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/Restriction
Applicant's election with traverse of Invention III and species A-C of Invention III, (i.e., the structure of Fig 2; the anti-CD3 comprises SEQ ID NOs: 29, 35, 31, 32, 37, and 39; and the anti-TAA comprises SEQ ID NOs: 07/08 and 07/06), specifically with regards to the anti-CD3 part of the construct in the reply filed on 12JUL2026 is acknowledged.
The traversal is on the grounds that the structures of the anti-CD3 component of the various Inventions are generic because i) HCDRs1-2 and LCDR1 are the same across the antibody clones and there is minimal difference between HCDR3 and LCDRs2-3 of the antibody clones and ii) the CD3 antibody clones have reduced or moderate affinity to CD3 making them suitable for the construction of bispecific or multispecific proteins. Thus, the Inventions comprising the anti-CD3 proteins have the same corresponding special technical features. This is not found persuasive because the technical feature upon which the applicant relies (i.e., minimal differences between anti-CD3 clones based on SEQ ID NOs and specific properties of said anti-CD3 clones based on SEQ ID NOs as drawn to in claim 45, for example) to show that the anti-CD3 component of all the inventions and specifically the anti-TAA x anti-CD3 protein molecule are a technical feature are not currently recited in the broadest claim of Invention III (i.e., claim 43) as discussed in the requirement for restriction mailed on 14MAY2026. Furthermore, although independent claim 43, drawn to essentially any anti-CD3 antibody fragment and essentially any anti-TAA to form the anti-CD3 x anti-TAA protein molecule gives preference for the anti-CD3 antibody fragment sequence of SP34, OKT3, UC[HT]1, or a derivative thereof; the variation of the HCDR3 sequence of each of the anti-CD3 clones (i.e., SP34, OKT3, and UCHT1) is expected to result in varied interaction with human CD3 (i.e., binding affinity) and potential differences in cross-reactivity. Additionally, the use of “preferably” in the claim is unclear, as to whether the limitation(s) following the phrase are part of the claimed invention. Therefore, the instant claimed invention has been found to lack unity of invention.
The requirement is still deemed proper and is therefore upheld.
Claims 33-42, 46, and 52-57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species.
Claim Status
Claims 40 and 48-49 have been amended.
Claims 1-32 have been canceled.
Claims 33-57 are pending in the instant application (i.e., Claims 33, 43, and 53 are independent).
Claims 33-42, 46, and 52-57 are withdrawn.
Claims 43-45 and 47-51 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/CN2022/096501, filed 31MAY2022, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of Chinese Application No. 202110628817.3 filed on 02JUN2021 has been received and is acknowledged.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 04DEC2023, 25MAR2025, and 06FEB2026 is/are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicant’s arguments, see p 17, I. Nucleotide and/or amino acid sequence disclosures section, filed 12JUL2026, with respect to specific sequence deficiencies have been fully considered and said deficiencies have been withdrawn in view of amendments to the specification filed as part of said response.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see for example, p 34). 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.
Appropriate correction is required.
Claim Objections
Claims 43, 45, and 47-49 are objected to because of the following informalities:
Claim 43 contains a typographical error: “UCTH1” should be corrected to “UCHT1” in the last line of the claim.
Claim 45 should be made parallel, for example, “…the amino acid sequences of VHCDR1, …, and VLCDR3 are shown in any group of the following (1) SEQ ID NOs: 29,…, and 39; (2) SEQ ID NOs: 29,…, and 40; or (3) SEQ ID NOs: 29,…, and 41, respectively.”
Claim 47 contains acronyms. While acronyms are permissible as shorthand in the claims, the first recitation of the term should include the full recitation followed by the acronym in parentheses. Additionally, it is unclear why slamf7 and folr1 are in lowercase.
Claims 48-49 are missing punctuation (i.e., “.”) at the end of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 43-44 and 47-51 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 43-44 and 48 recite the phrase “preferably” which renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Per MPEP §2173.05(d) description of examples or preferences should be properly set forth in the specification rather than the claims. Claims 47 and 49-51 are also rejected since they depend from claim 43, but do not remedy this deficiency.
Claims 47 and 48 appear to recite a Markush group, but the group of alternatives are not closed as required by a proper Markush group in MPEP §2173.05(h). In this instance, claim 47 recite Markush-type claims without reciting proper Markush-type language such as “selected from the group consisting of” and an “and” between the last two species. For example, in claim 47, an “and” should replace the “or” between GPNMB and Glypican-3. Claim 48 has the same deficiency.
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 43-45 and 47-51 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 and having support for:
“An anti-CLDN18.2/anti-CD3 protein molecule, wherein the molecule is a heterodimer of structures I), II), or III), comprising a first monomer and a second monomer, wherein:
the first monomer comprises: (a) an Fd fragment and (b) a light chain fragment and a first Fc chain;
the second monomer comprises: (a) an Fd fragment and (b) a light chain fragment, an anti-CD3 antibody fragment, and a second Fc chain;
wherein the light chain fragment comprises a VL domain and a CL domain;
wherein the Fd fragment comprises a VH domain and a CH1 domain;
wherein the light chain fragment pairs with the Fd fragment of the first monomer and wherein the light chain fragment pairs with the Fd fragment of the second monomer to form two anti-CLDN18.2 antibody fragments;
wherein the C-terminus of the light chain fragment of the first monomer is fused with the first Fc chain and wherein the N- terminus of the anti-CD3 antibody fragment is fused to the C-terminus of the light chain fragment of the second monomer, and the C-terminus of the anti-CD3 antibody fragment is fused to the N-terminus of the second Fc chain;
the first monomer comprises: (a) an Fd fragment and (b) a light chain fragment, a cytokine functional region, and a first Fc chain;
the second monomer comprises: (a) an Fd fragment; and (b) a light chain fragment, an anti- CD3 antibody fragment, and a second Fc chain;
wherein the light chain fragment comprises a VL domain and a CL domain;
wherein the Fd fragment comprises a VH domain and a CH1 domain;
wherein the light chain fragment pairs with the Fd fragment of the first monomer and wherein the light chain fragment pairs with the Fd fragment of the second monomer to form two anti-CLDN18.2 antibody fragments;
wherein the cytokine functional region comprises IL-15 and IL-15Ra;
wherein the N-terminus of the cytokine functional region is fused to the C-terminus of the light chain fragment of the first monomer, and the C-terminus of the cytokine functional region is fused to the N-terminus of the first Fc chain; and wherein the N- terminus of the anti-CD3 antibody fragment is fused to the C-terminus of the light chain fragment of the second monomer, and the C-terminus of the anti-CD3 antibody fragment is fused to the N-terminus of the second Fc chain; or
the first monomer comprises: an anti-CLDN18.2 antibody fragment, a cytokine functional region, and a first Fc chain;
the second monomer comprises: an anti-CLDN18.2 antibody fragment, an anti-CD3 antibody fragment, and a second Fc chain;
wherein the cytokine functional region comprises IL-15 and IL-15Ra
wherein the N-terminus of the cytokine functional region is fused to the C-terminus of the anti-TAA antibody fragment of the first monomer, and the C-terminus of the cytokine functional region is fused to the N-terminus of the first Fc chain; and wherein the N- terminus of the anti-CD3 antibody fragment is fused to the C-terminus of the anti-TAA antibody fragment of the second monomer, and the C-terminus of the anti-CD3 antibody fragment is fused to the N-terminus of the second Fc chain;
wherein the first Fc chain and the second Fc chain are interchangeable;
wherein the anti-CD3 antibody fragment of structures I), II), or III) comprise an scFv, wherein the scFv comprises a VH, a linker, and a VL, wherein the VH and VL comprise HCDRs1-3 and LCDRs1-3, respectively wherein the HCDR1, 2, 3, LCDR1, 2, and 3 comprise the amino acid sequences selected from the group consisting of: SEQ ID NOs: SEQ ID NO: 29, 35, 31, 32, 37, and 39; (2) SEQ ID NO: 29, 35, 36, 32, 37, and 40; and (3) SEQ ID NO: 29, 35, 36, 32,38, and 41, respectively; wherein the linker links the VH and VL of the anti-CD3 antibody fragment and comprises SEQ ID NO: 46; and
wherein the anti-CLDN18.2 antibody fragments of structures I) and II) comprise a Fab and of structure III) comprises an scFv, wherein the Fab and scFv comprise a VH and a VL, wherein the VH and VL comprise HCDRs1-3 and LCDRs1-3, respectively, wherein the HCDR1, 2, 3, LCDR1, 2, and 3 comprise the amino acid sequences: SYIMH, YINPYNDGTKYNEKFKG, LGFTTRNAMDY, KSSQSLLNSGNQKNYLA, GASTRES and QNDHSYPFT, respectively and wherein the scFv of the anti-TAA antibody fragment further comprises a linker which links the VH and VL which comprises SEQ ID NO: 46.” (claims 43-45 and 47) (i.e., the CDRs of the anti-CLDN18.2 antibody fragment were determined from a CDR delimiting program and would require SEQ ID NOs);
-AND-
“The anti-CLDN18.2/anti-CD3 protein molecule of claim 43, wherein the first Fc chain and the second Fc chain are polymerized to form an Fc fragment; the Fc fragment is selected from the group consisting of human IgG1 Fc, human IgG2 Fc, human IgG3 Fc, and human IgG4 Fc, wherein the Fc heterodimer is selected from the group consisting of:
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, according to EU numbering.” (Amended claim 43 and claim 48) (i.e., note that an “and” is inserted between combination 21 and 22);
-AND-
“The anti-CLDN18.2/anti-CD3 protein molecule of claim 43, wherein the protein molecule comprises an Fc fragment that selectively eliminates immune effector functions, wherein the Fc fragment comprises an Fc mutate selected from the group consisting of:
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, according to EU numbering.” (Amended claim 43 and claim 49) (i.e., note that an “and” is inserted between N297Q and N297G);
-AND-
“The anti-CLDN18.2/anti-CD3 protein molecule of claim 43,
wherein Structure I) comprises:
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 06, respectively and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 05, respectively;
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 06, respectively and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 08, respectively;
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 06, respectively and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 09, respectively; or
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 06, respectively and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 10, respectively; or
wherein Structure II) comprises:
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 17 and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 05;
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 18 and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 01;
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 17 and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 19; or
the amino acid sequences of the first monomer set forth in SEQ ID NOs: 07 and 18 and the amino acid sequences of the second monomer set forth in SEQ ID NOs: 07 and 19; or
wherein Structure III) comprises:
the amino acid sequences set forth in SEQ ID NOs: 20 and 21;
the amino acid sequences set forth in SEQ ID NOs: 22 and 21;
the amino acid sequences set forth in SEQ ID NOs: 20 and 23;
the amino acid sequences set forth in SEQ ID NOs: 22 and 23;
the amino acid sequences set forth in SEQ ID NOs: 24 and 25;
the amino acid sequences set forth in SEQ ID NOs: 25 and 26;
the amino acid sequences set forth in SEQ ID NOs: 24 and 27; or
the amino acid sequences set forth in SEQ ID NOs: 26 and 27.” (Amended claim 43 and claim 50); does not reasonably provide enablement or support for more.
Claim 51 is also rejected since it depends on claim 43 but does not remedy the deficiency. 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 nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
In the instance of a bispecific antibody, it is well known in the art that such a construct comprises two pairs of VH/VL regions (i.e., one pair for each binding domain) and each VH/VL pair consists of six CDRs for a total of 12 CDRs (Brinkmann, et al., MABS, 2017, 9, 182-212, see p 183, col 1, ¶1 and Fig 1-2). Furthermore, the pairing propensity of any two given germlines depends to a large extent on the sequence and conformation of HCDR3, which is highly variable and if HCDR3 is fixed, different VH/VL pairs can result in significant stability differences (Chiu, et al., Antibodies, 2019, 8, 1-80, Section 2.1.3). Additionally, in the instance of bispecific antibodies comprising an Fc domain, it is well known in the art that specific modifications/mutations to the Fc region result in improved pairing (e.g., knob-in-hole) (Liu, et al., Front Immunol, 2017, 8, 1-15, see entire document, specifically see Table 1) and/or modulate antibody effector function (Wang, et al., Protein & Cell, 2018, 9, 63-73, see entire document, specifically see Table 1). Single-chain Fv binding structures are considered fusion proteins which are comprised of the variable heavy (VH) and variable light (VL) chains, which are joined together by a flexible peptide linker (i.e., affects folding, stability, and target affinity). Similar to antibody structures the VH and VL chains of an scFv each consist of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Ahmad, et al., Clin Dev Immunol, 2012, 980250, 1-15, see entire document, specifically Figure 1). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982) or scFv (Winkler, et al., J Immunol, 2000, 165, 4505-4515, see entire document, specifically see abstract and Herold, et al., Sci Rep, 2017, 7, 1-17, see p 8, ¶1). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody or scFv which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves. Therefore, the art supports that for any antibody or antibody fragment, the nondegenerate CDR sequences for each antigen binding domain are necessary to define the structure of the antibody or antibody fragment, a single change in the CDRs can significantly impact the binding of the antigen binding domain, and the specific pairing of the VH and VL sequences for each antigen binding domain are necessary structural features to maintain functional binding. Furthermore, in the instance wherein the bispecific antibody comprises an Fc region, the art supports that it is specific mutations or mutation combinations within the Fc region, which provides specific pairing results or modulates effector function.
Artisans are also well aware that knowledge of a given antigen (for instance a specific epitope of CLDN18.2 or CD3) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
As presently claimed, the scope of claim 43 is extraordinarily broad (i.e., essentially any anti-TAA and essentially any anti-CD3 arranged in three different constructs) and per the prior art does not provide sufficient antibody structure for either antigen binding domain to function. With regard to claims 48 and 49 (dependent on claim 43) as presently claimed, drawn to essentially any combination of combinations 1-22 or Fc mutate, respectively, does not remedy the deficiency of claim 43 and results in a breadth of Fc mutation combinations, wherein per the art, only specific mutations are known in the art for specific outcomes, for example knob-in-hole pairing or electrostatic steering mechanism pairing, or effector function and it is unclear whether combinations of combinations of Fc mutations would result in the same outcome. In the instance of claim 50, dependent on claim 43, the instantly claimed product remedies the lack of structure of claim 43; however, the product is not obtained by “fusing the amino acid fragments” (i.e., typically fusing amino acid sequences utilizes a peptide bond and in some cases a linker to covalently attach an amino acid sequence to another amino acid sequence, for example, in the scFv, the VH is fused to the VL via a linker). In this instance, the bispecific antibody comprises the amino acid sequences, which are paired (i.e., VH-CH1 is paired with VL-CL) as recited in claim 43. Alternatively, a method of producing the bispecific antibodies may comprise multiple DNA sequences encoding the amino acid sequences of the bispecific antibody which may be “fused” in a vector that is expressed in a cell.
The specification discloses three different constructs comprising an anti-CLDN18.2 x anti-CD3 bispecific fusion protein; however, there are no examples of essentially any anti-TAA construct. Furthermore, certain constructs appear to have varied binding affinity for CLDN18.2 as shown in Figs 5 and Figs 29-30. This suggests that despite all of the knowledge regarding these specific anti-CLDN18.2 x anti-CD3 bispecific constructs there is still a lack of predictability.
Therefore, claims 43-45 and 47-51 as presently claimed are rejected because 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 nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 43, 47-49, and 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020/115115 A1 (MORPHOSYS AG, et al., 11JUN2020), herein referred to as “’115.”
‘115 teaches the bispecific antibody construct comprising a bivalent TAA (i.e., CH20, CD19, etc.) Fab binding domain and a monovalent CD3 Fv binding domain, with an Fc region which comprises “knob-into-hole” modifications (i.e., T366Y and Y407T) and may be further modified to include mutations which decrease immune effector functions (i.e., substitutions at one or more of the positions L234, L235, P331) as well as nucleotides encoding the antibody construct (see Fig 1 B; p 48, second to last paragraph continued to p 49, first paragraph; p 61, third paragraph continued to p 62, first paragraph; p 53, first paragraph; p 57, second paragraph; p 65, Nucleic acids section). Specifically, the structure comprises four polypeptides, wherein two polypeptides are comprised of the anti-TAA VH-CH1 domain which pair with either an anti-TAA VL-CL-anti-CD3 VH-CH2-CH3 or an anti-TAA VL-CL-anti-CD3 VL-CH2-CH3 (Fig 1B). Additionally, ‘115 teaches that the bispecific constructs allow for simultaneous bivalent and monovalent co-engagement of different antigens with all the desirable properties of a full-length immunoglobulin and which are easy to purify from the culture supernatant of respective production cell lines (p 2, last paragraph continued to p 3, first paragraph).
Therefore, the prior art anticipates the invention as presently claimed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over by WO 2020/115115 A1 (MORPHOSYS AG, et al., 11JUN2020), herein referred to as “’115” as applied to claims 43, 47-49, and 51 and in further view of US 2024/0247062 A1 (Bernett, et al., effectively filed 15JUN2021), herein referred to as “’062” as evidenced by Jager, et al., (FEBS Lett, 1999, 462, 307-312), herein referred to as “Jager.”
The teachings of ‘115 are summarized above.
However, they do not teach: wherein the anti-CD3 antibody fragment comprises an scFv
Nevertheless, ‘062 teaches the asymmetric bispecific antibody construct comprising a bivalent TAA (i.e., CLDN18.2) Fab binding domain and a monovalent CD3 scFv binding domain (see Fig 13B or 42F). Furthermore, CLDN18.2 is known to be highly expressed in gastric, esophageal and pancreatic cancers and by combining an anti-CLDN18.2 binding domain with an anti-CD3 domain, one is able to localize CD3+ effector T cells to CLDN18.2 expressing tumors (¶0005-0006). Furthermore, ‘062 teaches that due to the potential side effects of T cell recruitment, utilization of monovalent CD3 binding domains (i.e., Fig 13B) are preferable and that the CD3 binding affinity may be modified (high, medium, low) based on the anti-CD3 antigen binding domain in multiple scFv orientations (¶0069-0070).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bispecific antibody construct comprising a bivalent TAA (i.e., CH20, CD19, etc.) Fab binding domain and a monovalent CD3 Fv (i.e., VH/VL pair) binding domain, with an Fc region disclosed by ‘115 by utilizing an anti-CD3 scFv (i.e., VH-linker-VL) binding domain as disclosed by ‘062 because the stability of the binding domain is typically improved when the VH is linked to the VL to form an scFv binding domain as evidenced by Jager (see abstract). One would have been motivated to do so, given the teachings of ‘115 that the bispecific constructs allow for simultaneous bivalent and monovalent co-engagement of different antigens with all the desirable properties of a full-length immunoglobulin and which are easy to purify from the culture supernatant of respective production cell lines. There would have been a reasonable expectation of success, given the knowledge that insertion of an scFv in place of the Fv resulted in an asymmetric bispecific antibody construct comprising a bivalent anti-CLDN18.2 Fab binding domain and a more stable monovalent CD3 scFv binding domain, while maintaining the desirable properties of a full-length immunoglobulin as taught by ‘062.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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