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 of Group I, species of therapeutic agent which is a chemotherapeutic agent, in the reply filed on 11/12/2205 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)).
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 - 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. The Sequence Listing was not furnished by the Internation Bureau as part of this national stage filing.
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 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.
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, fourth paragraph, of the specification.)
Claim Objections
Claim 1 is 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 1 the first occurrence of “anti-CLND18.2” should be accompanied by “anti-claudin18.2” (see p. 1, fourth paragraph of the specification for basis). Claim 6 in line 2 should have parentheses around “HC”. 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 3, 6, 7, 11, 12, 17-19, 22 and 23 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 3 and 6 are indefinite. 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 6 recites the broad recitation respectively of at least 90% and 85%, and the claims also recite respectively at least 99% and 100% 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. If, for example, an amino acid sequence has 100% identity to another specific sequence, then it necessarily has at least 90% identity thereto.
Regarding claims 11, 12, 17-19, 22 and 23, the phrase "for example" or “e.g.” renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Similarly, claims 6, 7, 12(ii), 22 and 23 recite the term “preferably”, which renders the claims indefinite because it is unclear whether the limitation(s) following the term are part of the claimed invention, i.e., whether it is an actual limitation or merely a preferred embodiment. As a results, the metes and bounds of the claims are not clear.
The term “high affinity” in claim 12 is a relative term which renders the claim indefinite. The term “high affinity” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There is no means by which the one skilled in the art would know which antibodies were within the group having “high affinity”. As a result, the metes and bounds of the claim are not clear.
Claim 18 is indefinite because it is drawn to a pharmaceutical composition comprising the antibody or antigen-biding fragment thereof according to any one of claims 1-12 or the immunoconjugate of claim 17, and optionally another therapeutic agent or pharmaceutical supplementary material. According to 35 USC 101as 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 or antigen-binding fragment thereof or immunoconjugate thereof.
The term “elevated level” in claim 22 is a relative term which renders the claim indefinite. The term “elevated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There is no reference with which to compare to determine if the level is “elevated”. As a result, the metes and bounds of the claim are not clear.
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 10-12, 20, 22 and 23 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 claims are drawn to an anti-CLDN18.2 antibody having heavy and light chain variable domain CDR1-3 or full variable domains of SEQ ID NO:4 and 9, respectively. Claim 10 recites the limitation wherein the antibody is a humanized, human or chimeric antibody. The specification discloses one antibody that has those CDRs or variable domains, HB37A6, which is disclosed as a fully human antibody (e.g., first sentence of Example 9). This antibody was obtained by using spleen cells from a H2L2 fully human antibody transgenic mouse immunized with a human CLDN18.2 protein for hybridoma antibody production (Example 2 and Tables 1 and 2). As a result, the antibody produced was a monoclonal human antibody. It cannot be a humanized antibody, which by definition has nonhuman CDRs. This is distinct from a chimeric antibody which could have the human variable domains and constant regions from a different species. There is no disclosure of a humanized antibody that meets the limitations of the claims nor could the skilled artisan readily envision a representative number meeting the limitations of the claims. Therefore, a human or chimeric antibody of the instant invention meets the written description provision under 35 USC 112(a), but a humanized antibody does not.
Claim 11 recites wherein the antigen-binding fragment is one of several forms, including a single domain antibody (e.g., VHH) or a domain antibody (dAb). The only disclosed antibodies have both a variable heavy and variable light chain region (VH and VL, respectively). There is no disclosure of a single domain antibody, which encompasses a domain antibody, and the antigen-binding of which relies on a single variable set of CDRs, usually derived by immunization of camels (Yan et al., J. Transl. Med. 12:343, 2014), and these embodiments do not meet the requirements for written description under 35 USC 112(a).
The claimed binding members of claims 1-12 used in the method of treatment of claims 20, 22 and 23 may comprise a CLDN18.2-binding antibody fragment, a full-length immunoglobulin or an antibody having a nonimmunoglobulin scaffold. The specification does not disclose an antibody or antigen-binding fragment thereof comprising nonimmunoglobulin protein scaffold commensurate in scope with the claims with 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). Again, the HB35A6 antibody successfully used in the specification to kill tumor cells or inhibit their growth were full-length antibodies.
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 CDR1-3 of SEQ ID NO: 4 and 9 or SEQ ID NO:1-3 and 4-6 (e.g., claim 4), but not the full breadth of the claims.
Additionally, claim 12 requires the antibody or antigen-binding fragment thereof to bind human CLDN18.2 with a KD of less than about 15 nM and inhibit tumor growth with a tumor growth inhibition of at least about 25%. The specification has disclosed only a single antibody having those properties, which are particular and require more than mere binding to CLDN18.2. Antigen-binding regions of the variable domains of antibodies are made of three CDRs alternating with framework regions (FR or FWR). The prior art shows that it is more than the CDRs that determine the biophysical properties of antibodies. The framework regions are important for the activity of antigen binding as shown by Tsuji et al. (J. Virol., 96(11): 18 pages, 2022), which explored the effect of CDRs and framework regions (FWR) in the binding of anti-Zika virus antibodies, finding:
As expected, strong correlations were observed between antibody binding parameters and heavy-chain CDR mutation rate, since CDRs make up the antigen-binding site. Strong correlations were also observed between antibody binding parameters and FWR mutation rate, which was less expected as FWRs likely do not directly bind but provide structural support
for the CDRs. FWR mutations may increase antibody flexibility, facilitating CDR contact with epitopes (33, 34). The role of FWR mutations in potency and neutralization of anti-HIV MAbs is variable depending on the specific antibody (61). FWR mutations are important for MAbs against anti-vascular endothelial growth factor, VEGF (34), and FWR mutations have been widely applied, stabilizing the structure of humanized MAbs derived from mice (62).
Tsuji et al. conclude (end of p. 9), “Thus, we conclude that both SHM [somatic hypermutation] and FWR mutations of anti-ZIKV MAbs contribute to antibody affinity, specificity, and functionality.” For one antibody reversion of 4 HC FWR and 12 LC FWR to germline led to loss of binding to ZIKV E protein and reduced binding to ZIKV-VLPs (p. 5, last full sentence). The reversions represent about 3% of the VH and 10% of the VL. Sela-Culang et al. (Front. Immunol. 4:302, 13 pages, Oct. 2013, p. 7, paragraph bridging cols. 1-2), which states, “Framework region residues that affect Ag [(antigen)] binding can be divided into two categories. The first are FR residues that contact the Ag, thus are part of the binding-site (108, 109, 111, 116–123). Some of these residues are close in sequence to the CDRs (in fact they may be within the boundaries of CDRs according to some CDR identification methods, but not according to others, as shown in Figure 3). Other residues are those that are far from the CDRs in sequence, but are in close proximity to it in the 3-D structure.” While CDRs may be grafted into different acceptor antibody frameworks, generally some framework residues must be back mutated to restore affinity seen in the original antibody (Sela-Culang et al., ibid., p. 2, col. 1, third paragraph, and the instant specification on p. 42, lines 1-11). In agreement with this, Koenig et al. (Proc. Natl. Acad. Sci. USA, 114(4):E486-495, 2017) examined anti-VEGF antibody G6.31 for tolerance of mutations in the CDR and FR (FWR). It was found (p. E488, col. 2, first full paragraph) that, “Whereas most mutations appear to have a neutral or negative impact on binding or folding, many potentially beneficial mutations are located in CDRs as well as in nonconserved regions of the framework.” (See also Fig. 2A-2B) While the focus turned to one particular VL FR position (83), other FWR positions were examined, such as two positions found to be critical for thermostability though not antigen binding (p. E489, first paragraph). It was concluded (p. E493, col. 1, last full paragraph), “Our study provides insight into the active role of framework positions in modulating antibody affinity and stability. The CDRs typically provide the main direct contacts with antigens, but—as highlighted by our analysis—affinity also depends on framework residues, even when the FWR positions are structurally far away from the antigen.” Neither the instant disclosure nor prior art supports written description for particular embodiments of claim 12 wherein the antibody or antigen-binding fragment thereof does not comprise the VH and VL of SEQ ID NO:4 and 9, respectively.
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, i.e., those which are human or chimeric, are not single domain antibodies, for method of treatment administering an antibody or antigen-binding fragment thereof comprising a VH and VL comprising the CDR1-3 of SEQ ID NO:1-6, respectively, and for stringent functions those having the VH and VL of SEQ ID NO:4 and 9, respectively, 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 20 and 22-23 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 any reasonable expectation of success.
The instant method also includes wherein the treatment is of any tumor using an anti-CLDN18.2 antibody of claims 1-12 or immunoconjugate of claim 17, or pharmaceutical composition thereof. 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.” 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 cell lines used in the working examples of the specification showing cytotoxic or targeting activity of antibody HB37A6, the anti-CLDN18.2 antibody comprising the CDRs of the claims, all expressed 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, antigen-binding fragment thereof or immunoconjugate thereof.
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 1-12, 17-20, 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5-11, 17-22 of copending Application No. 18/246,939 (‘939, reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim an 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 (instant claims 1 and 2, and claim 2 of ‘939), variable heavy and light chain regions (VH and VL) of SEQ ID NO:4 and 9, respectively, or a sequence 90% identical thereto (instant claims 3-4, and claims 3, 11 and 22 of ‘939). The antibody comprising an IgG heavy chain constant region (HC) and light chain constant region (LC) are claimed (instant claims 5, 7, 8, and claims 5-8 of ‘939), including wherein the HC and LC sequence are respectively SEQ ID NO:5 and 10, which are comprised by SEQ ID NO:37 and 38, respectively of ‘939 (instant claim 6, and claim 11 of ‘939). Both claim wherein the antibody is in a pharmaceutical composition, including with another therapeutic agent, e.g., a chemotherapeutic (instant claims 18-19, and claims 17-18 of ‘939). Both claim a method for treating a tumor in a subject, wherein the tumor is a cancer, by administration of the anti-CLDN18.2 antibody, including with the further administration of another therapy, e.g.¸chemotherapy (instant claims 20, 22 and 23, and claims 19-22 of ‘939). Even though the anti-CLDN18.2 antibody of ‘939 is part of a bispecific antibody, that makes obvious a monoclonal anti-CLDN18.2 antibody (instant claim 9), which can be used to make the bispecific antibody (claim 8 of ‘939), as well as an immunoconjugate of the bispecific antibody of ‘939 which makes obvious an immunoconjugate of the instant antibody (instant claim 17). The antibodies are inherently human (instant claim 10, and claim 10 of ‘939) and have at least one of the properties listed in instant claim 12. An antigen binding fragment of the anti-CLDN18.2 antibody, e.g., Fv or Fab, is obvious in view of the antibody (instant claim 11).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 9-12, 18-20, 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 10, 17-19 of copending Application No. 18/258,877 (‘877, reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim an antibody (instant application) or chimeric receptor comprising an antigen-binding region (‘877) 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 (instant claims 1 and 2, and claim 1 of ‘877), variable heavy and light chain regions (VH and VL) of SEQ ID NO:4 and 9, respectively, or a sequence 90% identical thereto (instant claims 3-4, and claim 2 of ‘877). The CLDN18.2-binding region of ‘877 anticipates the antibody or antigen-binding fragment thereof of the instant application. While ‘877 does not claim a pharmaceutical composition comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof, this would have been obvious because it does claim a method of treating a tumor, e.g., cancer, by administering the chimeric antigen receptor comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof, including with another therapeutic agent, e.g., a chemotherapeutic, which method is also claimed in the instant application (instant claims 18-20 and 22-23, and claims 17-19 of ‘877). One skilled in the art would reasonably have expected the chimeric receptor would have needed to be in a pharmaceutical composition for administration. Even though the anti-CLDN18.2 antibody of ‘877 is part of a chimeric antigen receptor, that makes obvious a monoclonal anti-CLDN18.2 antibody, i.e., from a single clone (instant claim 9). The antibody or antigen-binding fragment thereof are inherently human (instant claim 10) and have a least one of the properties listed in instant claim 12. The antibody may be an scFv (instant claim 11, and claim 3 of ‘877).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-12, 17-20, 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13 and 24-33 of copending Application No. 18/719,023 (‘023, reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim an antibody (instant application) or antigen-drug conjugate comprising an antibody or antigen-binding fragment thereof (‘023) 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 (instant claims 1 and 2, and claims 1 and 13 of ‘023), variable heavy and light chain regions (VH and VL) of SEQ ID NO:4 and 9, respectively, or a sequence 90% identical thereto (instant claims 3-4, and claims 1 and 29 of ‘023). Both claim the CLDN18.2 antibody fragment is, e.g., a Fv or Fab (instant claim 11, and claim 33 of ‘023). The antibody comprising an IgG heavy chain constant region (HC) and light chain constant region (LC) are claimed (instant claims 5, 7, 8, and claims 30-31 of ‘023), including wherein the HC and LC sequence are respectively SEQ ID NO:5 and 10, which are comprised by or at least 99% identical to SEQ ID NO:11 and 12, respectively of ‘023 (instant claim 6, and claim 32 of ‘023). Both claim a pharmaceutical composition comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof, and including another therapeutic agent, e.g., a chemotherapeutic (instant claims18 and 19, and claims 24-25 of ‘023). Further, the antibody-drug conjugate of ’023 is a type of immunoconjugate of the antibody (instant claim 17). Both claim a method for treating a tumor in a subject, wherein the tumor is a cancer, by administration of the anti-CLDN18.2 antibody, including with the further administration of another therapy, e.g.¸ chemotherapy (instant claims 20, 22 and 23, and claims 26-28 of ‘023). Even though the anti-CLDN18.2 antibody of ‘023 is part of an antibody-drug conjugate, that makes obvious a monoclonal anti-CLDN18.2 antibody, i.e., from a single clone (instant claim 9). The antibody or antigen-binding fragment thereof are inherently human (instant claim 10) and have a least one of the properties listed in instant claim 12.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 7-12, 18-20, 22 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 10, 13-15, 23 and 24 of copending Application No. 18/850,651 (‘651) in view of US Patent 11,111,295 B2 (Wang).
The claims of the copending applications are not patentably distinct from each other because both applications claim an 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 (instant claims 1 and 2, and claims 1 and 9 of ‘651), variable heavy and light chain regions (VH and VL) of SEQ ID NO:4 and 9, respectively (instant claims 3-4, and claim 10 of ‘651). The antibody comprising an IgG heavy chain constant region (HC) and light chain constant region (LC) is claimed (instant claims 5, 7, 8, and claims 13-15 of ‘651). Both claim wherein the antibody is in a pharmaceutical composition, e.g., a formulation (instant claims 18-19, and claim 1 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 antibody (instant claims 20, 22 and 23, and claim 23 of ‘651). Even though the anti-CLDN18.2 antibody of ‘651 is part of a bispecific antibody, that makes obvious a monoclonal anti-CLDN18.2 antibody (instant claim 9), which can be used to make the bispecific antibody (claim 24 of ‘651). The antibodies are inherently human (instant claim 10, and claim 10 of ‘651) and have a least one of the properties listed in instant claim 12. An antigen binding fragment of the anti-CLDN18.2 antibody, e.g., Fv or Fab, is obvious in view of the antibody (instant claim 11). ‘651 does not claim wherein the antibody is part of an immunoconjugate or is in a composition with or administered with a further therapeutic agent, e.g, a chemotherapeutic. ‘651 does not recite a sequence for the HC and LC.
US Patent 11,111,295 (Wang) 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 antibody may be part of an immunoconjugate (col. 5, lines 3-5). 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 instant SEQ ID NO:5. The light chain sequence is SEQ ID NO:61, which comprises a light chain constant region identical to instant SEQ ID NO:10. (col. 51, lines 22-26)
It would have been obvious to one of ordinary skill in the art to have the anti-CLDN18.2 antibody, alone or as part of a bispecific antibody, used in a method of treating a tumor, e.g., cancer, alone or with an additional therapeutic, such as chemotherapy, in view of the teachings of Wang. If further would have been obvious wherein the antibody, alone or as part of a bispecific antibody, was part of an immunoconjugate for use in the detection of CLDN18.2-expressing tumors wherein the conjugate was a detectable label or in the treatment of said tumors wherein the conjugate was a drug. When the antibody is a full-length antibody, it would have been obvious to use the IgG1 constant domains disclosed in Wang for their known and expected properties and with a reasonable expectation of successful function.
This is a provisional nonstatutory double patenting rejection.
Claims 1-12, 17, 18, 19*, 20, 22 and 23* are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-32, 36, 37-40, 44 and 45-48 of copending Application No. 19/376,098 (‘098), claims 4-6, 20-24, 25*, 26 of copending Application 19/492,647 (‘647)* and claims 1-8, 18-21 and 23-24 of copending Application 19/493.385 (‘’385).
Although the claims at issue are not identical, they are not patentably distinct from each other because all applications claim an antibody (instant application) or antigen-drug conjugate comprising an antibody or antigen-binding fragment thereof (copending applications) 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 (instant claims 1 and 2), variable heavy and light chain regions (VH and VL) of SEQ ID NO:4 and 9, respectively, or a sequence 90% identical thereto (instant claims 3-4). All explicitly claim a CLDN18.2 antibody fragment, except ‘098, which requires no more than that it comprise the six CDRs or VH and VL (claims 29-30 of ‘098), which makes obvious a fragment which is, e.g., a Fv or Fab (instant claim 11). The antibody comprising an IgG heavy chain (HC) constant region and light chain constant region (LC) are claimed (instant claims 5, 7, 8), including wherein the HC and LC sequence are respectively SEQ ID NO:5 and 10, which are comprised by or at least 99% identical to SEQ ID NO:11 and 12, respectively of claims of copending applications (instant claim 6). All claim a pharmaceutical composition comprising the anti-CLDN18.2 antibody or antigen-binding fragment thereof (instant claim 18). Further, the antibody-drug conjugate of the copending applications is a type if immunoconjugate of the antibody (instant claim 17). All claim a use of the antibody-drug conjugate or method for treating cancer or a tumor in a subject, by administration of the anti-CLDN18.2 antibody (instant claims 20, 22 and 23). Even though the anti-CLDN18.2 antibody of the copending applications is part of an antibody-drug conjugate, that makes obvious a monoclonal anti-CLDN18.2 antibody, i.e., from a single clone (instant claim 9). The antibody or antigen-binding fragment thereof are inherently human (instant claim 10) and have a least one of the properties listed in instant claim 12.
*’467 claims a pharmaceutical composition and method of using the antibody-drug conjugate, further including a chemotherapeutic agent (instant claims 18 (optionally comprising), 19 and 23, and claims 25 and 26 of ‘467). The other copending application do not claim an additional therapeutic.
Note there are no official Sequence Listings for the copending application so the identity between the sequences of those and applications and the instant could not be readily confirmed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US 2018/0117174 A1 and US Patent 10,421,817 B1, both cited in the IDS filed 10/10/2024, teach antibodies the bind CLDN18.2 and methods of treating cancer therewith. These are two of many prior art references teaching such antibodies. However, none meet the structural limitations of instant independent claim 1. As a result, the prior art does not anticipate or make obvious the instant invention.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
January 31, 2026