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 amended claims filed May 10, 2023 are acknowledged. Claims 4-13, 15, 17, 19, 22-23, and 25 are amended. Claims 16, 18, 20-21, 24, and 26-28 are canceled.
Claims 1-15, 17, 19, 22-23, and 25 are pending and 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 November 10, 2020.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Accordingly, the filing date of the PCT/CN2021/129778 application, filed on November 10, 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 - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located on, e.g., pages 54 and 61, and correspond to glycine-serine peptide linkers (e.g., (G4S)1 and (G4S)3).
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See, e.g., page 59. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term “NANOBODY®”, which is a trade name or a mark used in commerce, has been noted in this application. See page 52. 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.
Note Regarding Claim Interpretation
Based on Applicant's disclosure, the Examiner is interpreting “full-length antibody” (e.g., as recited in claims 6 and 8-9) to mean “an antibody having a structure substantially similar to that of a native antibody structure or having an Fc region” (page 50, specification). The specification sets forth that native IgG antibodies have a structure composed of “a Y-type tetrameric protein comprising two heavy (H) polypeptide chains (HC) and two light (L) polypeptide chains (LC) held together by covalent disulfide bonds and non-covalent interactions” (page 49).
Claim Objections
Claims 1 and 10 are objected to because of the following informalities:
With respect to claim 1, it is suggested that the preamble should be amended to “A bispecific antibody comprising an anti-CLDN18.2 binding domain and an anti-CD3 binding domain” for clarity.
With respect to claim 10, it is suggested that the claim should be amended to recite “…having a structure of linking an anti-CD3 scFv…” in lines 1-2 for clarity.
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 2-3, 6-7, 10-12, 15, 17, 19, 22-23, and 25 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 claims 2-3, the claims recite “i.e.,” which is not clear language for designating the three CDRs as set forth in the claims. This rejection could be obviated if the claims were amended to recite, for example, “…wherein the anti-[antigen] binding domain comprises: a heavy chain variable region having three CDRshaving three CDRs
Claim 6 recites the limitation "the binding domain" in line 2. There is insufficient antecedent basis for this limitation in the claim. The claim depends from claim 1, which recites two binding domains – a first binding domain that is capable of binding to a CLDN18.2 protein, and a second binding domain that is capable of binding to CD3 – and it is unclear to which of these binding domains the claim limitations refer.
Regarding claim 7, the phrase “preferably” in line 2 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.
Further regarding claim 7, the term “a native Fc or a variant Fc” in line 3 is a relative term which renders the claim indefinite. The term “a native Fc or a variant Fc” is not defined by the claim, the specification does not provide a standard for ascertaining the meaning of what is considered “native” or “variant”, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification sets forth that native IgG antibodies are structured as Y-type tetrameric proteins comprising two heavy chain polypeptide chains (HC) and two light chain polypeptide chains (LC) held together by covalent disulfide bonds and non-covalent interactions (e.g., page 49). However, it is recognized in the art that antibodies having such a structure may be derived from a variety of organisms. Is “native” is intended to refer to the organism from which the antibody Fc is derived (e.g., human or mouse), or to indicate that the Fc is a wildtype Fc that does not contain mutations, or to something else?
Claim 10 recites the limitation "the C-terminus of the heavy or light chain of the full-length anti-CLDN18.2 antibody" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 10 depends, does not earlier recite “a heavy chain” or “a light chain” or “a full-length anti-CLDN18.2 antibody” to which these limitations may refer.
Claim 11 recites the limitations of “the anti-CD3 scFv” in line 2 and “the C-terminus of the heavy or light chains of the full-length anti-CLDN18.2 antibody” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 11 depends, does not earlier recite “an anti-CD3 scFv”, or “a heavy chain” or “a light chain” or “a full-length anti-CLDN18.2 antibody”, to which these limitations may refer.
Further regarding claim 11, the language of the claims appears to set forth that a single anti-CD3 scFv is simultaneously attached to two light chains, despite the claim later stating that the antibody comprises “two homologous light chains” and “two homologous heavy chains”. If Applicant is intending to claim a bispecific antibody having a structure similar to that of “31905-38AA” as depicted in Figure 1 (reproduced below), it is suggested that the claim should be amended to set forth that “a CD3 scFv” is fused to the C-terminus of each of the two light chains.
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In addition, because the claim recites that the heavy chains are homologous and that the light chains are homologous, it is suggested that the claim would be clearer if the relevant portions of the wherein clause in lines 3-4 were amended to recite that the fused light chains each have a sequence as set forth in SEQ ID NO: 2 and the heavy chains each have a sequence as set forth in SEQ ID NO: 1.
Claim 12 recites the limitations of “the anti-CD3 scFv” in line 2 and “the C-terminus of one heavy chain of the full-length anti-CLDN18.2 antibody” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 12 depends, does not earlier recite “an anti-CD3 scFv”, or “a heavy chain” or “a light chain” or “a full-length anti-CLDN18.2 antibody”, to which these limitations may refer.
In addition, because the claim recites that that there are two light chains and that these light chains are homologous, it is suggested that the claim would be clearer if the relevant portion of the wherein clause in line 5 were amended to recite that the light chains each have a sequence as set forth in SEQ ID NO: 5.
Regarding claim 15, the phrases “preferably” and “such as” render the claim indefinite because it is unclear whether the limitations following the phrases 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 17, which depends from claim 15 and does not remedy this deficiency, is similarly rejected.
Regarding claims 19, 23, and 25, the phrase “preferably” 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.
Claims 22-23 and 25, which depend from claim 19 and do not remedy the deficiencies of the claim, are similarly rejected.
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 4-5 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 bispecific antibody having a first binding domain that is capable of binding to CLDN18.2 and a second binding domain that is capable of binding to CD3, wherein the anti-CLDN18.2 binding domain comprises a heavy chain variable region (VH) having at least 80% sequence identity to SEQ ID NO: 23 and a light chain variable region (VL) having at least 80% sequence identity to SEQ ID NO: 24 (as recited in claim 4) and the anti-CD3 binding domain comprises a VH having at least 80% sequence identity to SEQ ID NO: 6 and a VL having at least 80% sequence identity to SEQ ID NO: 7 (as recited in claim 5). These claim limitations fail to satisfy the written description requirement because the claims define the binding domains by their ability to bind to a respective antigen (CLDN18.2 or CD3), but the corresponding structures (VH and VL) in the claim that are responsible for conferring this function are incompletely defined. Specifically, the VH and VL of each binding domain may comprise up to 20% variability in their amino acid sequences, including within the complementarity determining regions (CDRs), which confer their antigen-binding properties. This incompletely defined structure (amino acid sequence) is not sufficient for carrying out the instantly claimed functions based on what is understood in the art and in view of the teachings of Applicant's disclosure.
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 and light chain variable regions of a given 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), “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).
Bispecific antibodies which bind to both CLDN18.2 and CD3, having defined VH and VL amino acid sequences for each respective antigen-binding domain, have previously been disclosed in the art. See, e.g., Dahlhoff (WO 2020/025792 A1; cited in IDS); Yang (US 2023/0192903 A1); Sahin (US 2019/0309067 A1; cited in IDS); Sahin (WO 2014/075697 A1; cited in IDS); and Zhu (Scientific Reports (2019) 9: Article 8420; cited in IDS).
Scope of species disclosed in original specification. The disclosure describes two exemplary bispecific antibodies, designated “31905-38AA” and “31905-44AA”, the structural configurations of which are illustrated in Figure 1. The sequences and structures of the bispecific antibodies are summarized in Tables 1 and 2 (pages 62-65). The exemplary bispecific antibodies bind to human, murine, and cynomolgus CLDN18.2 and to human CD3 (e.g., Figures 2-3, 5, 7; Example 3).
The anti-CDLN18.2 binding domain of each bispecific antibody is derived from antibody 6#AA, which comprises heavy chain CDRs having the amino acid sequences of SEQ ID NO: 11, 12, and 13, respectively, and light chain CDRs having the amino acid sequences of SEQ ID NO: 14, 15, and 16, respectively (e.g., Summary; Table 2). Antibody 6#AA comprises a VH having the amino acid sequence of SEQ ID NO: 23 and a VL having the amino acid sequence of SEQ ID NO: 24 (Summary). Antibody 6#AA further comprises a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 5 (e.g., Example 1; Table 2).
The anti-CD3 binding domain of each bispecific antibody is an scFv derived from antibody h160C9AA (SEQ ID NO: 8), which comprises heavy chain CDRs having the amino acid sequences of SEQ ID NO: 17, 18, and 19, respectively, and light chain CDRs having the amino acid sequences of SEQ ID NO: 20, 21, and 22, respectively (e.g., Summary; Example 1; Tables 1-2). The h160C9AA antibody comprises a VH having the amino acid sequence of SEQ ID NO: 6 and a VL having the amino acid sequence of SEQ ID NO: 7 (e.g., Summary; Table 2). The h160C9AA antibody further comprises a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10 (e.g., Summary; Example 1; Table 2).
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. With respect to claims 4-5, Applicant's claims are drawn to a broad genus of possible bispecific anti-CLDN18.2/CD3 antibodies, with the requirement that the anti-CLDN18.2 antigen-binding domain comprises a VH having “at least 80% sequence identity” to SEQ ID NO: 23 and a VL having “at least 80% sequence identity” to SEQ ID NO: 24 (as set forth in claim 4) or that the anti-CD3 antigen-binding domain comprises a VH having “at least 80% sequence identity” to SEQ ID NO: 6 and a VL having “at least 80% sequence identity” to SEQ ID NO: 7 (as set forth in claim 5). However, Applicant is only in possession of bispecific antibodies in which the anti-CLDN18.2 antigen-binding domain comprises a VH having 100% sequence identity to SEQ ID NO: 23 and a VL having 100% sequence identity to SEQ ID NO: 24, and the anti-CD3 antigen-binding domain comprises a VH having 100% sequence identity to SEQ ID NO: 6 and a VL having 100% sequence identity to SEQ ID NO: 7. While two exemplary constructs were generated, they both comprise these same amino acid sequences.
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 enumerated in the State of the Art above, the CDRs present in the VH and VL of the antigen-binding domain of an antibody confer its antigen-binding function. With respect to claims 4-5, a claim drawn to an anti-CLDN18.2 antigen-binding domain having a VH having “at least 80% sequence identity” to SEQ ID NO: 23 and a VL having “at least 80% sequence identity” to SEQ ID NO: 24, or to an anti-CD3 antigen-binding domain comprises a VH having “at least 80% sequence identity” to SEQ ID NO: 6 and a VL having “at least 80% sequence identity” to SEQ ID NO: 7, without further defining the basic structural elements that confer their antigen-binding specificity (i.e., three CDRs in the VH and three CDRs in the VL), allows variability in the structure that would be expected to impact the antigen-binding ability of the resulting antibody. Applicant's disclosure does not identify which residue(s) in the CDRs of any of the claimed antigen-binding domains may be modified by up to 20% identity without impacting the specificity of the claimed bispecific antibody for CLDN18.2 and/or CD3.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other bispecific anti-CLDN18.2/CD3 antibodies encompassed by the highly general structural requirements of the claims would also possess the required functional activity. 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 bispecific antibodies as broadly claimed at the time the application was filed.
The rejection of claims 4-5 could be remedied by amending the claims to recite that the VH and VL of each antigen-binding domain comprise 100% sequence identity to the respective VH and VL amino acid sequences.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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, 3, 5-8, 10, 13-15, 17, 19, 22-23, and 25 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Yang (US 2023/0192903 A1; PCT filing date: May 29, 2020; hereafter “H. Yang”).
H. Yang discloses bispecific antibodies against CLDN18.2 and CD3 (e.g., Abstract), anticipating claim 1. H. Yang teaches that the bispecific antibodies of the invention have two specific antigen-binding sites enabling simultaneous binding of an immune cell surface antigen (CD3) and a tumor cell specific antigen (CLDN18.2), effectively bridging tumor cells and immune cells and promoting killing of the tumor cells by the immune cells (e.g., ¶ 0005). H. Yang discloses an embodiment in which the bispecific antibody comprises an anti-CD3 binding domain comprising a VH having the amino acid sequence of SEQ ID NO: 10 (which comprises the instantly claimed HCDRs comprising the amino acid sequences of instant SEQ ID NO: 17, 18, and 19, respectively) and a VL having the amino acid sequence of SEQ ID NO: 11 (which comprises the instantly claimed LCDRs comprising the amino acid sequences of SEQ ID NO: 20, 21, and 22, respectively) (e.g., ¶ 0006), anticipating claim 3. The VH and VL disclosed by H. Yang shares 93.6% sequence identity to the instantly claimed VH having an amino acid sequence of instant SEQ ID NO: 6 and 95.3% sequence identity to the instantly claimed VL having an amino acid sequence of instant SEQ ID NO: 7, anticipating claim 5. See sequence alignments between instant VH and VL (“Qy”) and those of H. Yang (“Db”) below.
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Regarding claim 6, H. Yang teaches an embodiment in which the antigen-binding domain specific for CLDN18.2 is in the form of a Fab fragment and the antigen-binding domain specific for CD3 is in the form of an scFv (e.g., Items 8 and 9, ¶ 0006; claims 8-9).
Regarding claim 7, H. Yang teaches that the Fc domain is wildtype or mutant Fc domain (e.g., ¶ 0006-0008).
Regarding claims 8 and 10, H. Yang teaches an embodiment in which an anti-CD3 scFv is linked to the C-terminus of a heavy chain of a full-length anti-CDLN18.2 antibody (e.g., Figure 4).
Regarding claims 13-15 and 17, H. Yang discloses nucleic acids, vectors, and host cells encoding the bispecific antibody of the invention, and use of the same in a method of preparation (e.g., ¶ 0006; Examples 1-2).
Regarding claims 19 and 22, H. Yang discloses pharmaceutical compositions and kits comprising a bispecific antibody of the invention (e.g., ¶ 0006, claim 18).
Regarding claim 25, H. Yang discloses a method of treating cancers such as gastric cancer or pancreatic cancer, which H. Yang teaches are associated with expression of CLDN18.2, that comprises administering a therapeutically effective amount of a pharmaceutical composition comprising the bispecific antibody to a subject (e.g., ¶ 0004-0006; claim 21). Upon administration of said pharmaceutical composition to a subject, the CLDN18.2-expressing tumor cells of said subject would be expected to be contacted by the bispecific antibody, thereby anticipating claim 23.
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.
Claims 1-2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over H. Yang (US 2023/0192903 A1; supra) as applied to claims 1, 3, 5-8, 10, 13-15, 17, 19, 22-23, and 25 above, and further in view of Yang (US 2022/0411492 A1, English language equivalent of WO 2020/228806 A1 (cited in IDS); PCT filing date: May 15, 2020; hereafter “Y. Yang”).
The applied reference of US 2022/0411492 A1 (“Y. Yang”) appears to have a common inventor (Yingying Yang) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of H. Yang, with respect to a bispecific anti-CLDN18.2/CD3 antibody, are discussed in the 35 U.S.C. § 102 rejection above.
However, H. Yang does not expressly teach an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising the combination of heavy chain and light chain CDRs set forth in claim 2, or the combination of VH and VL amino acid sequences set forth in claim 4.
Y. Yang discloses antibodies and antigen-binding fragments thereof comprising an antigen-binding domain specific for CLDN18.2, which have utility in treating cancers such as gastric cancer or pancreatic cancer (e.g., Abstract; claims 25-26). Relevant to claim 2, Y. Yang discloses an anti-CLDN18.2 antibody or antigen-binding fragment thereof that comprises a combination of heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 71, 72, and 73, respectively (which share 100% sequence identity to instant SEQ ID NO: 11, 12, and 13, respectively) and light chain CDRs comprising the amino acid sequences of SEQ ID NO: 112, 93, and 107, respectively (which share 100% sequence identity to instant SEQ ID NO: 14, 15, and 16, respectively) (e.g., claims 1-4; ¶ 0005-0012). Relevant to claim 4, Y. Yang further discloses an anti-CLDN18.2 antibody or antigen-binding fragment thereof that comprises a VH having the amino acid sequence of SEQ ID NO: 120 (which shares 100% sequence identity to instant SEQ ID NO: 23) and a VL having an amino acid sequence of SEQ ID NO: 124 (which shares 100% sequence identity to instant SEQ ID NO: 24) (e.g., ¶ 0015-0018). Y. Yang further provides bispecific antibodies comprising an anti-CLDN18.2 antibody or antigen-binding fragment thereof (e.g., ¶ 0024; claims 16-17).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the bispecific anti-CLDN18.2/CD3 disclosed by H. Yang by substituting into the anti-CLDN18.2 antigen-binding domain the antigen-binding domain taught by Y. Yang. The skilled artisan would have been motivated to do so because the anti-CLDN18.2 antibodies and antigen-binding fragments thereof have utility in treating CLDN18.2-expressing cancers such as gastric cancer, and are amenable for use in bispecific antibody constructs. There would have been a reasonable expectation of success because the skilled artisan would recognize that the two anti-CLDN18.2 antibodies are functional equivalents that are useful for achieving the same purpose.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8, 10, 13-15, 17, 19, 22-23, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,415,8531 in view of H. Yang (US 2023/0192903 A1; supra).
Relevant to claims 1-2 and 4, the reference patent claims a bispecific antibody comprising an anti-CLDN18.2 antibody or antigen-binding fragment thereof, comprising a combination of VH and VL CDRs having the amino acid sequences of SEQ ID NOs: 71, 72, 73, 112, 93, and 107, respectively, which share 100% sequence identity to instant SEQ ID NO: 11, 12, 13, 14, 15, and 16, respectively (‘853 claims 1, 6-7). Patent claim 2 further recites that the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a VH comprising at least 80% sequence identity to SEQ ID NO: 120 (which shares 100% sequence identity to instant SEQ ID NO: 23) and a VL comprising at least 80% sequence identity to SEQ ID NO: 124 (which comprises 100% sequence identity to instant SEQ ID NO: 24). Relevant to claim 6, because the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a VH and a VL, the construct comprises at least an Fv.
Relevant to claim 7, ‘853 claim 4 recites that the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising a native or a variant Fc as well as a light chain constant region.
Relevant to claims 13-15 and 17, ‘853 claims 10-13 recite a method of preparing the claimed antibody using a nucleic acid encoding the antibody, or a recombinant vector encoding said nucleic acid, or a host cell comprising said nucleic acid.
Relevant to claim 19, ‘853 claim 14 recites a pharmaceutical composition comprising the claimed antibody. Relevant to claim 23, ‘853 claim 15 recites a similar method of inducing cell death that comprises contacting the pharmaceutical composition of ‘853 claim 14 with CLDN18.2-expressing cells. Relevant to claim 25, ‘853 claims 16-18 recite a method of treating a disease associated with expression of CLDN18.2 in a subject comprising administering the pharmaceutical composition of ‘853 claim 14.
However, the reference patent does not expressly teach a bispecific antibody that specifically binds to both CLDN18.2 and CD3, wherein the anti-CLDN18.2 binding domain is a full-length antibody and the anti-CD3 binding domain is an scFv.
The teachings of H. Yang, with respect to anti-CD3 scFv binding domains and the amino acid sequences thereof, are recited in the 35 U.S.C. § 102 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the bispecific antibody claimed in the reference patent by incorporating an antigen-binding domain that is specific for CD3, e.g., the anti-CD3 scFv binding domain described by H. Yang. The skilled artisan would have been motivated to do so because H. Yang teaches that bispecific antibodies against CLDN18.2 and CD3 allow the simultaneous targeting of a tumor cell specific antigen (CLDN18.2) and an immune cell surface antigen (CD3), promoting a killing effect of the CD3-expressing immune cells on CLDN18.2-expressing tumor cells. There would have been a reasonable expectation of success because known work in one field of endeavor may prompt variation of it for use in the same field, and one of ordinary skill in the art would have recognized that the anti-CD3 antigen-binding domain in the bispecific antibody disclosed by H. Yang is able to be bodily incorporated into a bispecific antibody construct further comprising an anti-CLDN18.2 antigen-binding domain.
Allowable Subject Matter
Claim 9 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 U.S. Patent No. 12,415,853 is the issued patent corresponding to US 2022/0411492 A1 (“Y. Yang”), which is cited in the 35 U.S.C. § 103 rejection above. The reference patent appears to have a common inventor (Yingying Yang) with the instant application.