore, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 30, 33, 35, and 37-40, which depend from claim 29 and do not remedy these deficiencies, are similarly rejected.
Further regarding claim 30, the phrase “optionally” 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). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present case, it is unclear whether the metes and bounds of the claim are drawn broadly to any neutrophil biomarker or more narrowly to the specific examples recited in the claim (CD15 or CD66b).
Further regarding claim 33, the claim is indefinite because the claim recites “(for example, tumor size)” in parentheses. This renders the claim indefinite because it is unclear if the phrase in parentheses is limiting or merely exemplary of a way to determine cancer progression not set forth in the claim. Accordingly, the metes and bounds of the claims cannot be determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth in 35 U.S.C. § 112(b) so as permit the skilled artisan to know or determine infringing subject matter. Furthermore, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claim 38, the phrase “optionally” 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). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present case, it is unclear whether the metes and bounds of the claim are drawn broadly to any type of biological sample or more narrowly to the specific examples recited in the claim (whole blood) and, consequently, further comprises the step of destroying or lysing any red blood cells in the sample.
Regarding claim 46, the claim is indefinite because the claim recites “(for example, PMN-MDSCs)” in parentheses in step (c). This renders the claim indefinite because it is unclear if the phrase in parentheses is limiting or merely exemplary of a way to determine cancer progression not set forth. Accordingly, the metes and bounds of the claims cannot be determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth in 35 U.S.C. § 112(b) so as permit the skilled artisan to know or determine infringing subject matter. Furthermore, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 21, the claim recites the limitations that the antibody or epitope binding fragment thereof according to claim 1 is “an aptamer”, “an affibody”, “an affilin”, “an alphabody”, “an anticalin”, “a DARPin”, “a Fynomer”, “a Kunitz domain peptide”, or “a monobody”. As recited in the 35 U.S.C. § 112(b) rejection above, the prior art recognizes that these are antibody mimetics, not antibodies, and belong to a separate class of molecules. Accordingly, the claim fails to include all of the limitations of the claim from which it depends because it states that the instantly claimed “antibody or epitope binding fragment thereof” is an antibody mimetic despite these being two different classes of molecules.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-2, 17, 19-24, 26-27, 29-30, 33, 35, 37-40, and 46 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue is a recombinant antibody or an epitope binding fragment thereof that binds to an epitope of LOX-1 as recited in claim 1 and its dependent claims, comprising at least one of:
one or more of heavy chain CDRs encoded by the nucleotide coding sequences of 6A10, 3D8, 9E12, 12D9, 12E4, or 4D6 identified in Table 1, or a nucleic acid sequence having at least 85% identical thereto; or
one or more of heavy chain CDRs having CDR amino acid sequences of 6A10, 3D8, 9E12, 12D9, 12E4, or 4D6 identified in Table 2, or an amino acid sequence at least 85% identical thereto; or
one or more of light chain CDRs encoded by the nucleotide coding sequences of 6A10, 3D8, 9E12, 12D9, 12E4, or 4D6 identified in Table 3, or a nucleic acid sequence having at least 85% identical thereto; or
one or more of light chain CDRs having CDR amino acid sequences of 6A10, 3D8, 9E12, 12D9, 12E4, 4D6 clone 1 or 4D6 clone 2 identified in Table 2, or an amino acid sequence at least 85% identical thereto.
As set forth in the claim, the anti-LOX-1 antibody or epitope-binding fragment thereof does not satisfy the written description requirement does not recite a structure that would be expected to correlate with the instantly claimed function of binding to an epitope of LOX-1 commensurate in scope with Applicant’s disclosure or in light of the teachings of the prior art. In one aspect, the recitations of “at least one of” and “one or more of heavy chain CDRs” or “one or more of light chain CDRs” allows considerable variability in the antigen-binding (CDR) structure, wherein the instantly claimed antibody may not have a structurally defined set of light chain CDRs and/or heavy chain CDRs, and/or the antibody may not have a completely defined set of three CDRs in each of the heavy chain or light chain, thus reciting an insufficient structure relative to what is understood to be necessary to confer antigen binding function. Moreover, the “one or more of” language combined with a listing of alternative antibody clones from which the CDRs may be derived allows for individual CDR sequences to be “mixed and matched” among the clones. Such “mixing and matching” would also be expected to impact the ability of the antibody to bind to LOX-1 or otherwise to bind to the antigen with similar affinity. In another aspect, the language of “at least 85% identical” with respect to the instantly claimed CDRs does not satisfy the written description requirement because such variability in the CDR structure(s) would be expected to impact the functional binding of the resulting antibody in view of the state of the art. The dependent claims do not remedy these deficiencies of claim 1.
Claim 2 further recites that the instantly claimed antibody or epitope-binding fragment thereof comprises at least one of (a) a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 3, 7, 11, 15, 19, or 25, or at least 85% identical thereto; or (b) a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 5, 9, 13, 17, 21, 21, or 27, or at least 85% identical thereto; or (c) a VH encoded by a nucleic acid sequence of SEQ ID NO: 2, 6, 10, 14, 18, or 24, or a nucleic acid sequence at least 85% identical thereto; or (d) a VL encoded by a nucleic acid sequence of SEQ ID NO: 4, 8, 12, 16, 20, 22, or 26, or at least 85% identical thereto. As above, the claim language allows for the instantly claimed antibody or epitope-binding fragment thereof to be incompletely structurally defined; to have variability in the variable region sequences, including within the CDRs; and/or to have “mixed and matched” variable regions from different anti-LOX-1 antibody clones of the invention. Each of these would be expected to impact the binding of the instantly claimed antibodies to an epitope of LOX-1.
State of the prior art. It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy chain and light chain variable regions of said antibody, each of which comprises three CDRs (or hypervariable regions) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro (Frontiers in Immunology (2018) 8: 1751; supra), “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3).
Although the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. Ni (The Protein Journal (2024) 43: 683-696) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction). Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori (Almagro, pages 3 and 6-7).
Gershoni (Biodrugs (2007) 21(3): 145-156) teaches that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (page 146, Section 1.1). The skilled artisan therefore understands that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
Exemplary antibodies that bind to an epitope of LOX-1, having distinct combinations of completely defined heavy chain and light chain CDRs, have previously been described in the art. See, e.g., Heldwein (US 2014/0377281 A1; US 2015/0004168 A1, cited in IDS) and Buchanan (US 10,117,889 B2).
Scope of species disclosed in original specification. The working examples discuss the generation of monoclonal antibodies against an optimized human (h)LOX1 immunogen which was delivered via immunization to 6-8 week old female BALB/c mice (pages 80-81). The sera of immunogen-boosted mice were screened for the highest binding and spleens were harvested. Example 1 discloses that approximately 50-60 antibody-producing mouse hybridoma clones had at least four-fold greater binding activity than background. The cell lines of the top five highest performing hybridoma candidates were amplified (pages 82-83). Hybridomas were tested for avidity (e.g., Figures 2-3). Clones 6A10 and 12D9 displayed strong avidity, followed by 12E4 and 4D6 (Example 1, page 83; brief description of Figure 4, pages 4-5; Figure 4). Example 2 recites that expression of LOX-1 expression was observed by immunohistochemical analysis in tumor tissues from liver, breast, ovarian, pancreatic, kidney, and lung tissues, but not in colon or bladder tumor tissues (pages 84-85; Figure 9).
The nucleic acid sequences and amino acid sequences of the heavy chain and light chain CDRs corresponding to five antibody clones, 6A10, 12D9, 12E4, 4D6 (clones 1 and 2), and 3D8, are recited in Tables 1-4 (pages 31-35). Clone 4D6 has one VH region sequence and two possible VL region sequences. Corresponding nucleic acid sequences and amino acid sequences of the VH and VL regions of these clones is recited in Table 5 (pages 35-57). The antibody clone sequences (VH+VL) specifically enumerated in the disclosure is summarized below:
Clone 6A10 comprises a VH having an amino acid sequence of SEQ ID NO: 3 (nucleic acid sequence of SEQ ID NO: 2) and a VL having an amino acid sequence of SEQ ID NO: 5 (nucleic acid sequence of SEQ ID NO: 4);
Clone 9E12 comprises a VH having an amino acid sequence of SEQ ID NO: 7 (nucleic acid sequence of SEQ ID NO: 6) and a VL having an amino acid sequence of SEQ ID NO: 9 (nucleic acid sequence of SEQ ID NO: 8);
Clone 12D9 comprises a VH having an amino acid sequence of SEQ ID NO: 11 (nucleic acid sequence of SEQ ID NO: 10) and a VL having an amino acid sequence of SEQ ID NO: 13 (nucleic acid sequence of SEQ ID NO: 12);
Clone 12E4 comprises a VH having an amino acid sequence of SEQ ID NO: 15 (nucleic acid sequence of SEQ ID NO: 14) and a VL having an amino acid sequence of SEQ ID NO: 17 (nucleic acid sequence of SEQ ID NO: 16);
Clone 4D6 comprises a VH having an amino acid sequence of SEQ ID NO: 19 (nucleic acid sequence of SEQ ID NO: 18) and a VL having an amino acid sequence of SEQ ID NO: 21 (clone 1) or 23 (clone 2) (nucleic acid sequence of SEQ ID NO: 20 (clone 1) or 22 (clone 2)); and
Clone 3D8 comprises a VH having an amino acid sequence of SEQ ID NO: 25 (nucleic acid sequence of SEQ ID NO: 24) and a VL having an amino acid sequence of SEQ ID NO: 27 (nucleic acid sequence of SEQ ID NO: 26).
MPEP § 2163 states that 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. While many antibody clones against hLOX1 were generated, a limited number demonstrated avidity for the antigen, and the corresponding sequences of said higher-avidity clones are recited in Tables 1-5 and summarized above. Each of these clones comprises unique combinations of heavy chain and light chain CDRs. Humanized variants of said clones are not described. Single-domain antibodies against LOX-1 having only a VH domain or a VL domain and antibody mimetics against LOX-1 are also not described.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As illustrated by the state of the prior art, the complementary CDR structures of the VH and VL domains of a monoclonal antibody are critical for functional antigen-binding activity. Only those antibodies having the specifically defined combination of heavy chain and light chain CDRs set forth in the specification (e.g., Tables 1-5), which have a demonstrated ability to specifically bind an epitope of LOX-1 as specifically claimed, satisfy the written description requirement. The specification does not set forth which residue(s) in the CDR(s) may be mutated to achieve up to 15% variability in the CDR structures while maintaining the instantly claimed function of binding to LOX-1. Furthermore, the specification does not set forth that all of the many possible combinations of CDRs among the specifically enumerated antibody clones can be “mixed and matched” to produce an antibody that retains the ability to specifically bind LOX-1.
Conclusion. For the reasons presented above, one of skill in the art would not know which of the countless other antibodies encompassed by the highly general structural requirements of the claims would also possess the required functional activity of binding to an epitope of LOX-1. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of antibodies as broadly claimed at the time the application was filed.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643