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 .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 12/04/2025 is acknowledged. The traversal is on the ground(s) that claims 13-16 have been amended to recite that the nucleic acid encodes the antibody of claim 2 and that the method of claim 16, drawn to a method for preparing the antibody of claim 2, is by expression of a nucleic acid encoding the antibody of claim 2. While the Examiner agrees that the method of making the antibody of claim 2 does have unity of invention with Group I, it is not agreed that the nucleic acid, vector and host cell do. However, in the interest of compact prosecution, the restriction between Groups I and II is withdrawn.
Applicant’s election of species for claim 18 of one or more therapeutic agents which is chemotherapeutic agents and species for claim 21 of one or more therapies and/or therapeutic agents which is chemotherapeutic agents in the reply filed on 12/04/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The requirement is still deemed proper and is therefore made FINAL.
Claim Interpretation
Claim 6 uses the term “IgG-like structure”. This is interpreted as meaning comprising an Fc region consistent with the use of the term in the specification in the last paragraph of p. 11. A common IgG-like antibody type is described as comprising two Fab regions and one Fc region. “Non-IgG-like bispecific antibodies lack Fc region….” Therefore, it reasonably appears an “IgG-like structure” requires an Fc region.
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:
A) Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. (See below for name and size. N.b., the creation date is not necessarily the same as the receipt date.) The Sequence Listing was not furnished by the International Bureau as part of this national stage filing.
B) 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. These sequences do not appear to be in the Sequence Listing
The sequence disclosures are located in the fourth full paragraph of p. 12 of the specification.
C) 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). See sequences present in the fourth full paragraph of p. 12 of the specification.
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.
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Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. (See p. 1, third paragraph, and p. 20, last paragraph, of the specification.)
The use of the terms Beckman Coulter, Invitrogen, Hitrap, Gibco and Opti-Mem (e.g., pp. 45-46), each of which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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.
Applicant is encouraged to review the specification for other occurrences of trade names or marks.
Claim Objections
Claims 2, 8 and 19 are objected to because of the following informalities: The first occurrence of an abbreviation should be accompanied by its full meaning. In line with this, in claim 2 the first occurrence of "anti-CLND18.2" should be accompanied by "anti-claudin18.2" (see p. 1, third paragraph of the specification for basis). In claim 8, there should be a comma around the first occurrence of “A1-HC”, “A2-HC”, “A1-LC” and “A2-LC”. In claim 19, line 1, it appears “a” is missing before “tumor”.
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 3, 4, 7, 16-18, 20 and 21 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 3 and 4 recite the broad recitation at least 90% identity, and the claims also recite 91%..99% identity, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 3 and 4 are also indefinite because they have the parenthetical phrase “preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1”, as well as “preferably amino acid substitutions, more preferably amino acid conservative substitution”, as well as the phrase “preferably, the said amino acid changes do not occur in the CDR region”. It is unclear if the phrases beginning with “preferably” are actual limitations or merely preferred embodiments. As a result, the metes and bounds of the claims are not clear.
Claims 3 and 4 are also indefinite because they recite in claims 3 and 4, sections (i)-(iii), ‘sequence selected from SEQ ID NO:X’, where X is a single number. This makes the claim confusing because there is nothing for the sequence to be selected from, since there is only a single choice.
Claim 7 recites the antibody heavy chain is “preferably from IgG1”. It is unclear if the phrase beginning with “preferably” is an actual limitation or a merely preferred embodiment. As a result, the metes and bounds of the claims are not clear.
Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps is: expression of the antibody. Merely having a host cell cultured under conditions suitable for expression of a nucleic acid encoding the antibody does not mean the antibody has been prepared, as required by the claim. That would require actual expression of the antibody.
Claim 17 is indefinite because it is drawn to a pharmaceutical composition comprising the antibody of claim 2, and optionally a pharmaceutically acceptable supplementary material. According to 35 USC 101 as discussed in MPEP 2106.03(I), "A composition of matter is a "combination of two or more substances and includes all composite articles." Digitech, 758 F.3d at 1348-49, 111 USPQ2d at 1719 (citation omitted). This category includes all compositions of two or more substances and all composite articles, "whether they be the results of chemical union or of mechanical mixture, or whether they be gases, fluids, powders or solids." Chakrabarty, 447 U.S. at 308, 206 USPQ at 197 (quoting Shell Dev. Co. V. Watson, 149 F. Supp. 279, 280 (D.D.C. 1957); id. at 310 holding genetically modified microorganism to be a manufacture or composition of matter)." Because an additional agent is only "optional" and not required, it is unclear what distinguishes the pharmaceutical composition from the antibody.
Regarding claim 18, the phrase "such as" 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).
Claim 20 is indefinite for several related reasons. It recites the terms or phrases “preferably”, "such as" and "for example", each of which renders the claim indefinite because it is unclear whether the limitation(s) following the term/phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 21 is indefinite for several related reasons. It recites the terms or phrases “preferably” and "such as", each of which renders the claim indefinite because it is unclear whether the limitation(s) following the term/phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 19-21 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.
The instant method is drawn to preventing or treating (a) tumor in a subject by administering to the subject the bispecific antibody of claim 2. The bispecific antibody comprises a first and second binding domain. A bispecific antibody is defined in the specification (p. 11, last paragraph) as including IgG-like and non-IgG-like antibodies. Non-IgG-like bispecific antibodies lack an Fc and can be a “fusion protein that simulates the variable domain of two antibodies. The different binding domains are joined together by peptide connector, chemical coupling, non-covalent bond connection or other ways.” However, the specification does not disclose an antibody or antigen-binding fragment thereof comprising nonimmunoglobulin protein scaffold commensurate in scope with the claims to provide a reasonable expectation of successful CLDN18.2-binding to the extent necessary for therapeutic function.
Treatment with the antibody requires more than mere binding to the antigen. It requires binding of a sufficient degree and with sufficient activity, in this case antitumor cytotoxic activity (see, e.g., Examples 13 and 14). The HB35A6 anti-CLDN18.2 antibody successfully used in the specification to kill tumor cells or inhibit their growth was a full-length IgG antibody. Vazquez-Lombardi et al. (Drug Disc. Today, 20(10):1271-1283, Oct. 2015) discusses the use of non-antibody scaffolds, including Affibodies, Avimers and DARPins. Vazquez-Lombardi et al. acknowledges that (p. 1271, col. 2, last paragraph), "Despite the considerable promise of non-antibody scaffolds, conversion of the many examples of such modalities into differentiated drugs has been challenging. Although several candidates have progressed into clinical studies, only a single non-antibody scaffold, the Kunitz domain DX-88 (ecallantide; Dyax) has been granted regulatory approval (Box 1), with no further approvals since 2009." Affibodies and other non- antibody protein scaffolds have been used for imaging (Box 3 on p. 1278). Nevertheless, it is concluded (p. 1280, end of col. 2), "In summary, further creativity will be required to transform this promising class of binding molecules into validated therapeutic and diagnostic modalities." Consistent with this, Luo et al. (Royal Soc. Chem. Chem. Biol. 8:830-847, 2022, p. 831, col. 2, first paragraph), published after the effective filing date of the instant application, reviewed alternative antibody protein scaffolds and states, "Despite the many advantages of protein scaffolds, they are more suitable for short-term cancer imaging, not therapy." The different types of scaffolds, e.g., Anticalin® scaffolds, affibodies and DARPins, generally require modification of the original protein to compensate for structural limitations, e.g., rigid structure or less than full surface exposure of all 6 CDR loops, which the specification has not disclosed and antibodies produced with these scaffolds are generally obtained by screening libraries comprising the specific scaffold for binding to a specific target instead of placing VH and VL CDRs into a scaffold (e.g., Luo et al. at p. 833, col. 2, first full paragraph, p. 835, col. 1, second paragraph, p. 837, col. 1 second paragraph, p. 838, col. 1, last paragraph). Luo et al. concludes challenges remain (p. 841, second paragraph): "Despite some protein scaffolds showing promising performance in different fields, few can realize successful clinical translation for cancer imaging or therapy, partially due to their short half-life, immunogenicity, somewhat unspecific biodistribution, or other less good clinical effects during longterm different dose administration." It does not appear the inventors were in possession of the full scope of antibodies encompassed for use in the claimed methods, but only those comprising a VH and VL comprising the SEQ ID NO: 1-3 and 4-6 for the first binding domain and comprising HCDR1-3 and LCDR1-3 of one of claims 2 (i)-(iii) for a second binding domain, but not the full breadth of the claims.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
With the exception of the antibodies referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies meeting the functional limitations or usable in the claimed methods, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 19-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a tumor expressing claudin18.2 (CLDN18.2), does not reasonably provide enablement for treating a tumor that does not express CLDN18.2 or for preventing a tumor. 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 instant method is drawn to treating or preventing (a) tumor, e.g., cancer. However, in order to be able to prevent a disease such as cancer, one must first be able to anticipate its onset and second be able to maintain administration throughout the duration of susceptibility, so it does not occur. The term "preventing" generally carries the meaning of keeping something from happening. There is no guidance for or working example of anticipating the diseases encompassed by the instant claims, nor how to maintain treatment for the necessary duration to prevent the eventual onset of the disease or disorder. The prior art has yet to teach how to prevent cancer by administration of an antibody that binds that cancer with a reasonable expectation of success. The specification states (p. 55, last paragraph) that, “[I]n the case of negative expression of CLDN18.2, 030, 032 and 033 molecules all did not have non-specific killing effect (Fig. 11). This indicates that 030, 032 and 033 molecules all exhibit the specific killing of tumor cells that depends on the expression of CLND18.2. Moreover, the killing effect of the bispecific antibody of the invention is related to the abundance of CLDN18.2 on the cell surface.” These molecules are CLDN18.2- and CD3-binding bispecific antibodies
The instant method of claims 19 and 21 also includes wherein the treatment is of any tumor using the anti-CLDN18.2/anti-CD3 bispecific antibody of claim 2. However, the specification teaches "Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa and its expression is absent from the gastric stem cell zone. CLDN18.2 is expressed in a considerable portion of primary gastric cancers, and its expression level is retained in gastric metastatic cancer tissue. Expression of CLDN18.2 has also been found in pancreatic cancer in addition to gastric cancer, and it is an ideal target molecule for the treatment of these cancers." Claim 20 is limited to these particular cancers but still includes prevention thereof. There is no reasonable expectation that the antibody can be used to treat tumors in a subject where the tumor does not express CLDN18.2. The working examples in the specification testing the bispecific antibody comprising the CLDN18.2-binding domain of antibody HB37A6 use cell lines that all express CLDN18.2 (p. 16, first paragraph, and Examples 11, 13 and 14). If the antibody cannot bind to the tumor, it cannot be used for treatment of that tumor, regardless of whether it is a full-length antibody or antigen-binding fragment.
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 2-8, 11-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9, 10 and 13-24 of copending Application No. 18/850,651 (‘651, reference application) in view of US 2016/0208109 A1 (‘019).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim a bispecific antibody that binds claudin 18.2 (CLDN18.2) comprising the heavy and light chain CDRs (HCDRs and LCDRs) 1-3 of SEQ ID NO:4 and 9 (SEQ ID NO:1-6), respectively, and CD3 comprising the HCDR1-3 of SEQ ID NO:12, 20 and 29, or 19-21 or 19, 31 and 21 and LCDR1-3 of SEQ ID NO:24-26 (instant claim 2, and claims 1 and 9 of '651), variable heavy and light chain regions (VH and VL) of the anti-CLDN18.2 domain of SEQ ID NO:4 and 9, respectively, and of the anti-CD3 domain of SEQ ID NO:30, 22 or 32 and 27, respectively (instant claims 3 and 4 and claim 10 of '651). The antibody comprising an IgG heavy chain (HC)constant region and light chain (LC) constant region are claimed, including the orientation of the heavy and light chains and variable domains (instant claims 5-8, 11-12 and 22, and claims 13-15 and 24 of ‘651). Both claim wherein the antibody is in a pharmaceutical composition, e.g., a formulation (instant claims 17-18, and claims 1, 2 and 16-22 of ‘651). Both claim a method for treating a tumor in a subject, wherein the tumor is a cancer, by administration of the anti-CLDN18.2/anti-CD3 bispecific antibody (instant claim 19, and claim 23 of '651). ‘651 does not specify heavy or light chain constant domain sequences (instant claims 11 and 12). ‘651 does not claim inclusion of another therapeutic agent in the formulation or in the method of treatment (instant claims 18 and 21) or treatment of particular types of cancer (instant claim 20).
US 2016/0208019 teaches bispecific T cell activating bispecific antibodies that binds CD3 and another antigen. The antibody can have the structure having one heavy chain and one light chain that bind one antigen and a second heavy and light chain that binds a second antigen (e.g., Fig. 1I). Both the CD3 light chain and heavy chain of ‘019 are over 95% identical to the respective instant CD3 light and heavy chain (compare SEQ ID NO:35 of ‘019 to instant SEQ ID NO:40 and SEQ ID NO: 92 of ‘019 to instant SEQ ID NO:41, see comparisons below and [0665] of ‘019). In another bispecific antibody, the antigen-binding polypeptide has the LC constant region of SEQ ID NO:96 and HC constant region of SEQ ID NO:95, which are at least 98% identical to the constant domains of instant SEQ ID NO:38 and 37, respectively (see comparison below and [0664] of ‘019). The bispecific antibody can be used to treat cancer (e.g., Example 33), including pancreatic and gastric cancer ([0356]), It is taught that the portions of the constant regions can be swapped between heavy and light chains and from one binding polypeptide to another, called Crossmab format ([0124]-[0127] and [0327]). A nucleic acid encoding the antibody is taught, as well as an expression vector, host cell comprising the vector and method of preparing the antibody by expressing in a host cell a nucleic acid encoding the antibody ([0124]). It teaches the bispecific antigen-binding molecule can be conjugated to a cytotoxic agent, such as a chemotherapeutic agent ([0312]), and a pharmaceutical composition comprising a T cell activating bispecific antigen binding molecule and at least one therapeutic agent is taught ([0341]), e.g, an anti-cancer agent for treatment of the cancer, e.g, receptor antagonist, topoisomerase inhibitor ([0352] and [0366]).
It would have been obvious to one of ordinary skill in the art to use the anti-CLDN18.2/anti-CD3 bispecific antibody in a method of treating a tumor, e.g., cancer, such as pancreatic or gastric cancer, alone or with an additional therapeutic, such as a chemotherapeutic, in view of the teachings of ‘019. It would have been obvious wherein the CD3 LC and HC had the constant regions as taught in ‘091 for another highly related CD3 antibody that was part of a bispecific antigen binding molecule. It would have also been obvious if the VH and VL of the anti-CDLN18.2 binding portion of the bispecific antibody had the constant regions of SEQ ID NO: 95 and 96 of ‘019, which were compatible with those of the CD3-binding portion. ‘019 showed that both could be used successfully in a bispecific antigen-binding molecule. It would have been obvious to use well known and routine methods to prepare the bispecific antigen binding molecule by recombinant expression of an encoding nucleic acid in a host cell as taught by ‘019.
This is a provisional nonstatutory double patenting rejection.
CD3 LC of SEQ ID NO:35 of ‘019 compared to instant SEQ ID NO:40.
Query Match 95.8%; Score 1082; DB 1; Length 215;
Best Local Similarity 96.7%;
Matches 208; Conservative 1; Mismatches 6; Indels 0; Gaps 0;
Qy 1 QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGT 60
|||||||||||||||||||||| ||||||||||||||||:||||| |||||||||||||
Db 1 QAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPGV 60
Qy 61 PARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLGQPKAAPSVTL 120
|||||||||| |||||| ||||||||||||||||||||||| ||||||||||||||||||
Db 61 PARFSGSLLGDKAALTLLGAQPEDEAEYYCALWYSNLWVFGQGTKLTVLGQPKAAPSVTL 120
Qy 121 FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSY 180
Qy 181 LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 215
|||||||||||||||||||||||||||||||||||
Db 181 LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 215
CD3 HC of SEQ ID NO:92 (Fc knob) of ‘019 compared to instant SEQ ID NO:39
Query Match 95.9%; Score 2344; DB 1; Length 455;
Best Local Similarity 96.3%;
Matches 438; Conservative 5; Mismatches 12; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVSRIRSKYNNYAT 60
||||:|||||||||||||:||||||||||:|||||||||| ||||||| |||||||||||
Db 1 EVQLVESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQASGKGLEWVGRIRSKYNNYAT 60
Qy 61 YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGNSYVSWFAYWGQGTL 120
||||||| ||||||||||:|||||||||: |||||||| |||||| |||||||||||||
Db 61 YYADSVKDRFTISRDDSKSTLYLQMNSLKTEDTAVYYCARHGNFGQSYVSWFAYWGQGTT 120
Qy 121 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 180
Qy 181 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 240
Qy 241 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 300
Qy 301 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLP 360
|||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||
Db 301 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP 360
Qy 361 PCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 420
| ||||||||||| | |||||||||||||||||||||||||||||||||||||| |||||
Db 361 PSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTV 420
Qy 421 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 455
|||||||||||||||||||||||||||||||||||
Db 421 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 455
HC (Fc hole) constant domain only of SEQ ID NO:95 of ‘019 compared to HC constant domain only of instant SEQ ID NO:37
Query Match 98.0%; Score 1728; DB 1; Length 331;
Best Local Similarity 98.5%;
Matches 325; Conservative 0; Mismatches 5; Indels 0; Gaps 0;
Qy 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 61
Qy 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG 121
Qy 121 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 181
Qy 181 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDE 240
||||||||||||||||||||||||||||||| ||||||||||||||||||| ||||||||
Db 182 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE 241
Qy 241 LTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRW 300
|||||||| | |||||||||||||||||||||||||||||||||||||| ||||||||||
Db 242 LTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 301
Qy 301 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
||||||||||||||||||||||||||||||
Db 302 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 452
LC constant domain of instant SEQ ID NO:96 of ‘019 compared to LC constant domain of instant SEQ ID NO:38
Query Match 100.0%; Score 553; DB 1; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 108 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD 60
Qy 61 SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US Patent 11,111,295 B2 teaches an anti-CLDN18.2 antibody, including in a pharmaceutical composition with another therapeutic agent such as a chemotherapeutic agent (col. 40, lines 64-66). It also teaches a method of treating a tumor by administering the antibody and optionally another therapeutic agent such as a chemotherapeutic agent (col. 44, lines 20-32). The full heavy chain of the antibody is an IgG1 isotype with the sequence of SEQ ID NO:59, which comprises a heavy chain constant region at least 99% identical to the HC constant domains of instant SEQ ID NO:37 (the full HC is at least 85% identical to SEQ ID NO:37). The light chain sequence is SEQ ID NO:61, which comprises a LC constant domain identical to that of instant SEQ ID NO:38. (col. 51, lines 22-26). The variable domains and CDRs thereof of the antibody of the patent are different than those of the instant application. This reference is cumulative with US 2016/0208019 relied upon above for the teaching of heavy and light chain constant domains compatible with an anti-CLDN18.2 bispecific antibody.
WO 2020/025792 A1 (cited in the IDS filed 10/10/2024) is one of a number of prior art references disclosing a bispecific antibody binding CLND18.2 and CD3; however, none have the same sequences as the bispecific antibody required in instant independent claim 2.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
March 6, 2026