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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/4/2026 has been entered.
Claim Status
Claims 1-71 were canceled.
Claims 73-86 were added.
Claims 72-86 are pending.
Claims 84-86 are withdrawn from further consideration as being drawn to non-elected invention.
Claims 72-83 are under consideration.
Withdrawn Rejections
Rejection of Claims 39-54, 66-67 and 69-72 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn. Applicant provided a persuasive argument “Additionally, the specification describes exemplary physical arrangements for a polypeptide of the claimed bispecific binding agent (see page 5, fifth and sixth options of VH(CLDN)-CH 1-VH(T)-VL(T) and VH(CLDN)-CH 1-VL(T)-VH(T), respectively).” (Response 3/4/2026, page 7).
Rejection of Claims 39-54, 66-67 and 69-70 under 35 U.S.C. 103 as being unpatentable over WO2014/075788 (hereinafter WO788; 9/15/2023 6-page IDS) and Moore et al (US2014/0294823) is withdrawn. Applicant canceled the claims and therefore this rejection is moot.
NEW - Claim Rejections - 35 USC § 103
(based on reconsideration)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 72-83 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2014/075788 (hereinafter WO788; 9/15/2023 6-page IDS) and Mertens (Bispecific Antibodies, 2011, 135-149; 9/15/2023 6-page IDS).
Regarding claim 72, WO788 teaches bispecific binding agent CD3 x CLDN (claim 1-6). WO788 teaches claudin is claudin 18.2 (claim 7). WO788 teaches that the binding agent is in the format of a bispecific single chain antibody that consists of two scFv molecules connected via a linker peptide, wherein the heavy chain variable regions (VH) and the corresponding light chain variable regions (VL) are preferably arranged, from N-terminus to C-terminus, in the order VH(CLDN)-VL(CLDN)-VH(CD3)-VL(CD3), VH(CD3)-VL(CD3)-VH(CLDN)-VL(CLDN) or VH(CD3)-VL(CD3)-VL(CLDN)-VH(CLDN). WO788 teaches SEQ ID NO: 40 which comprises instant SEQ ID NO: 56, 57 and 58 (see SCV; result 58 of 56fus57fus58.rag) and instant SEQ ID NO: 62 and 64 and sequence “WAS” (see SCV; result 136 of 62fusWASfus64.rag).
Regarding claim 73-74, WO788 teaches SEQ ID NO: 60 which comprises instant SEQ ID NO: 5 (see SCV; result 25 of 5.rag) and instant SEQ ID NO: 6 (see SCV; result 23 of 6.rag).
result 25 of 5.rag
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result 23 of 6.rag
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Regarding claim 75-78, WO788 teaches SEQ ID NO: 40 which comprises instant SEQ ID NO: 20 (see SCV; result 44 of 20.rag) and instant SEQ ID NO: 22 (see SCV; result 42 of 22.rag).
result 44 of 20.rag
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result 42 of 22.rag
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Regarding claims 79-82, WO788 teaches SEQ ID NO: 73 which comprises instant SEQ ID NO: 21 (see SCV; result 8 of 21.rag) and instant SEQ ID NO: 23 (see SCV; result 8 of 23.rag).
result 8 of 21.rag
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result 8 of 23.rag
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Regarding claim 83, WO788 teaches a pharmaceutical composition as claimed (claim 34).
However, WO788 does not teach the tribody antibody format.
Regarding claim 72, Mertens teaches Fab-scFv tribody format (figure 1B; reproduced below).
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Mertens teaches that these heterodimers are stable and that this design allows easy engineering of multispecificity in a single molecule, e.g. bispecific antibodies bivalent for the target and monovalent for effector activation (abstract). Mertens teaches that proteins will be cleared rapidly by the kidneys when they are below 60-80 kDa in size (page 3, first paragraph). Mertens teaches that an intermediate sized molecule should avoid kidney clearance and ideally provide a half-life sufficient for improved tumor accumulation while also avoiding a body detainment which would hamper targeting toxic function to the tumor (page 3, second paragraph). Mertens further teaches that the tribody manifold has the potential to generate more active and potent molecules by possibilities to create better binding (through multivalency) as well as through more binding (by targeting more antigens) (page 13, second paragraph).
One of ordinary skill in the art would have been motivated to use Fab-scFv tribody format taught by Mertens to make an alternative CD3 x CLDN bispecific antibody because Mertens teaches advantages of tribody format compared to bispecific scFv (e.g. stability and longer half-life for an intermediate sized tribody format). As discussed above, Mertens teaches that these heterodimers are stable and that this design allows easy engineering of multispecificity in a single molecule, e.g. bispecific antibodies bivalent for the target and monovalent for effector activation (abstract). In this case, effector activation is done by anti-CD3 portion of the bispecific binding agent and target is CLDN antigen expressed on target cancer cells. Therefore, Mertens teaches one domain for anti-CD3 (i.e. “monovalent for effector activation” as taught by Mertens) and two domains for anti-CLDN (i.e. “bivalent for the target” as taught by Mertens). Therefore, there would be two possible arrangements of each binding domains in bispecific Fab-scFv tribody format: (i) CD3 (Fab) + CLDN (scFv) + CLDN (scFv); and (ii) CLDN (Fab) + CLDN (scFv) + CD3 (scFv). Option (ii) corresponds to “VH(CLDN18.2)-CH1-VH(CD3)-VL(CD3)” recited by instant claim 72. One of ordinary skill in the art would have been motivated to make bispecific antibodies in these formats to select effective therapeutics. It would have been obvious to one of ordinary skill in the art to try the finite number of identified predictable solutions (e.g. two options explained above) through routine experimentation. Making protein construct in the different orientation of components was routine experimentation to one of ordinary skill in the art at the time the claimed invention was filed. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because Mertens teaches that the tribody format can be effectively used as cancer therapeutics. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
(based on reconsideration)
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.
NSDP1
Claims 72 and 75-76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,093,736 (hereinafter patent’736; 9/15/2023 6-page IDS) in view of Mertens (Bispecific Antibodies, 2011, 135-149; 9/15/2023 6-page IDS).
Regarding claims 72 and 75-76, claim 1 of patent’736 claims method of treating cancer using a binding agent comprising at least two binding domains, wherein a first binding domain binds to claudin (CLDN) and a second binding domain binds to CD3, and wherein said CLDN is CLDN18.2. Claim 9 of patent’736 claims that the binding agent is in the format of a bispecific single chain antibody that consists of two scFv molecules connected via a linker peptide. Claim 1 of patent’736 claims that VH(CLDN) comprises an amino acid sequence SEQ ID NO: 8 which is 100% identical to instant SEQ ID NO: 20 (duplicate of result 1 of 20.rai). Patent’736 claims that the VL(CLDN) comprises an amino acid sequence SEQ ID NO: 15 (claim 1) which is 100% identical to instant SEQ ID NO: 22 (duplicate of result 1 of 22.rai).
However, patent’736 does not claim the tribody antibody format.
Mertens teaches Fab-scFv tribody format (figure 1B; reproduced below).
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Mertens teaches that these heterodimers are stable and that this design allows easy engineering of multispecificity in a single molecule, e.g. bispecific antibodies bivalent for the target and monovalent for effector activation (abstract). Mertens teaches that proteins will be cleared rapidly by the kidneys when they are below 60-80 kDa in size (page 3, first paragraph). Mertens teaches that an intermediate sized molecule should avoid kidney clearance and ideally provide a half-life sufficient for improved tumor accumulation while also avoiding a body detainment which would hamper targeting toxic function to the tumor (page 3, second paragraph). Mertens further teaches that the tribody manifold has the potential to generate more active and potent molecules by possibilities to create better binding (through multivalency) as well as through more binding (by targeting more antigens) (page 13, second paragraph).
One of ordinary skill in the art would have been motivated to use Fab-scFv tribody format taught by Mertens to make an alternative CD3 x CLDN bispecific antibody because Mertens teaches advantages of tribody format compared to bispecific scFv (e.g. stability and longer half-life for an intermediate sized tribody format). As discussed above, Mertens teaches that these heterodimers are stable and that this design allows easy engineering of multispecificity in a single molecule, e.g. bispecific antibodies bivalent for the target and monovalent for effector activation (abstract). In this case, effector activation is done by anti-CD3 portion of the bispecific binding agent and target is CLDN antigen expressed on target cancer cells. Therefore, Mertens teaches one domain for anti-CD3 (i.e. “monovalent for effector activation” as taught by Mertens) and two domains for anti-CLDN (i.e. “bivalent for the target” as taught by Mertens). Therefore, there would be two possible arrangements of each binding domains in bispecific Fab-scFv tribody format: (i) CD3 (Fab) + CLDN (scFv) + CLDN (scFv); and (ii) CLDN (Fab) + CLDN (scFv) + CD3 (scFv). Option (ii) corresponds to “VH(CLDN18.2)-CH1-VH(CD3)-VL(CD3)” recited by instant claim 72. One of ordinary skill in the art would have been motivated to make bispecific antibodies in these formats to select effective therapeutics. It would have been obvious to one of ordinary skill in the art to try the finite number of identified predictable solutions (e.g. two options explained above) through routine experimentation. Making protein construct in the different orientation of components was routine experimentation to one of ordinary skill in the art at the time the claimed invention was filed. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because Mertens teaches that the tribody format can be effectively used as cancer therapeutics. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
NSDP2
Claims 72 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,739,145 (hereinafter patent’145; cited in nonfinal 11/18/2024) in view of Mertens (Bispecific Antibodies, 2011, 135-149; 9/15/2023 6-page IDS).
Regarding claim 72, claim 1 of patent’145 claims a bispecific binding agent comprising a first binding domain that binds to human CLDN18.2, a second binding domain that binds to human CLDN18.2, and a third binding domain that binds to human CD3, wherein the bispecific binding agent comprises four polypeptide chains of SEQ ID NO: 73, 74, 78 and 78, respectively. SEQ ID NO: 73 of patent’145 comprises instant SEQ ID NO: 56, 57 and 58 (see SCV; result 13 of 56fus57fus58.rai). SEQ ID NO: 78 of patent’145 comprises instant SEQ ID NO: 62, sequence “WAS” and instant SEQ ID NO: 64 (duplicate of result 58 of 62fusWASfus64.rai).
However, patent’145 does not claim the tribody antibody format comprising VH(CLDN18.2)-CH1-VH(CD3)-VL(CD3) or VH(CLDN18.2)-CH1-VL(CD3)-VH(CD3) as claimed by instant claim 72.
Mertens teaches Fab-scFv tribody format (figure 1B; reproduced below).
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Mertens teaches that these heterodimers are stable and that this design allows easy engineering of multispecificity in a single molecule, e.g. bispecific antibodies bivalent for the target and monovalent for effector activation (abstract). Mertens teaches that proteins will be cleared rapidly by the kidneys when they are below 60-80 kDa in size (page 3, first paragraph). Mertens teaches that an intermediate sized molecule should avoid kidney clearance and ideally provide a half-life sufficient for improved tumor accumulation while also avoiding a body detainment which would hamper targeting toxic function to the tumor (page 3, second paragraph). Mertens further teaches that the tribody manifold has the potential to generate more active and potent molecules by possibilities to create better binding (through multivalency) as well as through more binding (by targeting more antigens) (page 13, second paragraph).
One of ordinary skill in the art would have been motivated to use Fab-scFv tribody format taught by Mertens to make an alternative CD3 x CLDN bispecific antibody because Mertens teaches advantages of tribody format compared to bispecific scFv (e.g. stability and longer half-life for an intermediate sized tribody format). As discussed above, Mertens teaches that these heterodimers are stable and that this design allows easy engineering of multispecificity in a single molecule, e.g. bispecific antibodies bivalent for the target and monovalent for effector activation (abstract). In this case, effector activation is done by anti-CD3 portion of the bispecific binding agent and target is CLDN antigen expressed on target cancer cells. Therefore, Mertens teaches one domain for anti-CD3 (i.e. “monovalent for effector activation” as taught by Mertens) and two domains for anti-CLDN (i.e. “bivalent for the target” as taught by Mertens). Therefore, there would be two possible arrangements of each binding domains in bispecific Fab-scFv tribody format: (i) CD3 (Fab) + CLDN (scFv) + CLDN (scFv); and (ii) CLDN (Fab) + CLDN (scFv) + CD3 (scFv). Option (ii) corresponds to “VH(CLDN18.2)-CH1-VH(CD3)-VL(CD3)” recited by instant claim 72. One of ordinary skill in the art would have been motivated to make bispecific antibodies in these formats to select effective therapeutics. It would have been obvious to one of ordinary skill in the art to try the finite number of identified predictable solutions (e.g. two options explained above) through routine experimentation. Making protein construct in the different orientation of components was routine experimentation to one of ordinary skill in the art at the time the claimed invention was filed. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because Mertens teaches that the tribody format can be effectively used as cancer therapeutics. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHEOM-GIL CHEONG whose telephone number is (571)272-6251. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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