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 (claims 17-24, 27, 33, and 34) and the below-listed species in the reply filed on 12/15/2025 is acknowledged.
Elected Species:
Antibody JS012-Chi2-hu2-v3-2/JS012-Chi2-hu2-v3-a2 which comprises HCDRs1-3 and LCDRs1-3 corresponding to SEQ ID NOs: 1, 41, 3, 7, 8, and 9, respectively; VH and VL regions corresponding to SEQ ID NOs: 60 and 61, respectively; and full heavy and light chains corresponding to SEQ ID NOs: 64 and 65, respectively.
With regard to the traversal of Restriction/Election Requirement, Applicant argues the following on Pages 10-13 of Remarks (12/15/2025):
The instant claims meet the standard for unity of invention wherein all pending claims are united by a relationship involving a shared technical feature that is novel an nonobvious over the prior art of record; independent claim 17 is directed to an anti-CLDN-18.2 antibody, or antigen binding fragment thereof, defined by the amino acid sequences of the complementarity determining regions (CDRs) of the antibody heavy and light chains wherein all remaining claims depend from claim 17 and therefore incorporate the antibodies and their CDRs recited in claim 17.
The antibodies and antigen binding fragments thereof were generated using a shared method that is nowhere taught or suggested in the prior art of record. The method of producing the claimed antibodies not only constitutes a relationship that unites the instant claims, but the method amounts to a special technical feature that is both novel and nonobvious over the cited prior art.
Applicant’s argument have been fully considered, but are deemed not persuasive.
With regard to the argument that all pending claims are directed to an anti-CLDN-18.2 antibody, or antigen binding fragment thereof, defined by the amino acid sequences of the complementarity determining regions (CDRs) of the antibody heavy and light chains, it is specifically noted that the recited CDR sets of claim 17(I)-(XVII) are variable and do not comprise the same CDR sequences. It is well established in the art that CDR variability is highly unpredictable and the specific CDR sequences and their subsequent combinations affect antibody properties including specificity and affinity. With regard to the argument that the method of producing the antibodies is novel and nonobvious over the cited prior art, it is specifically noted that not all identified groups of invention require the argued method of production; Group I is only drawn to the antibodies themselves, Group II comprises the method of production, and Group III is drawn to methods of treating/preventing diseases comprising administering the antibodies. As such, the shared feature of Groups I-III is, more generally, an anti-CLDN-18.2 antibody or antigen binding fragment thereof, which is taught by US 2021/0214433 (previously cited on PTO-892; herein after referred to as “Lin”).
As such, the Restriction/Election requirement is deemed proper and is made FINAL.
Claim Status
Claims 1-16 have been cancelled and claim 21 has been amended, as requested in the amendment filed on 12/15/2025. Following the amendment, claims 17-34 are pending in the instant application.
Claims 25-26 and 28-32 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions in the Response filed 12/15/2025, there being no allowable generic or linking claim.
Claims 17-24, 27, and 33-34 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, it is noted that no English translation of the foreign priority document has been provided and therefore the claim to foreign priority has not been perfected.
Claims 17-24, 27, and 33-34 have an effective filing date of July 13, 2021 corresponding to PCT/CN2021/106125.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/16/2023 and 06/27/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because Figures 1-6 comprise text/labels that are blurry and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at Page 37. 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 disclosure is further objected to for the use of the terms MEGALIGN, DNASTAR, FACS, and BIACORE, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
With regard to claim language drawn to sequences, the following are noted:
The recitation of, for example, “HCDR1, HCDR2, and HCDR3, with amino acid sequences as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively” is being interpreted as closed claim language such that the exact, full-length sequences corresponding to SEQ ID NOs: 1-3 are required to satisfy the limitation. This interpretation pertains to claim 17.
The recitation of, for example, “comprises a sequence selected from SEQ ID NOs: 42, 45, 47…” is being interpreted as open claim language such that any amino acid sequence of two or more consecutive amino acids comprised within SEQ ID NOs: 42, 45, 47, etc. is sufficient to satisfy the limitation. This interpretation pertains to claim 18.
The recitation of, for example, “an amino acid sequence having at least 95%, 96%, 97%, 98%, or 99% identity to any of the sequences as shown in SEQ ID NOs: 42, 45, 47…” is being interpreted such that any amino acid sequence having at least 95% identity to the full-length sequences corresponding to SEQ ID NOs: 42, 45, 47, etc. is sufficient to satisfy the limitation. This interpretation pertains to claims 18 and 20.
The recitation of, for example, “comprising an amino acid sequence as shown in SEQ ID NO: 42” is being interpreted as open claim language such that any amino acid sequence of two or more consecutive amino acids comprised within SEQ ID NO: 42 is sufficient to satisfy the limitation. This interpretation pertains to claims 19-20.
Art-Free Subject Matter
It is noted that the elected anti-CLDN-18.2 antibody species JS012-Chi2-hu2-v3-2/JS012-Chi2-hu2-v3-a2 which comprises HCDRs1-3 and LCDRs1-3 corresponding to exact, full-length SEQ ID NOs: 1, 41, 3, 7, 8, and 9, respectively; VH and VL regions corresponding to SEQ ID NOs: 60 and 61, respectively; and full heavy and light chains corresponding to SEQ ID NOs: 64 and 65, respectively, has been thoroughly searched and is free of the prior art. However, it is noted that the instant claims suffer from deficiencies under (i) 35 USC § 112, (ii) 35 USC § 102, and (iii) nonstatutory double patenting.
Claim Rejections - 35 USC § 112
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.
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for murine, chimeric, and humanized antibodies and fragments thereof, does not reasonably provide enablement for fully human antibodies and fragments thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims. This is a SCOPE OF ENABLEMENT rejection.
The Breadth of the Claims
Independent claim 1 is drawn to an isolated anti-CLDN-18.2 antibody or antigen binding fragment thereof comprising the recited HCDR1-3 and LCDR1-3 sets. Dependent claim 21 is drawn to the antibody or antigen binding fragment thereof of claim 17 wherein the antibody is selected from a group of “a murine antibody, a chimeric antibody, a humanized antibody, and a fully human antibody; or the antigen binding fragment is selected from a group of an Fab, an Fab', an Fab'-SH, an Fv, an scFv, an F(ab')2, and a diabody”. However, it is noted that the recited CDRs of claim 17 are murine CDRs derived from mouse hybridoma cell lines; as such, the antibody or antigen binding fragment thereof of claim 17 cannot be fully human, as the recited CDRs are not human, and thus the full scope of claim 21 is not enabled.
The State of the Prior Art/Level of Predictability in the Art
As disclosed by Bernett et. al. (J. Mol. Biol., 2010, 396, 1474-1490; herein after referred to as “Bernett”), deriving fully human antibodies from transgenic mice or full human antibody libraries was well known and understood in the prior art, and Bernett further disclosed a novel method of generating fully human mAbs from nonhuman variable regions using information from the human germline repertoire comprising the rational engineering of residues within and proximal to CDRs and the VH/VL interface by iteratively exploring substitutions to the closest human germline sequences using semi-automated computational methods to generate fully human antibodies comprising over 40 substitutions relative to the parental murine variable regions with a large number of substitutions occurring in the CDRs (Abstract; Figure 2; see entire document). Thus, Bernett establishes known methods of producing fully human antibodies, including transgenic animals and fully human antibody libraries, or generating fully human antibodies from murine sequences; however the production of fully human antibodies from non-human sequences requires extensive sequence modifications (e.g., over 40 substitutions total) wherein many substitutions occur within the CDRs themselves. Thus, while fully human antibodies may be generated from non-human parental antibodies, significant modification and more specifically CDR modification is required.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
Examples 2-4 of the instant specification (Pages 35-38) disclose the preparation of mouse hybridoma cells, screening of said hybridoma cells and performance testing of the resultant mouse-derived anti-CLDN-18.2 antibodies, and the determination of the variable region sequences thereof. Examples 5-6 are drawn to the production and detection of chimeric antibodies and Examples 7-12 are drawn to the humanization of antibody variable regions and the detection/characterization/testing of humanized antibodies thereof (see Pages 38-47). Thus, the instant specification demonstrates that the only working example for producing antibodies of the invention yields non-human (i.e., murine) CDRs, and the working antibodies disclosed are murine, chimeric, or humanized antibodies. No working examples of the production of fully-human antibodies are provided.
In view of the state of the prior art, lack of the predictability of the art to which the invention pertains as evidenced by Bernett above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make functional, fully human monoclonal antibodies with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are (1) fully human and (2) functional, commensurate in scope with the claimed invention.
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.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 20, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For example, with regard to the recitation of “preferably, the variant of SEQ ID NO: 64 comprises S50C, S63T, or a combination thereof”, it is unclear if the limitation following the recitation of “preferably” is intended to be limiting or if it is merely an exemplary variant that is not intended to be limiting. As such, the claim is considered to be indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 20 fails to further limit the subject matter of the claim from which it depends. As currently presented, claim 20 recites that “the variant comprises 1, 2, 3, 4 or 5 amino acid changes in its variable region”; the variable region includes the CDRs recited in claim 17 and as such claim 20 is drawn to variants that can include mutations within the antibody CDRs. Thus, claim 20 as currently presented is broader than claim 17 from which it depends and therefore fail to further limit the subject matter of claim 17. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
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.
Claim 24 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2020/0040101 A1 (herein after referred to as "Lu").
The invention of Lu is drawn to novel antibodies for Claudin 18.2 (CLDN-18.2) (Abstract). More specifically, Lu discloses Example 10, wherein murine antibodies against human CLDN-18.2 were generated using the DNA immunization approach; two fusions were carries out with each of up to 10 mice and culture supernatant were analyzed to screen for hybridomas with binding to HEK293 cells expressing CLDN-18.2 but not CLDN-18.1 and positive clones were expanded, single cell clones, and confirmed by assays (Paragraph 0195). It is further noted that Lu discloses function analysis with an ADCC reporter assay, and the results are presented in Figure 10 (Paragraph 0206). Lu further produced humanized antibodies against CLDN-18.2 (see Examples 12-13, Paragraphs 0207-0212) wherein said humanized antibodies were evaluated with an ADCC reporter assay (Example 14, Paragraphs 0214) and a CDC Assay (Example 16, Paragraphs 0215-0216) and the results are presented in Figures 12 and 13, respectively. Thus, Lu discloses anti-CLDN-18.2 antibodies wherein said antibodies have one or more of the following properties: (i) they bind to human CLDN-18.2, but not human CLDN-18.1; (ii) they induce the ADCC effect in cells expressing human CLDN-18.2; and/or (iii) they induce the CDC effect in cells expressing human CLDN-18.2. As such, Lu anticipates instant claim 24.
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 17-22, 23-24, 27, and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-10, and 13 of copending Application No. 18/686,817 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of the reference application is drawn to an anti-CLDN-18.2 antibody-drug conjugate (ADC) wherein the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, of said ADC comprises HCDRs1-3 with amino acid sequences shown in SEQ ID NOs: 1, 41, and 3, respectively, and LCDRs1-3 with amino acid sequences shown in SEQ ID NOs: 7, 8, and 9, respectively. It is noted that reference application SEQ ID NOs: 1, 41, 3, 7, 8, and 9 are exact matches to instant SEQ ID NOs: 1, 41, 3, 7, 8, and 9. Reference application claim 5 is drawn to the anti-CLDN-18.2 ADC of claim 1, wherein the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region with an amino acid sequence shown in or having at least 95% identity to any one of SEQ ID NOs: 60, 76, or 78 and a light chain variable region with an amino acid sequence shown in or having at least 95% identity to SEQ ID NO: 61. It is noted that reference application SEQ ID NOs: 60 and 61 are exact matches to instant SEQ ID NOs: 60 and 61, respectively. Reference application claim 6 is drawn to the anti-CLDN-18.2 ADC of claim 1, wherein the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, comprises a heavy chain with an amino acid sequence shown in or having at least 95% identity to SEQ ID NO: 64 and a light chain sequence shown in or having at least 95% identity to SEQ ID NO: 65. It is noted that reference application SEQ ID NOs: 64 and 65 are exact matches to instant SEQ ID NOs: 64 and 65, respectively. Reference application claims 7-9, respectively, are drawn to the anti-CLDN-18.2 ADC of claim 1 wherein (i) the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, is a murine, chimeric, or humanized antibody; (ii) the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, is Fab, Fab’, Fab’-SH, Fv, scFv, F(ab’)2, or sdAb; and (iii) the anti-CLDN-18.2 antibody, or antigen binding fragment thereof is of any IgG subtype, such as IgG1, IgG2, IgG3, or IgG4 and preferably the antibody is hypofucosylated or afucosylated. Reference application claim 10 is drawn to a pharmaceutical composition comprising the anti-CLDN-18.2 ADC of claim 1 and a pharmaceutically acceptable carrier or excipient. Reference application claim 13 is drawn to a pharmaceutical combination comprising the anti-CLDN-18.2 ADC of claim 1 and one or more additional therapeutic agents. It is further noted that specification of the reference application discloses that a feature of hypo- and/or afucosylated antibodies is that the binding affinity of such antibodies to receptors expressed on effector cells is significantly increased, resulting in enhanced ADCC activity; thus the antibodies of the claimed anti-CLDN-18.2 ADCs are expected to induce ADCC effects in cells expressing human CLDN-18.2. As such, the claims of the reference application directly read on the anti-CLDN-18.2 antibody and the pharmaceutical compositions thereof of instant claims 17-22, 23-24, 27, and 33.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 34 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-10, and 13 of copending Application No. 18/686,817 (reference application) in view of US 2020/0040101 A1 (herein after referred to as "Lu").
Claim 1 of the reference application is drawn to an anti-CLDN-18.2 antibody-drug conjugate (ADC) wherein the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, of said ADC comprises HCDRs1-3 with amino acid sequences shown in SEQ ID NOs: 1, 41, and 3, respectively, and LCDRs1-3 with amino acid sequences shown in SEQ ID NOs: 7, 8, and 9, respectively. It is noted that reference application SEQ ID NOs: 1, 41, 3, 7, 8, and 9 are exact matches to instant SEQ ID NOs: 1, 41, 3, 7, 8, and 9. Reference application claim 5 is drawn to the anti-CLDN-18.2 ADC of claim 1, wherein the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region with an amino acid sequence shown in or having at least 95% identity to any one of SEQ ID NOs: 60, 76, or 78 and a light chain variable region with an amino acid sequence shown in or having at least 95% identity to SEQ ID NO: 61. It is noted that reference application SEQ ID NOs: 60 and 61 are exact matches to instant SEQ ID NOs: 60 and 61, respectively. Reference application claim 6 is drawn to the anti-CLDN-18.2 ADC of claim 1, wherein the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, comprises a heavy chain with an amino acid sequence shown in or having at least 95% identity to SEQ ID NO: 64 and a light chain sequence shown in or having at least 95% identity to SEQ ID NO: 65. It is noted that reference application SEQ ID NOs: 64 and 65 are exact matches to instant SEQ ID NOs: 64 and 65, respectively. Reference application claims 7-9, respectively, are drawn to the anti-CLDN-18.2 ADC of claim 1 wherein (i) the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, is a murine, chimeric, or humanized antibody; (ii) the anti-CLDN-18.2 antibody, or antigen binding fragment thereof, is Fab, Fab’, Fab’-SH, Fv, scFv, F(ab’)2, or sdAb; and (iii) the anti-CLDN-18.2 antibody, or antigen binding fragment thereof is of any IgG subtype, such as IgG1, IgG2, IgG3, or IgG4 and preferably the antibody is hypofucosylated or afucosylated. Reference application claim 10 is drawn to a pharmaceutical composition comprising the anti-CLDN-18.2 ADC of claim 1 and a pharmaceutically acceptable carrier or excipient. Reference application claim 13 is drawn to a pharmaceutical combination comprising the anti-CLDN-18.2 ADC of claim 1 and one or more additional therapeutic agents. It is further noted that specification of the reference application discloses that a feature of hypo- and/or afucosylated antibodies is that the binding affinity of such antibodies to receptors expressed on effector cells is significantly increased, resulting in enhanced ADCC activity; thus the antibodies of the claimed anti-CLDN-18.2 ADCs are expected to induce ADCC effects in cells expressing human CLDN-18.2. As such, the claims of the reference application directly read on the anti-CLDN-18.2 antibody and the pharmaceutical compositions thereof of instant claims 17-22, 23-24, 27, and 33. It is further noted that the specification of the reference application indicates that the anti-CLDN-18.2 ADC of the invention may be used in the preparation of a medicament for the treatment of a disease or condition mediated by CLDN-18.2, preferably cancer (Paragraph 0022). However, the reference application does not claim a pharmaceutical combination comprising an anti-CLDN-18.2 antibody and one or more additional therapeutic agents wherein the one or more additional therapeutic agents are selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-LAG-3 antibody, an anti-CTLA4 antibody, Oxaliplatin, and 5-fluorouracil (5-FU). This deficiency is remedied by Lu.
The invention of Lu is drawn to novel antibodies for Claudin 18.2 (CLDN-18.2) (Abstract). More specifically, Lu discloses Example 10, wherein murine antibodies against human CLDN-18.2 were generated using the DNA immunization approach; two fusions were carries out with each of up to 10 mice and culture supernatant were analyzed to screen for hybridomas with binding to HEK293 cells expressing CLDN-18.2 but not CLDN-18.1 and positive clones were expanded, single cell clones, and confirmed by assays (Paragraph 0195). It is further noted that Lu discloses function analysis with an ADCC reporter assay, and the results are presented in Figure 10 (Paragraph 0206). Lu further produced humanized antibodies against CLDN-18.2 (see Examples 12-13, Paragraphs 0207-0212) wherein said humanized antibodies were evaluated with an ADCC reporter assay (Example 14, Paragraphs 0214) and a CDC Assay (Example 16, Paragraphs 0215-0216) and the results are presented in Figures 12 and 13, respectively. Lu also discloses pharmaceutical compositions comprising the antibodies of the invention as well as methods of treating cancer comprising administering said pharmaceutical composition to a patient in need thereof, and in combination with a chemotherapy regimen suitable for said cancer; said chemotherapy regimen consists of gemcitabine, 5-fluorouracil, oxaliplatin, irinotecan, paclitaxel, prodrugs thereof, salts thereof, and combinations thereof (Paragraphs 0051-0056).
Thus, it would have been prima facie obvious to one of ordinary skill in the art that the claimed anti-CLDN-18.2 ADC of the reference application could be combined with the chemotherapeutic regimen of Lu consisting of gemcitabine, 5-fluorouracil, oxaliplatin, irinotecan, paclitaxel, prodrugs thereof, salts thereof, and combinations thereof. One of ordinary skill in the art would have been motivated to combine the anti-CLDN-18.2 ADC of the reference application with the chemotherapeutic regimen of Lu, in the form of a pharmaceutical combination as claimed by the reference application (see claim 13), to arrive at a composition useful in the treatment of cancer with a reasonable expectation of success.
Those of skill in the art recognize that the two agents useful in treating cancer, the anti-CLDN-18.2 ADC of the reference application and the chemotherapeutic regimen of Lu, both known to successfully, pharmaceutically treat cancer, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of cancer, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating cancer.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 17-34 are pending. Claims 25-26 and 28-32 are withdrawn. Claims 17-24, 27, and 33-34 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642