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 .
Claim Status
Claims 1-17 are pending and under examination in the instant office action.
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. 13 line 25, p. 16 lines 9 and 13.
Claim Objections
Claim 7 is objected to because of the following informalities: Claim 7 recites "wherein an Fc region is an Fc region of an IgG class antibody"; however, although it is implied, it is never stated that the bispecific antibody of claim 1, from which claim 7 depends, comprises an Fc region. The Examiner suggests amending to recite”.
Claim objected to because of the following informalities: Claim ”.
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.
Claim 1-3, and 5-17 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 instant claim(s) 1 and 3 recites “comprises 3 heavy chain CDRs contained in […]” and “comprises 3 light chain CDRs contained in […] in e.g. lines 4-6, 7-9, 10-12, 13-15, of claim 1 rendering the claim indefinite. The instant disclosure provides that for CDR definitions “In a given heavy chain variable region amino acid sequence, a precise amino acid sequence boundary of each CDR may be determined using any one or a combination of many known antibody CDR assignment systems”” (e.g., p. 13), and discloses examples of the Chothia, Kabat, AbM, Contact, IMGT, and North definitions (p. 13). The specification further discloses tables defining the CDRs by AbM number (Tables 1a-b and 1d). As the claim does not recite the CDR definition scheme, and the instant disclosure teaches one set of CDRs in tables 1a-b and d, but also that CDRs may comprise any one or more of the non-limiting examples of CDR definitions in the specification, it is unclear if the phrases reciting CDRs in claim 1 (1) use Kabat definition, (2) Chothia definition, (3) AbM definition, (4) contact definition, (5) extended definition, (6) conformational definition, (7) a mixture of definitions, (8) the CDRs recited in Tables 1a-b and d for the VH and VL sequences of claim 1, or (9) something else. For the purposes of compact prosecution, the CDRs are considered to be the AbM definition CDRs as specified in Tables 1a-b and d. Applicant may overcome this rejection by amending claim(s) 1 to recite (I) the SEQ ID NOs of the 6 CDRs (e.g., HCDR1-3 and LCD1-3) of the anti-CD40 antibody, without variability in the CDR sequences thereof, (II) recite the SEQ ID NOs for each of the 6 CDR sets for each definition (e.g., a) Kabat HCDR1-3 and LCDR1-3; b) Chothia HCDR1-3 and LCDR1-3; c) IMGT HCDR1-3 and LCDR1-3; etc.), without variability in the CDR sequences thereof, or (III) to otherwise clearly recite the limitations of the instant invention. Dependent claim(s) are rejected for failing to resolve the indefiniteness as described.
Claim 13 recites the limitations "the host cell of the present invention" in lines 2-3 and "the bispecific antibody of the present invention" in lines 4-5. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the host cell of the present invention” requires a particular cell type and whether “the bispecific antibody of the present invention” refers only to the bispecific antibody of claim 1 as recited in the preamble, or whether is refers to other embodiments in the claims or specification.
The terms “preferably” in claim 6 line 2; claim 11 line 2; claim 15 line 3; claim 16 line 5; “for example” in claim 6 line 3; “more preferably” in claim 6 line 4; and “such as” in claim 7 line 2-3; are exemplary terms which render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant revise the claims to remove the term “preferably”, “for example”, and “more preferably” and the limitations following it.
Regarding instant claim 16, the metes and bound of the claims are indefinite for the recitation of “A use of the bispecific antibody according to claim 1”. MPEP 2173.05(q) states attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness. Recitation of a use without any active, positive steps delimiting how this use is practiced is indefinite. For the purposes of expedited prosecution, the claim will be interpreted as being directed towards a medicament or a kit comprising the bispecific antibody according to claim 1.
Claim 6 is indefinite for the recitation of “wherein the VHH is connected to Fc through a linker” because claim 1 from which it depends does not recite an Fc or a VHH; therefore there is no antecedent basis for the limitations and they are unclear. For the purposes of expedited prosecution, claim 6 will be interpreted as wherein the anti-CLDN18.2 antibody or a fragment thereof is connected to an Fc domain through a linker.
Claim Rejections - 35 USC § 112(a)- Written Description
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 1-2 and 5-17 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.
Regarding claim 1, the option “or variants thereof” allow for changes to the CDR within the VH and VL of the antibody which is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the recited function of binding CD40 and CLDN18.2.
Scope of the claimed genus
Claim 1 recites a genus of polypeptides comprising an antibody which specifically binds to CD40 and CLDN18.2 wherein the anti-CD40 antibody or fragment thereof comprises 3 heavy chain CDRs contained in SEQ ID NO: 11 and 3 light chain CDRs contained in SEQ ID NO: 10; 3 heavy chain CDRs contained in SEQ ID NO: 12 and 3 light chain CDRs contained in SEQ ID NO: 10; 3 heavy chain CDRs contained in SEQ ID NO: 13 and 3 light chain CDRs contained in SEQ ID NO: 10; or 3 heavy chain CDRs contained in SEQ ID NO: 14 and 3 light chain CDRs contained in SEQ ID NO: 10 or variants thereof, wherein the variants have one or two amino acid substitutions, additions, and/or deletion compared to sequences derived therefrom.
Claim 2 recites the anti-CD40 x CLDN18.2 bispecific wherein the anti-CLDN18.2 antibody of fragment thereof is a single domain antibody (VHH) and the single domain antibody comprises 3 CDRs contained in SEQ ID NO: 18 or variants thereof wherein the variants have one or two amino acid substitutions, additions, and/or deletion compared to sequences derived therefrom.
Claim 5 recites limits the VH and VL to sequences with 90% identity to SEQ ID NO: 11 and 10, 12 and 10, 13 and 10, or 14 and 10, and limits the VHH to 90% identity to SEQ ID NO: 18, but still allows variability with the CDRs.
Claim 9 limits the heavy chain and light chain to the structure VH-CH1-Fc-VHH and VL-CL and limits the heavy chain and light chain sequence to 90% identity to SEQ ID NO: 19 and 23, 20 and 23, 21 and 23, or 22 and 23.
Claims 6-8, and 10-17 are ultimately dependent on claim 1 without further limiting the structure of the CDRs which determine antigen binding.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “90% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function. Even variants comprising only one or two amino acid substitutions relative to the original sequences may not retain binding ability.
In regards to anti-CD40 antibodies, other anti-CD40 antigen binding sites are known in the art. For example, WO2021081303 A1 to Wang et. al. (Of record, IDS dated 5/31/2024) teaches antibodies binding to CD40 and a second suitable antigen such as a tumor antigen or an immune checkpoint molecule. For example, the VH of the anti-CD40 of Wang et. al. is 61.4% identical to instant SEQ ID NO: 11 and comprises different CDRs:
Query Match 61.4%; Score 408; DB 1; Length 127;
Best Local Similarity 63.6%;
Matches 82; Conservative 13; Mismatches 26; Indels 8; Gaps 3;
Qy 1 EVQLVESGGGLVQPGGSLKLSCAASGFNFNDSFMNWVRQASGKGLEWVGQIRNKNYNYAT 60
||||:|||||||:|||||:|||||||| | ||||||| ||||||| | : |
Db 1 EVQLLESGGGLVRPGGSLRLSCAASGFTFGSYEMNWVRQAPGKGLEWVSYISSS--GETT 58
Qy 61 YYTESLEGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTR--YYYDGFADY----FDYWG 114
| :|::||||:|||:||| |||||||: |||||||| | :::| | | ||
Db 59 DYADSVKGRFTVSRDNSKNLLYLQMNSLRAEDTAVYYCARDVFFFDSSGDNGAYGMDVWG 118
Qy 115 QGTTVTVSS 123
||| |||||
Db 119 QGTMVTVSS 127
U.S. 20180340030 (Of record, IDS dated 5/31/2024) teaches a bispecific protein comprising one anti-CD40 antibody and an antigen binding domain capable of binding to a tumor cell antigen such as FAP (Abstract) and teaches format wherein a single-chain antibody is linked to the C-terminus of the Fc domain of a full-length anti-CD40 antibody.
WO2022032004 A2 to An et. al. teaches an anti-claudin 18.2 multispecific antibody (Abstract, [0005]) that also comprises anti-CD3 (e.g. [00320]) and may bind to additional targets including CD40 (e.g. [0030]).
Summary of Species disclosed in the original specification
The instant specification discloses anti-CD40 x CLDN18.2 bispecific antibodies comprising anti-CD40 antibodies C8-WT, C8-2, C8-6, and C8-10 (Table 1a-1c, Example 1) and an anti-CLDN18.2 nanobody comprising SEQ ID NO: 18 (Table 1d, Example 1). The specification teaches the particular format of full-length anti-CD40 antibody wherein the VHH of the anti-CLDN18.2 antibody was connected to the C-terminus of the heavy chain constant regions of the CD40 antibody through a linker sequence [0160]. Thus, four species of anti-CD40 x CLDN18.2 bispecific antibodies were made as in Table 2 of the instant specification. There were no other variants of the anti-CD40 or anti-CDLN18.2 tested. There is no additional guidance on which CDR residues may be varied and retain either CD40 or CLDN18.2 binding.
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants to allow substitution, addition, or deletion of up to 2 amino acids in the CDRs of SEQ ID NOs: 10-14 and 18 of the described anti-CD40 binding domains and anti-CLDN18.2 binding domain that would still allow for the described function of binding to CD40 and CLDN18.2.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein CD40 and CLDN18.2. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1 at the time of filing. Regarding claims 2, and 5-17, the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected. Claims 2 and 3 are omitted from the rejection because they limit to the CDRs of the instant VH and VL and VHH sequences.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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 1-2 and 5-17 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:
1) making and using an anti-CD40 x CLND18.2 bispecific antibody comprising an anti-CD40 antibody comprises 3 heavy chain CDRs and 3 light chain CDRs defined by AbM numbering of SEQ ID NO: 11 and 10; SEQ ID NO: 12 and 10; SEQ ID NO: 13 and 10; or SEQ ID NO: 14 and 10 and 2) A method for a treating a cancer expressing CLDN18.2:
does not reasonably provide enablement for: 1) making and using any variant comprising up to 2 amino acid variations in the CDRs; 2) a method of treating any generic disease related to CD40 or a disease related to CLDN18.2 comprising administering a therapeutically effective amount of the bispecific antibody to a patient in need.
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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention
Claim 1 recites a genus of polypeptides comprising an antibody which specifically binds to CD40 and CLDN18.2 wherein the anti-CD40 antibody or fragment thereof comprises 3 heavy chain CDRs contained in SEQ ID NO: 11 and 3 light chain CDRs contained in SEQ ID NO: 10; 3 heavy chain CDRs contained in SEQ ID NO: 12 and 3 light chain CDRs contained in SEQ ID NO: 10; 3 heavy chain CDRs contained in SEQ ID NO: 13 and 3 light chain CDRs contained in SEQ ID NO: 10; or 3 heavy chain CDRs contained in SEQ ID NO: 14 and 3 light chain CDRs contained in SEQ ID NO: 10 or variants thereof, wherein the variants have one or two amino acid substitutions, additions, and/or deletion compared to sequences derived therefrom.
Claim 2 recites the anti-CD40 x CLDN18.2 bispecific wherein the anti-CLDN18.2 antibody of fragment thereof is a single domain antibody (VHH) and the single domain antibody comprises 3 CDRs contained in SEQ ID NO: 18 or variants thereof wherein the variants have one or two amino acid substitutions, additions, and/or deletion compared to sequences derived therefrom.
Claim 5 recites limits the VH and VL to sequences with 90% identity to SEQ ID NO: 11 and 10, 12 and 10, 13 and 10, or 14 and 10, and limits the VHH to 90% identity to SEQ ID NO: 18, but still allows variability with the CDRs.
Claim 9 limits the heavy chain and light chain to the structure VH-CH1-Fc-VHH and VL-CL and limits the heavy chain and light chain sequence to 90% identity to SEQ ID NO: 19 and 23, 20 and 23, 21 and 23, or 22 and 23.
Claims 6-8, and 10-17 are ultimately dependent on claim 1 without further limiting the structure of the CDRs which determine antigen binding.
Regarding claim 17, the claim is directed towards a method “for treating a disease related to CD40 or a disease related to CLDN18.2” comprising administering the bispecific antibody according to claim 1.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “90% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function. Even variants comprising only one or two amino acid substitutions relative to the original sequences may not retain binding ability.
In regards to anti-CD40 antibodies, other anti-CD40 antigen binding sites are known in the art. For example, WO2021081303 A1 to Wang et. al. (IDS 5/31/2024) teaches antibodies binding to CD40 and a second suitable antigen such as a tumor antigen or an immune checkpoint molecule. For example, the VH of the anti-CD40 of Wang et. al. is 61.4% identical to instant SEQ ID NO: 11 and comprises different CDRs:
Query Match 61.4%; Score 408; DB 1; Length 127;
Best Local Similarity 63.6%;
Matches 82; Conservative 13; Mismatches 26; Indels 8; Gaps 3;
Qy 1 EVQLVESGGGLVQPGGSLKLSCAASGFNFNDSFMNWVRQASGKGLEWVGQIRNKNYNYAT 60
||||:|||||||:|||||:|||||||| | ||||||| ||||||| | : |
Db 1 EVQLLESGGGLVRPGGSLRLSCAASGFTFGSYEMNWVRQAPGKGLEWVSYISSS--GETT 58
Qy 61 YYTESLEGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTR--YYYDGFADY----FDYWG 114
| :|::||||:|||:||| |||||||: |||||||| | :::| | | ||
Db 59 DYADSVKGRFTVSRDNSKNLLYLQMNSLRAEDTAVYYCARDVFFFDSSGDNGAYGMDVWG 118
Qy 115 QGTTVTVSS 123
||| |||||
Db 119 QGTMVTVSS 127
U.S. 20180340030 (IDS 5/31/2024) teaches a bispecific protein comprising one anti-CD40 antibody and an antigen binding domain capable of binding to a tumor cell antigen such as FAP (Abstract) and teaches format wherein a single-chain antibody is linked to the C-terminus of the Fc domain of a full-length anti-CD40 antibody.
WO2022032004 A2 to An et. al. teaches an anti-claudin 18.2 multispecific antibody (Abstract, [0005]) that also comprises anti-CD3 (e.g. [00320]) and may bind to additional targets including CD40 (e.g. [0030]).
In regards to diseases “associated with” CD40 or CLDN18.2, this category includes many etiologically distinct diseases other than cancer. For example, Peters, Anna L., et. al. "CD40 and autoimmunity: the dark side of a great activator." Seminars in immunology. Vol. 21. No. 5. Academic Press, 2009 teaches that CD40 plays a pathogenic role in autoimmune diseases such as autoimmune thyroiditis, type 1 diabetes, inflammatory bowel disease, psoriasis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus (Abstract).
Regarding CLDN18.2, Cao, Weijie, et al. "Claudin18. 2 is a novel molecular biomarker for tumor-targeted immunotherapy." Biomarker Research 10.1 (2022): 38 teaches that the CLDN18.2 positive rate varies due to different detection methods, positive thresholds, and patient populations used in different studies and that “Further research is necessary to standardize the optimal cutoff value used to determine CLDN18 positive expression for the identification of patients who should receive the targeted therapy” (p. 16 right column ¶2), suggesting that anti-CLDN18.2 therapy is not appropriate for CLDN18.2-negative cancers. There are no other diseases associated with CLDN18.2 of record.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification discloses anti-CD40 x CLDN18.2 bispecific antibodies comprising anti-CD40 antibodies C8-WT, C8-2, C8-6, and C8-10 (Table 1a-1c, Example 1) and an anti-CLDN18.2 nanobody comprising SEQ ID NO: 18 (Table 1d, Example 1). The specification teaches the particular format of full-length anti-CD40 antibody wherein the VHH of the anti-CLDN18.2 antibody was connected to the C-terminus of the heavy chain constant regions of the CD40 antibody through a linker sequence [0160]. Thus, four species of anti-CD40 x CLDN18.2 bispecific antibodies were made as in Table 2 of the instant specification. There were no other variants of the anti-CD40 or anti-CDLN18.2 tested. There is no additional guidance on which CDR residues may be varied and retain either CD40 or CLDN18.2 binding.
Regarding methods of treating, the instant specification uses a MC-38 tumor model overexpressing CLDN18.2 to detect whether the instant bispecific antibodies have effect in vivo (Example 4). Bispecifics C8-WT-NA3S-HC and C8-2-NA3S-HC were tested against anti-CD40 or anti-CLDN18.2 monoclonal antibodies (Fig. 7, Table 3 and 4), with C8-2-NA3S-HC showing better tumor control than the monoclonal antibody controls.
Conclusion
Applicant does not have enablement to make and use a genus of antibodies comprising variants with up to two amino acid changes in the CDRs of the recited sequences because it would take undue experimentation to determine which of the variants retains the required anti-CD40 and anti-CLDN18.2 binding functions of the antibodies.
Applicant does not have enablement for a genus of methods of treating any disease associated with CD40 or CLDN18.2 comprising administering the bispecific antibody of claim 1 to any patient in need thereof because it would take undue experiment to determine which diseases other than cancers expressing CLDN18.2 may be treated with the instant bispecific antibody.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 16 rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claim is directed to the “use” of the anti-CD40 x CLDN18.2 bispecific antibody. The claims are not directed toward a: 1) composition of matter; 2) machine; 3) manufacture; or 4) process, but rather a “use” of a composition of the anti-CD40 x CLDN18.2 bispecific antibody, wherein no active method steps are present to suggest a process is being claimed. "Use" claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101. See MPEP 2173.05(q).
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, 6-7, and 10-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-17, and 19-20 of copending Application No. 185585534 in view of WO2018140831 to Thompson et. al. published 2 August 2018.
This is a provisional nonstatutory double patenting rejection.
The claims of Application No. 185585534 are directed towards an anti-CD40 antibody or an antigen-binding fragment thereof comprising three LCDRs and three HCDRs identified by SEQ ID NOs (claims 1 and 2), wherein the antibody comprises e.g. a VH and a VL of SEQ ID NO: 25 and SEQ ID NO: 23 (identical to instant SEQ ID NO: 11 and 10 as shown below):
Query Match 100.0%; Score 667; Length 127;
Best Local Similarity 100.0%;
Matches 127; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVRPGGSLRLSCAASGFTFGSYEMNWVRQAPGKGLEWVSYISSSGETTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVRPGGSLRLSCAASGFTFGSYEMNWVRQAPGKGLEWVSYISSSGETTDY 60
Qy 61 ADSVKGRFTVSRDNSKNLLYLQMNSLRAEDTAVYYCARDVFFFDSSGDNGAYGMDVWGQG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTVSRDNSKNLLYLQMNSLRAEDTAVYYCARDVFFFDSSGDNGAYGMDVWGQG 120
Qy 121 TMVTVSS 127
|||||||
Db 121 TMVTVSS 127
Query Match 100.0%; Score 551; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLTASVGDRVTITCRSSQGIRSSLAWYQQKPGKPPKLLIYGASSLEGGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLTASVGDRVTITCRSSQGIRSSLAWYQQKPGKPPKLLIYGASSLEGGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQLNSFPSTFGQGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQLNSFPSTFGQGTKLEIK 107
Which comprise CDRs identical to instant SEQ ID NOs: 4, 5, and 6 and 1, 2, and 3 (reads on instant claims 1, 3, 4, 5).
Regarding claims 7 and 9, the ‘534 application teaches that the anti-CD40 antibody is an IgG1, IgG2, IgG3, or IgG4 antibody (claim 5) and wherein the anti-CD40 antibody wherein a glycosylation site in a CH2 domain of an immunoglobulin Fc region is eliminated by mutating N297 residue in a CH2 domain of a human IgG Fc region.
Regarding instant claim 10, claim 9 teaches an isolated nucleic acid encoding the anti-CD40 antibody or antigen-binding fragment according to claim 1.
Regarding instant claim 11, claim 10 teaches a vector containing the nucleic acid according to claim 9, wherein the vector is an expression vector.
Regarding claim 12, claim 11 teaches a host cell containing the nucleic acid according to claim 9.
Regarding claim 13, claim 12 teaches a method for preparing the anti-CD40 antibody or antigen-binding fragment according to claim 1 comprising culturing a host cell under conditions suitable for the expression of a nucleic acid encoding the anti-CD40 antibody or the antigen binding fragment and optionally isolating the anti-CD40 or the antigen binding fragment from the host cell.
Regarding claim 14, claim 13 teaches an immunoconjugate comprising the anti-CD40 antibody.
Regarding claims 14-16, claim 14 teaches a pharmaceutical composition comprising the anti-CD40 antibody and a pharmaceutical adjuvant. Regarding claim 16, for the purposes of expedited prosecution “a use of the bispecific antibody in a medicament or kit for treating” is understood to be directed towards a medicament or kit comprising the bispecific antibody; therefore a pharmaceutical composition reads on the claimed medicament or kit. ‘534 claim 19 further teaches a kit comprising the anti-CD40 antibody.
Regarding claim 17, claim 17 teaches a method of treating a tumor in a subject comprising administering the anti-CD40 antibody.
Thus, the major difference between the claims of ‘534 and the instant claims is that the ‘534 claims to not explicitly recite wherein the anti-CD40 antibody is a bispecific antibody, or wherein the bispecific antibody is an anti-CD40 x anti-CLDN18.2 bispecific antibody.
This deficiency is resolved by WO2018140831 A2 to Thompson et. al.
Thompson et. al. teaches a recombinant bispecific antibody comprising a target antigen binding domain, wherein the target antigen binding domain specifically binds to a tumor associated antigen and an effector antigen binding domain, wherein the effector antigen binding domain specifically binds to an antigen on an antigen presenting cell and wherein the antigen is a molecule on the antigen presenting cell (e.g. [0005]-[0007]).
Thompson et. al. teaches that the target antigen binding domain specifically binding to a tumor associated antigen may be CLDN18.2 (e.g. [0149]) and that the effector antigen binding domain may be CD40 (e.g. [0193], [0198]).
Regarding claim 6, Thompson et. al. teaches that the second binding domain can be attached to the Fc domain via a linker [0196].
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the anti-CD40 antibody or antigen-binding fragment thereof of ‘534 in an anti-CD40 x CLDN18.2 bispecific in order to benefit from targeting a known tumor associated antigen in combination with a known effector antigen binding domain on an antigen presenting cell as taught by Thompson et. al. This would have a reasonable expectation of success because a person of ordinary skill in the art would understand how to combine a known VH/VL targeting CD40 into the anti-CD40 x tumor antigen of Thompson et. al. and would have been able to choose and appropriate anti-CLDN18.2 binding domain as taught by Thompson et. al.
Claims 2 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-17, and 19-20 of copending Application No. 185585534 in view of WO2018140831 to Thompson et. al. published 2 August 2018 as applied to claim 1 above and in further view of WO2022256449 to Bader et. al effectively filed 9 November 2021.
The teachings of ‘534 in view of Thompson et. al. are in the NSDP rejection above. ‘534 in view of Thompson et. al. does not teach the bispecific antibody wherein the anti-CLDN18.2 antibody is a VHH, and wherein the single domain antibody comprises 3 CDRs contained in SEQ ID NO: 18 or variants thereof, and wherein the VHH comprises a sequence shown in SEQ ID NO: 18 or a sequence having at least 90% sequence identity with SEQ ID NO: 18.
This deficiency is resolved by Bader et. al.
Bader et. al. teaches T-cell antigen coupler comprising an anti-CLDN18.2 nanobody 2 comprising SEQ ID NO: 56, wherein SEQ ID NO: 56 is 100% identical to instant SEQ ID NO: 18 and comprises instant CDRs SEQ ID NOs: 15, 16, and 17 as shown below:
RESULT 1
US-18-715-119-18
Query Match 100.0%; Score 615; DB 1; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGLVQPGGSLRLSCAASGSIFHIPVMGWYRQAPGKGLELVAGISRGGTTNYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGLVQPGGSLRLSCAASGSIFHIPVMGWYRQAPGKGLELVAGISRGGTTNYA 60
Qy 61 DSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS 120
Bader et. al. teaches that anti-CD3 x CLDN18.2 bispecific T-cell antigen couplers caused T-cell activation and cytotoxicity when co-cultured with CLDN18.2 positive cells (Example 8). Bader et. al. further teaches that in an in vivo mouse model of NALM6 tumor cells administration of the anti-CD3 x CLDN18.2 T-cell antigen coupler was sufficient to completely irradicate the tumors compared to negative controls (Example 9, Fig. 21).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the anti-CLDN18.2 VHH of Bader et. al. in the CD40 x CLDN18.2 bispecific of ‘534 in view of Thompson in order to benefit from an anti-CLDN18.2 single-chain binding domain demonstrated to be effective in the context of targeting an immune cell to the CLDN18.2 tumor antigen. This would have a reasonable expectation of success because a person of ordinary skill in the art would have used art-known anti-CLDN18.2 binding domains known to be effective for the same anti-cancer targeting in order to make a specific embodiment of the CD40 x CLDN18.2 bispecific as taught by ‘534 in view of Thompson et. al.
Claims 3, 4, and 8-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-17, and 19-20 of copending Application No. 185585534 in view of WO2018140831 to Thompson et. al. published 2 August 2018 as applied to claim 1 above and in further view of WO2022256449 to Bader et. al effectively filed 9 November 2021 and US 20180340030 A1 to Bruenker et. al. published 29 November 2018 (IDS 5/31/2024) as evidenced by Uniprot P01857 “IGHG1_Human” and Uniprot P01834 “IGKC_Human”.
The teachings of ‘534 in view of Thompson et. al. are in the NSDP rejection above. ‘534 in view of Thompson et. al. does not teach the bispecific antibody wherein the anti-CLDN18.2 antibody is a VHH, and wherein the single domain antibody comprises 3 CDRs contained in SEQ ID NO: 18 or variants thereof, and wherein the VHH comprises a sequence shown in SEQ ID NO: 18 or a sequence having at least 90% sequence identity with SEQ ID NO: 18.
This deficiency is partially resolved by Bader et. al.
Bader et. al. teaches T-cell antigen coupler comprising an anti-CLDN18.2 nanobody 2 comprising SEQ ID NO: 56, wherein SEQ ID NO: 56 is 100% identical to instant SEQ ID NO: 18 and comprises instant CDRs SEQ ID NOs: 15, 16, and 17 as shown below:
RESULT 1
US-18-715-119-18
Query Match 100.0%; Score 615; DB 1; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGLVQPGGSLRLSCAASGSIFHIPVMGWYRQAPGKGLELVAGISRGGTTNYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGLVQPGGSLRLSCAASGSIFHIPVMGWYRQAPGKGLELVAGISRGGTTNYA 60
Qy 61 DSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS 120
Bader et. al. teaches that anti-CD3 x CLDN18.2 bispecific T-cell antigen couplers caused T-cell activation and cytotoxicity when co-cultured with CLDN18.2 positive cells (Example 8). Bader et. al. further teaches that in an in vivo mouse model of NALM6 tumor cells administration of the anti-CD3 x CLDN18.2 T-cell antigen coupler was sufficient to completely irradicate the tumors compared to negative controls (Example 9, Fig. 21).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the anti-CLDN18.2 VHH of Bader et. al. in the CD40 x CLDN18.2 bispecific of ‘534 in view of Thompson in order to benefit from an anti-CLDN18.2 single-chain binding domain demonstrated to be effective in the context of targeting an immune cell to the CLDN18.2 tumor antigen. This would have a reasonable expectation of success because a person of ordinary skill in the art would have used art-known anti-CLDN18.2 binding domains known to be effective for the same anti-cancer targeting in order to make a specific embodiment of the CD40 x CLDN18.2 bispecific as taught by ‘534 in view of Thompson et. al.
‘534 in view of Thompson et. al. and Bader et. al. does not the bispecific wherein the format is a heavy chain with a structure VH-CH1-Fc-VHH and the light chain with the structure VL-CL. This deficiency is resolved by Bruenker et. al.
Bruenker et. al. teaches anti-CD40 binding molecules comprising an anti-CD40 antigen binding domain and a second domain binding to a target cell antigen wherein the antigen is capable of binding to tumor-specific or tumor associated targets, wherein the activation of APCs through CD40 is provided by cross-linking through the target cell antigen [0010]. Bruenker et. al. teaches formats wherein the tumor targeting domain is an anti-CD40 with two Fab fragments connected to an Fc region and at least one antigen binding domain capable of specific binding to Fap (the exemplary anti-tumor antigen) connected to the C-terminus of the Fc region (e.g. [0094-0096], Fig. 1). The light chain comprises VL-CL and the heavy chain comprises VH-CH1-Fc-FAP antigen binding domain (e.g. [0115-0118]). Bruenker et. al. teaches antibody fragments of the invention include single domain antibodies [0193]. Bruenker et. al. teaches the antibodies connected by peptide linkers including exemplary linker (G4S)3 SEQ ID NO: 152 [0233].
Regarding claim 8, Bruenker et. al. teaches that the light chain of the antibody may have a kappa or lambda constant domain [0192].
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to make an anti-CD40 x CLDN18.2 bispecific antibody as taught by ‘534 in view of Thompson et. al. and Bader et. al., above, in order to benefit from the specific effectively anti-CD40 tumor-targeting format as taught by Bruenker et. al. combined with a VHH targeting CLDN18.2 as taught by Bader et. al. and suggested by Bruenker et. al. This would have a reasonable expectation of success because bispecific antibody formats were well-known in the art and a person of ordinary skill in the art would understand that the effective anti-CD40 antibody could be combined with an effective anti-CLDN18.2 VHH at the Fc C-terminus as taught by Bruenker et. al.
Regarding claim 9, the anti-CD40-IgG1-CLDN18.2VHH heavy chain made obvious by ‘534 in view of Thompson et. al., Bader et. al., and Bruenker et. al. as taught above would have the anti-CD40 VH as taught by ‘534, the human IgG1 heavy chain sequence comprising the N297Q mutation as taught by ‘534 as evidenced by IGHG1_Human Uniprot P01857 and Thompson et. al., the G4S linker as taught by Bruenker et. al., and the CLDN18.2 VHH taught by Bader et. al. resulting in a heavy chain that is 100% identical to instant SEQ ID NO: 19 as shown below:
RESULT 1
US-18-715-119-19
Query Match 100.0%; Score 3132; DB 1; Length 592;
Best Local Similarity 100.0%;
Matches 592; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVRPGGSLRLSCAASGFTFGSYEMNWVRQAPGKGLEWVSYISSSGETTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVRPGGSLRLSCAASGFTFGSYEMNWVRQAPGKGLEWVSYISSSGETTDY 60
Qy 61 ADSVKGRFTVSRDNSKNLLYLQMNSLRAEDTAVYYCARDVFFFDSSGDNGAYGMDVWGQG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTVSRDNSKNLLYLQMNSLRAEDTAVYYCARDVFFFDSSGDNGAYGMDVWGQG 120
Qy 121 TMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF 180
Qy 181 PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 240
Qy 241 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 300
Qy 301 PREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 PREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 360
Qy 361 LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 420
Qy 421 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSQVQLVESG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSQVQLVESG 480
Qy 481 GGLVQPGGSLRLSCAASGSIFHIPVMGWYRQAPGKGLELVAGISRGGTTNYADSVKGRFT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GGLVQPGGSLRLSCAASGSIFHIPVMGWYRQAPGKGLELVAGISRGGTTNYADSVKGRFT 540
Qy 541 ISRDNAKNTLYLQMNSLRAEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS 592
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 ISRDNAKNTLYLQMNSLRAEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS 592
And a light chain comprising the anti-CD40 VL as taught by ‘534 with the kappa constant region as taught by Bruenker as evidenced by IGKC_Human Uniprot P01834, resulting in a light chain identical to instant SEQ ID NO: 23:
RESULT 1
US-18-715-119-23
Query Match 100.0%; Score 1104; DB 1; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLTASVGDRVTITCRSSQGIRSSLAWYQQKPGKPPKLLIYGASSLEGGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLTASVGDRVTITCRSSQGIRSSLAWYQQKPGKPPKLLIYGASSLEGGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQLNSFPSTFGQGTKLEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQLNSFPSTFGQGTKLEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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