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 February 13, 2026, has been entered. Applicant's election without traverse of the antibody species corresponding to “S008-NB148-13”, which comprises three CDRs having the amino acid sequences of SEQ ID NO: 72-74, respectively (according to IMGT numbering), SEQ ID NO: 75-77, respectively (according to Kabat numbering), and SEQ ID NO: 78-80, respectively (according to Chothia numbering), and the corresponding variable region sequence of SEQ ID NO: 21, is acknowledged.
Applicant submits that claims 1-18, 20, and 22 are drawn to the elected species.
The amended claims filed on June 8, 2023 remain pending. Claims 3-11, 13, 15-18, 20, and 22 were previously amended. Claims 19 and 21 are canceled.
Claims 1-18, 20, and 22 are under examination herein.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, support for the claimed invention cannot be determined because the foreign priority documents provided are not in English. Therefore, the instant application is not entitled to the benefit of the foreign priority date of December 9, 2020. The filing date of the PCT/CN2021/136362 application, filed on December 8, 2021, will be used for the purpose of applying prior art.
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:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Specifically, the linker sequence of “GGGGS” in ¶ 0110 at page 47.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Objections to Specification and Abstract
The use of at least the terms “NANOBODY®”, “NANOBODIES®”, and “ALEXA FLUOR®” (“Alexa 488”), which are a trade name or a mark used in commerce, has been noted throughout this application (i.e., specification, title, abstract). 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.
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.
It is suggested that recitations of “nanobody” be amended to single-domain antibody or another equivalent term consistent with the disclosed invention.
The disclosure is objected to because of the following informalities:
The specification at ¶ 0021 recites that “a NKT cell” is a “natural killer cell”. However, “NKT” is understood in the art to refer to a “natural killer T cell”, which Wu (Frontiers in Bioscience (Schol Ed) (2011) 3: 236-251) describes as “a subset of T lymphocytes that share surface markers and functional characteristics of both conventional T lymphocytes and natural killer cells” (Abstract). The specification should be updated accordingly.
The specification at ¶ 0104 recites “alpacas (Llama)”. However, it is recognized in the art that alpacas and llamas, though related as camelids, are distinct species (Lama pacos and Lama glama, respectively). If llamas were not used in the immunization methods described in the Examples, it is suggested that references to llamas should be removed.
Appropriate correction is required.
The abstract of the disclosure is further objected to because it contains misspellings of “EGFR” (i.e., “EGRF” and “EGRFvIII”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 12 is objected to because of the following informalities: The claim recites in parentheses that “a NKT cell” refers to “a natural killer cell”. For the reasons discussed in the objection to the specification above, it is suggested that the claim should be updated to recite “a natural killer T cell”.
Appropriate correction is required.
Applicant is advised that should claim 1 be found allowable, claim 2 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 1-18, 20, and 22 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.
Claims 1-11, 13, and 16 contain the trademark/trade name “NANOBODY®”. 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 is used to identify/describe a single-domain antibody derived from camelids and, accordingly, the identification/description is indefinite.
Claims 12 and 17 (which depend from claim 11), claims 14-15 (which depend from claim 13), and claims 18, 20, and 22 (which depend from claim 1) are similarly rejected.
Further regarding claims 1-3, 5, 8-10, 12, 15, 18, and 20, the phrases “preferably” and/or “more preferably” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
Claims 4, 6-7, 11, 13-14, 16-17, and 22, which depend directly or indirectly from claim 1, are similarly rejected.
Further regarding claims 4 and 7, 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). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims.
Claim 5 recites the limitation “the antibody” in line 2. There is insufficient antecedent basis for this limitation in the claim. Neither claim 5, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Claim 6 recites the limitation “the antibody” in line 2. There is insufficient antecedent basis for this limitation in the claim. Neither claim 6, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Claim 7 recites the limitation “the antibody” in lines 2, 3, 5, 7, and 9. There is insufficient antecedent basis for this limitation in the claim. Neither claim 7, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Claim 8 recites the limitation “the antibody” in lines 2 and 6. There is insufficient antecedent basis for this limitation in the claim. Neither claim 8, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Further regarding claim 8, the claim recites that the nanobody® or antigen-binding fragment of claim 1 is a “fully human antibody”. This limitation renders the claim indefinite because a “fully human antibody” is necessarily derived from a human source and does not contain sequences from another species. However, the specification discloses that the CDR amino acid sequences recited in claim 1 are derived from single-domain antibodies generated in alpacas (e.g., Example 1). It is also notable that humans do not naturally produce single-domain antibodies. Accordingly, it is unclear how the instantly claimed antibodies can be fully human antibodies while comprising the alpaca-derived CDR sequences that are recited in claim 1.
In addition, claim 8 recites that the antibody or antigen-binding fragment of claim 1 is “Fab, Fab’, F(ab’)2, Fd, Fv, scFv, a diabody” (lines 10-11). This limitation renders the claim indefinite because the combinations of CDR amino acid sequences recited in the claim 1 are alpaca-derived sequences corresponding to VHH CDRs, whereas the instantly claimed structures are understood in the art to refer to various conventional immunoglobulin structures that comprise the combination of a heavy chain variable domain and a light chain variable domain, each having three CDRs. It is unclear how a VHH-derived structures recited in claim 1 can be any of a Fab, scFv, etc.
Finally, claim 8 is indefinite because the claim recites “(for example, a bispecific antibody)” in parentheses. This renders the claim indefinite because (1) “for example” is exemplary language, and (2) the use of parentheses in the claim renders it unclear whether the phrase in parentheses is intended to be limiting or merely exemplary. In the instant case, it’s unclear whether “a bispecific antibody” is intended to merely be exemplary of a type of multispecific antibody that may anticipate the limitations of the claim or is a required limitation. Parenthetical limitations should be avoided in patent claims.
Claim 16 recites the limitation “the antibody” in lines 1 and 3-4. There is insufficient antecedent basis for this limitation in the claim. Neither claim 16, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Claim 18 recites the limitation “the antibody” in line 2. There is insufficient antecedent basis for this limitation in the claim. Neither claim 18, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Claim 20 recites the limitation “the antibody” in line 2. There is insufficient antecedent basis for this limitation in the claim. Neither claim 20, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
Claim 22 recites the limitation “the antibody” in line 1. There is insufficient antecedent basis for this limitation in the claim. Neither claim 22, nor claim 1 from which it depends, earlier recites “an antibody” to which this phrase has antecedent basis. Claim 1 does recite “a nanobody”, which as noted above is a trademarked term.
It is noted for Applicant that “preferred” or “optional” claim limitations will not be considered as required in order for a prior art reference to anticipate the instantly claimed invention under 35 U.S.C. § 102 and 103.
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 2 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.
Claim 2 recites the nanobody® or the antigen-binding fragment of claim 1, wherein the three CDRs comprise a combination of sequences as set forth in one of (1) through (66), or “the CDR1, CDR2, and CDR3 have a sequence combination having 1, 2, 3, or more amino acid insertions, deletions and/or substitutions compared with the above sequence combinations (1)-(66)” … “preferably a substitution, more preferably a substitution of a conservative amino acid residue”. These limitations are substantially identical to those recited in claim 1, and thus fail to further limit the claimed subject matter.
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.
(1)
Claims 1-18, 20, and 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.
“[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).
Amgen Inc. v. Sanofi, Aventisub LLC, 872 F.3d 1367 (Fed. Cir. 2017) supported previous decisions (Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014)) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. Thus, claiming an antibody by describing the invention by what it does (function) rather than what it is (structure) is invalid. This can be overcome if a relevant number of species with structure/function correlation is known to the art or present in the specification.
The claimed invention. The nature and scope of the claimed invention at issue is a nanobody® or antigen-binding fragment that specifically binds to EGFR and EGFRvIII, comprising a combination of three CDRs (CDR1, CDR2, and CDR3) having a sequence combination with 1, 2, 3, or more amino acid insertions, deletions, and/or substitutions compared to one of the 66 sequence combinations set forth in claim 1 and in claim 2. The specification defines the term “antigen-binding fragment” as “one or more antibody fragments that retain the ability to specifically bind to a target antigen”, and states that exemplary antigen-binding fragments include a Fab fragment, a F(ab’)2 fragment, an Fd fragment, and an Fv fragment (¶ 0042). Altogether, these claim limitations fail to satisfy the written description requirement because, based on what is understood in the prior art and in view of the teachings of the Applicant's disclosure, these limitations do not sufficiently define a complete structure (i.e., three completely defined CDRs in a nanobody® or six completely defined CDRs in a conventional immunoglobulin) that would be expected to correlate with the stated function of binding to EGFR and EGFRvIII as required by the claim. Claims 2-18, 20, and 22, which depend directly or indirectly from claim 1, do not remedy this deficiency. Pursuant to the election of species requirement, this rejection will focus upon the antibody species corresponding to “S008-NB148-13”, which comprises the combination of CDRs having the amino acid sequences of SEQ ID NO: 72-74, respectively (according to IMGT numbering), SEQ ID NO: 75-77, respectively (according to Kabat numbering), and SEQ ID NO: 78-80, respectively (according to Chothia numbering), and a variable domain comprising the amino acid sequence of SEQ ID NO: 21.
Claim 3 further sets forth that the nanobody® or antigen-binding fragment of claim 1 comprises a variable region having at least 90% sequence identity to SEQ ID NO: 21 or comprises the framework region of a nanobody® or antigen-binding fragment having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 21. These claim limitations do not remedy the deficiencies noted above with respect to the incompletely defined CDRs comprised in the instantly claimed nanobody®.
Claim 4 further sets forth that the nanobody® or antigen-binding fragment of claim 1 “binds to human EGFR and EGFRvIII with a dissociation constant (KD) of no more than 10-7 nM, and binds to cynomolgus monkey EGFR with a dissociation constant (KD) of no more than 10-8 nM”, and optionally “binds to or does not bind to monkey EGFR protein”, and optionally “binds to or does not bind to murine EGFR protein”, and optionally “does not compete with antibody C225 or antibody 7D12”. These claim limitations serve to further limit the instantly claimed subject matter by its functional characteristics (i.e., binding with a specific level of affinity to the antigen, or binding to a specific epitope not bound by antibody C225 or antibody 7D12). These functional characteristics are understood in the art to be influenced by the antibody structure (i.e., amino acid sequence), and the claim does not recite a sufficient or complete level of structure (i.e., three completely defined CDRs in a nanobody®) that would be expected to correlate with these functions.
In addition, claim 10 sets forth a multispecific antigen-binding molecule comprising a first antigen-binding module comprising the nanobody® or antigen-binding fragment of claim 1 and a second antigen-binding module that “binds to an EGFR epitope different from the first antigen-binding module”. This limitation further fails to satisfy the written description requirement because the second antigen-binding module is defined by its function (i.e., binding to a separate epitope from the first antigen-binding module) without reciting a sufficient or complete level of structure that would be expected to correlate with this function.
State of the prior art. Schroeder (Journal of Allergy and Clinical Immunology (2010) 125(2, Suppl.2): S41-S52) teaches that conventional immunoglobulins (antibodies) known in the art are composed of two heavy and two light chains, which can be separated functionally into variable domains that are responsible for antigen binding and constant domains that specify effector functions (Abstract). Each variable domain can be split into three regions of sequence variability (i.e., CDRs). These six heavy and light chain CDRs are paired to form the antigen-binding site as classically defined and constitute the structural element that correlates with antigen-binding function. As discussed by Sela-Culang (Frontiers in Immunology (2013) 4: 302), “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, left column, “CDRs Identification”). However, while 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. This unpredictability is underscored by Ni (The Protein Journal (2024) 43: 683-696), who sets forth, “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).
The importance of the CDR sequences in mediating antigen recognition is also true for single domain antibodies such as those derived from camelids. Mitchell (Protein Engineering, Design & Selection (2018) 31(7-8): 267-275) describes nanobodies® as “a class of antigen-binding protein derived from camelid immune systems, which achieve equivalent binding affinities and specificities to classical antibodies (Abs) despite being comprised of only a single variable domain” (Abstract). Mitchell illustrates that camelid heavy chain antibodies comprise two polypeptides comprising a VHH domain, a CH2 domain, and a CH3 domain (e.g., Figure 1). Jovčevska (BioDrugs (2020) 34:11-16) teaches that VHH domains share the same structural architecture as the heavy chain variable domain (VH) of human immunoglobulins: four conserved sequence regions (i.e., framework regions) that surround three hypervariable antigen-binding loops (i.e., CDRs). CDR3 is the main contributor for antigen recognition and specificity, whereas CDR1 and CDR2 assist in the binding strength (Section 1.2). Bannas (Frontiers in Immunology (2017) 8: 1603) additionally teaches, “The CDR3 loop of camelid VHHs shows a much broader distribution of lengths (3-28 amino acids) than human VH domains (8-15 amino acids). The long CDR3 of a VHH enlarges the potential interaction surface with the target antigen, thereby compensating in part for the missing VL-domain” (pages 2-3). It is understood in the art that nanobody® CDRs are not interchangeable with conventional antibody CDRs.
Single-domain antibodies (or nanobodies®) against EGFR have previously been described in the art. See, for example, Laeremans (WO 2007/042289 A2), Zhang (WO 2008/141449 A1; cited in IDS), Zhang (WO 2019/014891 A1), and Chen (US 2021/0115146 A1).
Scope of species disclosed in original specification. The specification discloses the generation of nanobodies® against human EGFR, which were prepared by immunizing two alpacas against human EGFR and recovering and screening nanobodies® of interest (Examples 1-2, pages 35-52). Twenty-two nanobody® clones were obtained, the VHH amino acid sequences of which are summarized in Table 2 (pages 38-40) and the corresponding three CDR sequences (according to IMGT, Kabat, and Chothia numbering schemes, respectively) are summarized in Table 4 (pages 44-46). Applicant determined that a VHH-Fc antibody construct comprising the nanobody® corresponding to S008-NB148-13 (as elected on February 13, 2026) binds to human EGFR, human EGFRvIII, murine EGFR, and monkey EGFR (e.g., Examples 4-6; Tables 11-15; Figures 10-12 and 14-15). Each of the nanobodies® comprising the CDR amino acid sequences of SEQ ID NO: 72-74, respectively, SEQ ID NO: 75-77, respectively, and SEQ ID NO: 78-80, respectively, are drawn to a single embodiment having a VHH comprising the amino acid sequence of SEQ ID NO: 21.
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. 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 demonstrated by the state of the prior art, a complete complement of three CDRs (for a camelid-derived VHH antibody) or six CDRs (for a conventional antibody comprising a VH and a VL) are required for the function of antigen binding, and it is understood that mutating one, two, or more amino acid residues within the CDRs of either type of antibody has an unpredictable effect on this function of antibodies. Applicant's disclosure has not demonstrated which of the “1, 2, 3 or more” amino acid residues in the CDRs of the elected nanobody® clone may be altered without altering the ability of the nanobody® clone to specifically bind to EGFR and EGFRvIII as required by the instant claims. Furthermore, Applicant's disclosure does not demonstrate that the three VHH-derived CDR sequences of an exemplary nanobody® construct of the invention may be combined with those of a light chain variable domain to produce a functional antigen-binding fragment such as a Fab, F(ab’)2, or scFv, commensurate in scope with the instant claims.
Conclusion. For the reasons presented above, one of skill in the art would not know which of the countless other nanobodies® or antigen-binding fragments encompassed by the highly general structural requirements of the claims would also possess the required functional activity of specifically binding to EGFR and EGFRvIII. 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 nanobodies® or antigen-binding fragments as broadly claimed at the time the application was filed.
(2)
Claim 20 is 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 treating a tumor disease or inflammatory disorder associated with EGFR overexpression by administering a nanobody® of claim 1, does not reasonably provide enablement for (1) preventing a tumor disease or an inflammatory disease, regardless of EGFR overexpression, or (2) for treating a tumor disease or inflammatory disorder that is not associated with EGFR overexpression, by administering a nanobody® or an antigen-binding fragment of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to use the claimed invention at the time the application was filed without undue experimentation. MPEP § 2164.01 states: “The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).”
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors, which have been outlined in the Federal Circuit decision of In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman, 230 USPQ 546 (BPAI 1986).
Nature of the invention / Breadth of the claims. The method of claim 20 is drawn to treating and/or preventing a tumor disease or an inflammatory disease, comprising the step of administering an effective amount of the antibody or antigen-binding fragment of claim 1 to a patient in need thereof. (The subject matter of claim 1 is discussed in more detail in the 35 U.S.C. § 112(a) written description rejection above.) Claim 20 recites several limitations which are not required (i.e., “preferably, …”).
State of the prior art / Predictability of the prior art. Overexpression of EGFR (HER-1) and/or EGFRvIII has long been understood in the art to be implicated in various cancers, including breast cancer, non-small cell lung cancer (NSCLC), head and heck squamous cell carcinoma (HNSCC), glioblastoma multiforme, and others. Anti-EGFR antibodies have shown promise as a treatment strategy in these conditions. Consider, for example, the work of Atalay (Annals of Oncology (2003) 14(9): 1346-1363; cited in IDS); Modjtahedi (British Journal of Cancer (1996) 73: 228-235; cited in IDS); Kuan (Endocrine-Related Cancer (2001) 8: 83-96; cited in IDS); and Bianco (International Journal of Biochemistry & Cell Biology (2007) 39: 1416-1431). However, Dubé (Journal of Clinical Investigation (2012) 122(8): 2780-2792) notes that EGFR inhibition is not universally efficacious, as “resistance to EGFR inhibition occurs in tumors with mutant BRAF or KRAS” (Introduction).
Clinical trials aimed at proving preventative cancer activity by a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossibly long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a select few malignancies with treatments such as tamoxifen and finasteride. See review by Lee (Nature Reviews Cancer (2011) 11: 211-218) at page 211; Cancer Prevention Overview ((PDQ®)–Patient Version, National Cancer Institute).
With respect to inflammatory disorders, which cover a broad range of conditions, the teachings of the art are less predictable. Wang (American Journal of Translational Research (2019) 11(2): 520-528) teaches that EGFR is upregulated in psoriatic lesions, and that EGFR inhibition improves this phenotype (e.g., Abstract; pages 522-525; Figures 2 and 4; Table 1). Chen (Scientific Reports (2019) 9: 2516; see whole document) teaches that use of the EGFR inhibitor afatinib (a small molecule inhibitor) attenuates oxygen/glucose deprivation (OGD)-induced neuroinflammation. By contrast, Dubé (supra) teaches that human inflammatory bowel disease (IBD) patients have reduced EGFR signaling, suggesting that impaired EGFR contributes to disease etiology (e.g., Introduction). Wang (e.g., page 523), Holcmann (Molecular & Cellular Oncology (2015) 2(4): e104969; see whole document) and Perez-Soler (The Oncologist (2005) 10(5): 345-356; see whole document) disclose that while use of EGFR inhibitors, including anti-EGFR antibodies, in cancer therapy shows clinical benefit for cancer, this treatment also promotes inflammation and dermatologic rashes.
Similarly to tumor diseases, the art does not seem to recognize EGFR inhibition as an established preventative agent for inflammatory diseases.
Working examples / Guidance in the specification. A summary of relevant teachings of the instant disclosure is discussed in the 35 U.S.C. § 112(a) rejection above. While the disclosure does set forth that the nanobodies® of the invention do bind to EGFR expressed in tumor cell lines (e.g., A431 cells as shown in Figure 17A) and would be expected to inhibit EGFR activity (e.g., Figure 21), the working examples do not include experiments illustrating that the antibodies of the invention were directly tested for their anti-tumor activity or anti-inflammatory activity in any disease model for these respective conditions. The working examples also do not provide a showing that the antibodies may be used as a preventative agent for either a tumor-related disease or an inflammatory disease.
Conclusion. Upon careful consideration of the factors used to determine whether undue experimentation is required, the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enable the skilled artisan to use the claimed invention at the time the application was filed to (1) prevent any tumor disease or any inflammatory disease or (2) to treat a tumor disease or inflammatory disease that is not associated with EGFR overexpression, without undue and/or unreasonable experimentation.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The 2019 Patent Subject Matter Eligibility Guidance (“Guidance”) provides a means of
determining whether a particular claim is patent eligible under 35 U.S.C. 101. See MPEP 2106.
The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, article of manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
Claim 8 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without significantly more. The claim recites the nanobody® of claim 1, wherein the nanobody is “a natural antibody.” The specification defines the term “natural antibody” to mean “an antibody produced and paired by the immune system of a multicellular organism” (¶ 0037). This is considered distinct from an engineered antibody, which Applicant defines as “a non-natural antibody obtained through genetic engineering” (¶ 0037). The claimed limitation of “a natural antibody” reads on a product that does not have markedly different characteristics compared to what occurs in nature.
The judicial exception is not integrated into a practical application because the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception, e.g., effecting a transformation of a particular article to a different state or thing via genetic modification. See MPEP § 2106.04(d)(2) and MPEP § 2106.05(c).
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-4, 8-10, 13-16, 18, 20, and 22 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ren (US 2022/0160766 A1; earliest priority date: November 20, 2020).
Ren discloses monospecific and bispecific chimeric antigen receptors (CARs) and T-cell engagers, including CARs and T-cell engagers comprising an anti-EGFR VHH having specificity for EGFR and EGFRvIII (e.g., Abstract; Figures 47 and 65). In a particular embodiment, Ren discloses bispecific T-cell engagers (BiTE®) comprising an EGFR VHH arm having the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 155 (which at residues 22-138 share 100% sequence identity to the VHH domain comprising the amino acid sequence of instant SEQ ID NO: 21, with its corresponding CDRs) and an antigen-binding domain recognizing a separate target (e.g., Table 9, pages 56-57; Figures 6 and 10), anticipating claims 1-4, 8, and 10. (With respect to claim 4, Applicant is reminded that products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01.) Figure 6 illustrates that the bispecific T-cell engagers of the invention may comprise an anti-EGFR VHH coupled with an anti-CD3 scFv, the latter reading on a “therapeutic agent” (i.e., an immunomodulator, which in the present case exerts an effect on T cells) as recited in claim 9.
Regarding claims 13-16, Ren discloses a method of preparing a bispecific T-cell engager by integrating a polynucleotide encoding a T-cell engager of the invention into a host cell (e.g., a T lymphocyte), with or without a viral vector comprising said polynucleotide (e.g., Abstract; ¶ 0006-0015, 0124-0126).
Regarding claims 18, 20, and 22, Ren discloses pharmaceutical compositions and kits comprising a fusion protein or T lymphocyte of the invention and methods of use thereof for treating cancer (e.g., ¶ 0014-0020, 0433-0585).
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.
(1)
Claims 1 and 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Ren (US 2022/0160766 A1; supra) as applied to claims 1-4, 8-10, 13-16, 18, 20, and 22 above, and further in view of Goldman (Frontiers in Immunology (2017) 8: Article 865) and Rossotti (Biochemical Journal (2019) 476: 39-50).
The teachings of Ren are discussed in the 35 U.S.C. § 102 rejection above.
However, Ren does not expressly teach an antibody construct comprising an anti-EGFR VHH of the invention and an Fc domain.
Goldman reviews modifications that enhance stability of camelid single domain antibodies. Goldman recites, “One advantage of VHHs is that their ease of expression in many systems facilitates the development of a wide variety of fusion constructs. The vast majority of these constructs have been designed to enhance the utility of VHHs or add additional functionality. … Fusions to Fc domains or anti-Fc receptor sdAbs can endow them with effector function” (page 8).
Rossotti teaches that inhibitory anti-EGFR antibodies have shown clinical benefit in treating colorectal and head and neck cancers (Introduction). Rossotti further teaches, “One advantage of sdAb-based biologics for cancer therapy is that they tend to penetrate solid tumors better than full-length IgGs” (Introduction). Rossotti generated single-domain antibodies (sdAbs or VHHs) against human EGFR and fusions thereof to a human IgG1 Fc (e.g., Abstract; Experimental, pages 40-41), relevant to claims 5-7. (As understood by those of ordinary skill in the art, the human IgG1 Fc domain comprises a CH2 domain and a CH3 domain, and lacks a CH1 domain.) Rossotti discloses that the VHH-Fc fusions inhibited EGFR signaling by binding to EGF with a potency similar to cetuximab (e.g., Abstract; Results, pages 45-47; Figure 4).
Based on the further teachings of Goldman and Rossotti, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate an antibody construct comprising the fusion of (1) an anti-EGFR VHH (e.g., that taught by Ren) and (2) a human IgG1 Fc domain. The skilled artisan would have been motivated to do so because Goldman teaches that the fusion of an Fc domain to a sdAb enhances its therapeutic utility by conferring additional effector function. There would have been a reasonable expectation of success because Rossotti provides a proof-of-concept that a camelid-derived VHH domain can be effectively fused to a human IgG1 Fc domain while retaining its binding potency, and furthermore, one of ordinary skill in the art would recognize that the anti-EGFR VHHs taught by Rossotti and Ren are functional equivalents capable of use for the same purpose.
(2)
Claims 1, 11-12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Ren (US 2022/0160766 A1; supra) as applied to claims 1-4, 8-10, 13-16, 18, 20, and 22 above, and further in view of Zhang (WO 2019/014891 A1; published January 24, 2019; machine and original translations attached).
The teachings of Ren are discussed in the 35 U.S.C. § 102 rejection above.
However, Ren does not expressly teach a chimeric antigen receptor (CAR) construct wherein the extracellular domain comprises an anti-EGFR VHH of the invention.
Zhang discloses CAR-T cells modified by an EGFR single-domain antibody which have utility in treating tumors (e.g., Abstract). Zhang teaches that single-domain antibodies have several advantages over the single-chain variable fragments (scFvs) presently used in CARs, including higher antigen affinity, smaller size (which may overcome steric hindrance), and easier accessibility into complex antigen molecules (e.g., ¶ 0007 of machine translation). Pertinent to claims 11-12, the CAR-T cells of the invention, e.g., third-generation CAR-T cells, comprise an anti-EGFR single-domain antibody derived from llama, a CD8α hinge region, and intracellular signaling domains including 4-1BB and CD3ζ (e.g., 0015-0036, 0042-0057 of machine translation; Figure 3). Pertinent to claim 17, Zhang describes the process of generating said CAR-T cells by producing a lentiviral vector comprising the synthesized gene encoding the CAR of the invention and introducing said vector into T cells (e.g., ¶ 0054-0056, 0081-0157 of machine translation).
In view of the further teachings of Zhang, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a CAR-T cell construct comprising an anti-EGFR VHH, e.g., the anti-EGFR VHH taught by Ren. The skilled artisan would have been motivated to do so because Zhang teaches that using VHH antibodies in a CAR construct has several advantages over traditionally used scFvs (e.g., higher antigen affinity and smaller size). There would have been a reasonable expectation of success because Zhang provides a proof-of-concept that a camelid-derived VHH domain can be effectively incorporated into a CAR construct and exert potent killing activity (e.g., Figure 9 of Zhang), and furthermore, one of ordinary skill in the art would recognize that the anti-EGFR VHHs taught by Zhang and Ren are functional equivalents capable of use for the same purpose.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643